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(NOT) ATYPICAL
ULCERS AUTOIMMUNOPATHY AND CONNECTIVE
TISSUE DISORDERS: THE TRUE INTRINSIC
DISEASES OF WOUND HEALING Marc E. Gottlieb, MD, FACS Phoenix, AZ Revision 10b, November 5, 2009, Copyright © 2009 |
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Section 0 - Preamble An
introduction of concepts and orientation to chronic and pathological wounds,
including the general meaning of “chronic and pathological wounds” and the
importance of proper diagnosis as to the cause of the wound. |
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This
specific presentation was first given on September 26, 2009, but it is a
continuation of similar presentations given for the past few years. The requested title for this presentation
was “Atypical Wounds”. One of the main
goals of this presentation is to demonstrate that “atypical wounds” are
not. They are typical, and good care
is contingent on understanding the spectrum of wound diseases and
diagnoses. This will not be a
comprehensive survey of all wound causes and diagnoses. Instead, it will focus on the
autoimmunopathies and connective tissue disorders as the intrinsic diseases
of wound healing. |
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This
is an alternate title slide listing the major concepts to be conveyed,
focused on the concept that the autoimmune connective tissue disorders are
the diseases of wound healing, and they are one of the major categories of
chronic problem wounds. |
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Throughout
this or any discussion of chronic wounds, remember the distinction between
chronic wounds and acute trauma wounds.
Acute wounds and normal wound healing are not relevant to these discussions. There
is a tendency for non-experts to perceive problem wounds as falling into 4
categories: arterial, venous,
pressure, and diabetes. Non-experts
can also easily recognize incidental other causes such as radiation or toxic
chemical ulcers, because the history is obvious, but these are a minor
fraction of all chronic wounds. The 4
“classic” categories are indeed important, but there are other MAJOR
categories of ulceration and chronic wounds.
Because these other categories are also large, they can hardly be
considered atypical – just unaware to the naïve. |
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This slide shows ulcers of causes other than
arterial-venous-pressure-diabetes.
They are TYPICAL, in fact paradigm ulcers of other major
categories. Left: rheumatoid and factor V Leiden. Center:
rheumatoid and probable hypercoagulable.
Right: Sjögren’s. |
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More TYPICAL ulcers non-arterial-venous-pressure-diabetes. Left
top: minor infection due to lack of any care after a simple injury with
subdermal hematoma, in an otherwise normal person, Left
center: hypercoagulable, proteins C & S deficiency. Left
bottom: calciphylaxis and coagulopathy.
Right top: scleroderma
& lupus, protein S deficiency. Right center: acute panniculitis due
to venous vasculitis (this actually is venous disease, its acute state of
venous vasculitis and panniculitis that leads to the ulcers). Right
bottom: Sjögren’s. |
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And yet some more non-arterial-venous-pressure-diabetes
ulcers: Left upper: Sjögren’s. Center upper: pyoderma gangrenosum. Center
lower: hyperthyroidism-calciphylaxis.
Right upper: necrobiosis
lipoidica. Left lower: hypercoagulable. Right
lower: rheumatoid. |
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And some more again of non-arterial-venous-pressure-diabetes
ulcers: Left lower: This actually is a classic diabetic wound, the
plantar malperforans ulcer. It is
included for the sake of comparison to the left upper case. Left
upper: lupus synovitis. This lupus
patient does coincidentally have diabetes, but that does not mean that any
foot wound is a diabetic ulcer, no more than trying to claim that a diabetic
patient ipso facto has diabetic appendicitis or diabetic vehicular trauma. The diabetic foot and ulcer is a specific
syndrome, and this foot, with inflammation along the tibialis anterior and
adductor hallucis tendons is a manifestation of autoimmune synovitis Right
upper: rheumatoid synovitis. Right center: rheumatoid synovitis. Right
lower: lupus synovitis. |
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This presentation is NOT a comprehensive review of all
diagnostic categories of chronic wounds.
The focus is on the autoimmune and connective tissue disorders. However, this slide is included to
demonstrate that chronic ulcers are due to a variety of categorical problems
and pathologies that have nothing to do with arterial-venous-pressure-diabetes. The MECHANICAL ulcers are one of the major
categories. This is a huge important
subject that cannot be fully covered here.
Simply put, the cells and tissues derived from the embryonic mesoderm
sense and transduce mechanical force.
Normal loading (tangential, shear) and orthogonal loading (axial,
tension-compression) all have predictable effects on wounds, connective
tissues, and musculoskeletal structures.
The science behind this was first recognized by Julius Wolff,
enunciated in 1870 & 1892 as his law of bone biology and bone healing. Wolff’s Law can be generalized to two
principles concerning mesenchymal tissue:
(1) tissues subjected to
chronic or repetitive stress will adapt in such a way as to minimize the
resulting strain; and (2), tissues subjected to chronic or
repetitive strain will adapt in such a way as to minimize the resulting
stress. This simple principle has a
crucial role in normal embryonic development and in wound healing and repair,
including positive effects (formation of moving parts such as tendons,
joints, and serosal surfaces; proper
healing of bone, tendon, and ligament); and negative effects (e.g. joint
contractures, heterotopic ossification, hypertrophic scars). Many chronic wounds are due to these
mechanical effects. While these ulcers
can be frustrating to treat, and they often require surgery, they are not
genuinely pathological, i.e. not disease related. The persistence of these wounds is often
due to the embryological intent of these mechanical effects. Shearing for instance is interpreted as the
need for metaplasia to a gliding synovial surface, and it will simply turn
off normal wound repair. When open
tendons and tendon sheaths do not heal, or when a large broad flap does not
adhere to the structures underneath and a serosal bursa persists, the
shearing is why. Left upper: a popliteal ulcer, resolved by topical agents plus
splinting to eliminate motion effects.
Left lower: a chronic
venous ulcer, otherwise resolved by compression and skin grafts, with a
persistent central wound due to shearing of the tibialis posterior tendon
(the arrows and the blue dot on the tendon show the motion). Center
lower: polyarteritis nodosa, now under control, free of inflammation, and
healing elsewhere. This ulcer has
shearing of the tibialis anterior tendon, and as expected, there are signs of
a wound module in the most exposed areas, and teno-synovial metaplasia of the
contact shearing surfaces. This wound
is trying to heal, but cannot close because of the mechanics of shear and the
geometry and topology of the tendon bursa.
Right: rheumatoid
ulceration along tendon sheaths in an advanced rheumatoid patient. Acute synovitis and rheumatoid panniculitis
have subsided, and a wound module is appearing, but as in the center-lower
case, it can never close on its own without some sort of deliberate coverage
(or excision of the tendon). |
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Here
are two examples of common mechanical ulcers with no pathology, just adverse
mechanics. Upper: a young boy with a simple trauma laceration of the ankle
which became a chronic ulcer after a period of non-specific care. Perforation of the skin into the malleolar
bursa is one of the mechanical factors affecting the problem, and perforation
into the tibialis posterior tendon sheath, with gliding of the tendon is the
other problem. Conventional principles
of plastic surgery dictate that a flap is needed to restore the overlying
tissue, but modern strategies and technologies give us opportunities to close
this without autogenous flaps. Tissue
restoration with regenerative matrices is one good approach. Another approach is to try using wound
stimulatory therapies, successful here using PDGF. For all of these methods, especially the
non-operative ones, concurrent immobilization is mandatory to control the
contrary motion and mechanics that are inhibiting the wound. Lower:
an adult spina bifida patient with a chronic pseudarthrosis in the lower
thoracic spine, at the site of an old fusion.
Open joints, real or false, are bursas or spaces that need surgery and
immobilization. The initial wound
(left) was excised, including removal of the arthrosis enough to avoid
bone-on-bone contact. A catheter was
left in this restricted space for the sake of good preparatory care prior to
closure (irrigation with silver sulfadiazine, center). When ready for closure, the void was filled
with a regenerative matrix, and the skin was also reconstructed with the same
matrix, in lieu of conventional flaps (Integra collagen-gag matrix). A TLSO (thoraco-lumbo-sacral orthosis, i.e.
splint) was crucial for immobilization, and the wound healed completely. |
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Preceding
slides show wounds where the correct diagnosis might be overlooked. The misdiagnosis of wounds also has a flip
side – making up bogus diagnoses that ignore reality. If a doctor misses a rheumatoid wound and
calls it a venous wound, that is a reasonable and fair mistake due to an
understandable lack of expert knowledge.
When a doctor attributes the wound to “spider bite”, that is ignorant
in the pejorative sense – it’s just plain stupid. “Spider bite”, usually implying
envenomation by Loxosceles reclusa, the brown recluse spider, is a “romantic
diagnosis”, something you heard about in medical school, never bothered to
actually read about, never actually saw a case, thought it was just way too
cool to forget, and so you romanticize the whole concept into something
melodramatic rather than academic and clinical. “Necrotizing arachnidism” is in fact real,
and it occurs due to two species with specific geographic ranges. The brown recluse spider has a range that
covers the southeast and central United States, its western extent ending
more or less at the Rio Grande. The
genus Loxosceles has over a dozen species worldwide, including 5 in Arizona. They all envenomate, but other than L.
reclusa, they do not cause serious problems.
Only the brown recluse spider, Loxosceles reclusa, in its designated
geographic range causes the bad problems.
The other bad spider is the hobo spider, Tegenaria agrestis, native to
Europe, and now introduced in the Americas, causing necrotizing arachnidism
cases in the Pacific Northwest areas of the United States and Canada. Another real problem are arthropod bites
that cause problems not by envenomation, but by inoculation with pathogenic
microorganisms. I live in
Arizona. We occasionally see
infectious ulcers due to bacteria, mycetes, and mycobacteria, vectored by an
arthropod bite that was directly witnessed, but that is different than the
toxic chemical necrosis of the recluse-hobo bites. However, “spider bite” diagnoses are handed
out like Halloween candy by emergency room and primary physicians for any
skin problem, and they are essentially 100% bogus. The patients of course have no idea. They are told “spider bite” by a clueless
doctor, and that is what they believe.
Remember – not knowing much about spider bites is okay if you take the
time to get educated when a case and potential diagnosis presents itself. To just tell that to a patient though, “spider
bite”, having zero knowledge of the subject, betrays the professional
obligations and trust of the physician to be knowledgeable and accurate and
get relevant information when needed.
When a person living in an endemic area gets a recluse or hobo spider
bite (and even assume for a moment that their range was unlimited), the
injury generally has been observed by the patient, and the resulting lesion
is recognizable as such to a knowledgeable physician. This problem can be quite severe for those
who get the real thing, but nonetheless, this is a “novelty diagnosis”, quite
infrequent in the big picture of chronic wounds. The referenced article is by Dr. Vetter, a
non-physician biologist and expert on recluse spiders, who wrote an article
decrying the ridiculous use of the “spider bite” diagnosis by dumb
doctors. Don’t be one of them. This problem extends beyond spider bites,
to every time you make an uninformed, uneducated, disingenuous lazy and
erroneous diagnosis. Those who profess
to be expert in wounds must master the full spectrum of wound pathologies and
proper diagnosis, and then educate others.
Making up bogus diagnoses born of utter ignorance simply leads to
expensive bad care with bad outcomes. |
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This slide simply sums up what is being said about proper
diagnosis. Diagnoses must be accurate
for care to be informed and successful.
Attributing every wound naively to
“arterial-venous-pressure-diabetes”, or stupidly to “spider bite” serves no
one. Those who profess or aspire to be
expert in wounds must stop putting square pegs of diverse diseases and
diagnoses into the 5 round holes just named.
Make the correct diagnosis. The illustration is a woodblock engraving. It first appeared in Harper’s Monthly in
1864, as part of J. Ross Browne’s reports on the Arizona Territory (A Tour Through Arizona (Second Paper),
Harper's New Monthly Magazine, Vol. 29, No. 174, November 1864, pp
689-711.) It was republished in 1869
in his book “Adventures in the Apache Country: A Tour Through Arizona and Sonora,
with Notes on the Silver Regions of Nevada”,
J. Ross Browne, 1869. This was
when Arizona was still largely terra incognito to the United States, which
had acquired this area in the Gadsden Purchase of 1853, and had to suspend
exploration of the area during the War of the Rebellion (the Civil War as we
now know it). You can see the article
at Cornell University’s fabulous website, MOA (Making of America) at http://digital.library.cornell.edu/m/moa/. Go to Browse, then follow the links to the
above issue of Harper’s Monthly. The
text from that article quotes: “. . . A few miles beyond the Maricopa Village, on a rocky hill
to the right of the road, our attention was attracted by a spectacle at once
startling and characteristic of the country through which we were
traveling. Looming up on the side of
the hill, in bold outline against the sky, stood a rude cross upon which hung
the dried body of an Apache, crucified about two years ago by the Maricopas.
The legs and arms were fastened with cords, and the head hung forward,
showing a few tufts of long hair still swinging bout the face. It was a
strange and ghastly sight. The Maricopas do not profess the Christian faith,
but this much they had learned from the missionaries who had attempted their
conversion, that crucifixion was a species of torture practiced by the
whites. As it was a novel mode of punishment to them, the probability is they
adopted it as a warning to their enemies not to come in that neighborhood
again. . . “ If only we could do the same to the spider bite scare mongers .
. . |
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This
slide editorializes further on this subject, the importance of proper
knowledge and diagnosis of wounds, and on professional obligations for
physicians and experts. (1) Chronic and pathological wounds
(CAP wounds) are a distinctive class of disease and clinical activity. (2)
There is a non-expert legacy misunderstanding of wounds that focuses only on
trauma and a few standard categories of CAP wounds - arterial, venous,
pressure, diabetes. (3) Legitimate purveyors, professors,
and practitioners of this specialty must have the professional level of
knowledge required to master these diseases.
Like all specialties, this starts with an understanding of the full spectrum
of relevant pathologies. (4) What are often dismissed as
"atypical wounds" are not atypical at all. In fact, they are the core of chronic and
pathological wounds, and they are far more abundant and significant than
naives and non-experts perceive. |
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CAP
wounds: Chronic and Pathological
Wounds. This is the subject of modern
wound care, not the simple trauma and surgical wounds in healthy people that
will heal anyway, but rather the sick wounds that cannot heal. CAP wounds result from 2 general
problems: (1) wounds that are caused and maintained by some sort of chronic
illness or pathology; (2) wounds, from whatever cause, that
fail (fail to heal, are wound healing incompetent) due to diseases of the
wound healing process. |
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There
are many causes of CAP wounds (including the infrequent genuine spider
bite).
Arterial-venous-pressure-diabetes are indeed prominent causes, but
they are far from being the only major diagnostic categories. Major diagnostic categories, concepts, and
groups include: arterial,
micro-occlusive, micro-angiopathies, hemopathologies, hypercoagulable,
venous, immunopathies & collagen vascular / connective tissue disorders
(cvd-ctd), panniculopathies, dermatoses, diabetes, neuropathy, pressure,
mechanical, metabolic, toxic & chemical, physical & energy, cancer,
infectious, genetic, factitious & iatrogenic, mixed diagnoses,
unknown. These various diseases cause
the wounds or else inhibit the wounds from healing. Consider arterial disease. It affects wound healing, but it is not a
disease of wound healing. Patients
with athero-occlusive ischemia of the feet can heal wounds just fine anywhere
else, and they heal their foot wounds as soon as revascularization restores
blood flow. Pressure ulcers are
trauma, and such patients heal any wound other than those subject to the
repetitive injury of prolonged positional ischemia. Neuropathic wounds occur because of altered
skeletal biomechanics leading to pressure without the protective sensation
and mobility needed to avoid injury.
Diabetic ulcers are a multifactorial mix of arterial, pressure,
neuropathic, and biomechanical factors, and if you do a thyroidectomy or fix
a broken wrist, things heal properly because the risks for diabetic
ulceration are not global affects on the machinery of wound healing. Radiation ulcers are notoriously
problematic, because radiation does kill the machinery of wound healing, but
this is a local trauma, not a system-wide deficiency of wound healing
biology. Do you see the trend here? All of these chronic wounds are attributable
to some disease or injury extrinsic to the innate wound healing system. It begs the question then: What then are the intrinsic diseases of
wound healing? Given that every other
cell, tissue, organ, and system in the body is subject to some greater or
lesser affliction, why then do we not recognize or acknowledge those diseases
of the wound healing system? Surely
they must exist. The main purpose of
this whole presentation is precisely that, to illuminate these diseases for
you. It will show why “atypical
wounds” are not atypical at all, and why the typical and common diseases of
wound healing are naively overlooked and pigeon-holed into the few categories
that non-experts are aware of, such as arterial and venous. |
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“Necrosis”
and “ulceration” are the two main words that describe the active onset and
evolution of a pathological wound. In
trying to understand the intrinsic diseases of healing and the persistence of
CAP wounds, the first major concept to understand is that there are two
patterns and final pathways to necrosis and ulceration – the
thrombo-infarctive pattern and the inflammatory-lytic pattern. (1) Thrombo-infarctive
necrosis and ulceration is a consequence of primary obstruction of
micro-vessels, causing ischemia and infarction. This results from the various
micro-occlusive disorders, including micro-angiopathies, formed element
hematopathologies, and hypercoagulopathies and dysproteinemias. Clinically, the pattern is one of dry
gangrenous infarction, including dry eschar, cyanotic vascular stasis or else
pallor, and absence of edema and gross inflammatory changes. (2) Inflammatory-lytic
necrosis and ulceration is due to active inflammatory states, including
primary neutrophilic inflammation, atopic-allergic inflammation, and
immune-lymphocytic inflammation, all resulting from various underlying
diseases including the autoimmunopathies, collagen-vascular connective tissue
disorders, and lymphoreticular diseases.
Immunoglobulins, complement, and matrix proteases are abundant along
with other acute inflammatory chemistry.
Clinically, these are ulcers which have overt acute inflammation,
including edema and scarlet red erythema.
Rather than having dry infarcts and eschar, these ulcers simply erode,
getting larger by the literal dissolution of the tissue by complement killing
and protease effects. Because of the
intimate and intricate inter-dependence of inflammation and thrombosis, many
ulcers will have features of both patterns, but many can be easily
discriminated by simple physical exam as to which underlying pathology
predominates. There
is a third major pattern of ulceration, trauma, which includes simple
mechanical or surgical injury along with pressure, radiation, burns, toxic
chemicals, etc. What discriminates
trauma as a cause of a wound is that trauma is incidental and self-limited,
whereas thrombo-infarctive and inflammatory-lytic ulceration are generally
persistent and long-lasting due to active ongoing disease. As will be explained further in later
slides, angiocytes and fibroblasts, the two constituent cells of the generic
stroma and wound healing process, are robust, with extraordinarily few
intrinsic diseases and pathologies.
They can be obliterated by trauma, by critical deprivation of blood
supply, and by killers such as antibodies and targeted lymphocytes. Aside from the trauma causes of wounds,
thrombo-infarctive and inflammatory-lytic ulceration and necrosis are the two
– and the only two – common pathophysiological mechanisms by which the basic
stroma of the body can be killed and degenerated. |
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Section 1 – Reviews of
essential subjects Reviews
of three basic subjects relevant to understanding CAP wounds and the
intrinsic diseases of wound healing:
the hypercoagulable disorders and ulcers, the autoimmune connective
tissue diseases and ulcers, and the basic anatomy and cellular biology of
wound healing. |
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Section 1-A This
is a review of the hypercoagulable disorders and the CAP wounds that they
make. Hypercoagulability is one of the
major categories of chronic and pathological ulceration. This subject started to appear in published
journals in the early to mid 1990’s, so it can hardly be considered new. However, it is still arcane in the sense
that most practitioners remain largely unaware of it. So, to reiterate, hypercoagulable wounds
are a MAJOR category of CAP wounds. As
will be shown later, these are one of the major groups of primary disorders
which can then lead to secondary auto-immune wound failure. This short introduction will cover the
essentials. Much more information on
this subject can be found on the website arimedica.com,
under the category “Coagulopathies”. [The
trade card illustrated is typical of the patent medicines sold in the latter
19th century. This one has
no relevance to wounds – it just looked good on the page.] |
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There are many diseases that cause thrombosis, and many sequelae
and syndromes that result from thrombosis.
Large vessel thrombotic and embolic events are “old hat” medicine,
recognized and understood by all. Our
interest is in micro-thrombosis and micro-occlusion. However, all thrombotic disorders can be
grouped by major pathophysiological mechanisms. 1 – Hemodynamic
disorders: Blood vessels, blood,
and coagulation are all intrinsically normal.
Thrombosis occurs from blood stasis due to hemodynamic alterations
related to gross cardiovascular anatomy and function (e.g. atrial
fibrillation, vascular compression). 2 –
Endovasculopathies: Intrinsic and luminal
vasculopathies in which blood vessels are abnormal. Blood is normal, and coagulation is
intrinsically normal. Thrombosis
occurs in response to blood stasis or thrombotic activation created by endoluminal
and endothelial alterations in the vessels (e.g. atherosclerosis,
hyperparathyroidism). 3 – Exovasculopathies: Extrinsic and mural vasculopathies in which
blood vessels are abnormal. Blood is
normal, and coagulation is intrinsically normal. Unlike the endovasculopathies in which
thrombosis is triggered by thrombogenic surfaces and flow turbulence or
stasis, the exovasculopathies tend to be inflammatory or immune in origin,
with inflammatory mediators triggering thrombosis in passing blood (e.g. venous
vasculitis, the connective tissue disorders, and classic arteritides such as
polyarteritis nodosa and thromboangiitis obliterans). 4 – Non-hypercoagulable
hemopathologies: Micro-occlusive
disorders in which vessels are normal and the plasma protein coagulation
system is intrinsically normal, but other elements of the blood are abnormal. The clotting system responds “correctly” to
abnormal conditions of stasis or thrombotic activation (1 - hemoglobinopathies,
e.g. sickle, thalassemia, hemolytic anemias;
2 - dys- and cryoproteinemias, e.g. cryoglobulins, cryofibrinogen,
macroglobulins, gammopathies & myeloma;
3 - red cell & platelet abnormalities, e.g. spherocytosis,
myeloproliferative disorders, polycythemias, leukemias). 5 – Hypercoagulable
hemopathologies: Vessels are normal. Blood is normal (formed elements and serum). What is abnormal is the plasma protein
clotting system. In the above
categories, the clotting system is behaving properly in response to abnormal
conditions. In the
hypercoagulopathies, abnormal inappropriate thrombosis is the primary event. Blood stasis and vascular occlusion are
consequences, not causes. The
hypercoagulable disorders can be intrinsic (the “pre-thrombotic” primary
disorders of the coagulation system) or extrinsic due to metabolic or
auto-immune alterations. See the
following slides for specifics. The hypercoagulable states can cause both large vessel
thrombosis and micro-thrombosis. “Old
medicine syndromes” due to macro-thrombosis, such a coronary or
cerebrovascular occlusion, femoro-popliteal embolism, pulmonary embolism, and
Budd-Chiari hepatic thrombosis are overt, dramatic, and easy to
recognize. Micro-thrombosis tends to
be subtle, ongoing, frustrating, and easy to overlook, misinterpret, or
misdiagnosis. One point worth
remembering is the clinical syndrome of occult hypercoagulopathy. It is a dependable tetrad or pentad of
features, and if on history alone your wound patient has these things (not
all of them need to be present), then they have a hypercoagulable
disorder: 1 - history of thrombotic or
embolic events; 2- history of miscarriages; 3 – history of wound pathergy (unexpected
wound complications following trauma or surgery) or soft tissue problems
including chronic ulceration; 4 – an
auto-immune or connective tissue disorder;
& 5 (what makes it the pentad) – a family history of the main 4
counts equally as a positive personal history. |
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The slide lists relevant basic pathological features of the
hypercoagulopathies. These lists are
not comprehensive. The hypercoagulable
disorders can be intrinsic (“pre-thrombotic”) primary disorders of the
coagulation system) or extrinsic due to metabolic and auto-immune
alterations. They have important
associations with other diseases and clinical syndromes. They can cause commonly recognized large
vessel thrombotic and embolic events, or poorly recognized micro-thrombotic
events. Common intrinsic causes are gene mutations (e.g., factor 5
Leiden, prothrombin 20210G), coagulation protein alterations (e.g., proteins
C & S, anti-thrombin-3, plasminogen, fibrinogen), and various other
pathologies with a tie-in to the formation and metabolism of these factors
(e.g. liver disease, estrogens and pregnancy, paroxysmal nocturnal
hemoglobinuria, dicoumarol-derivative complications). The extrinsic causes include miscellaneous
metabolic and pathological states (e.g. homocysteinemia and
cancer-Trousseau), but they are dominated by the antiphospholipid antibody
syndromes and other immune thrombogens and auto-immune states. Virtually all of the classic connective
tissue or collagen-vascular diseases have a high incidence of
hypercoagulopathy, and vice versa. The
importance of the gene mutations must be emphasized. You cannot cheat on a gene test, so when a
patient has an altered gene and then a bunch of other syndromic clinical problems,
it is a good bet that the genetic mutation is the root cause. These last two points, concerning
prethrombotic gene mutations and the connective tissue disorders will be
discussed in much greater detail in later slides. To emphasize how this knowledge must change
traditional practices, consider venous disease. The hemodynamics of venous reflux and
hypertension have been understood for well over 200 years, yet altered
hemodynamics alone do not explain the whole picture of chronic venous
ulceration. Why do these people get
thrombosis and damaged valves in the first place? Why are their wounds hard to heal? Because many of them have factor V Leiden,
prothrombin 20210G, or another of the hypercoagulable entities as the primary
underlying cause. Hypercoagulable states can cause large and small vessel
thrombi. The items on the list of
large vessel vascular events have one thing in common – they are acute,
overt, and life-and-limb threatening events.
In comparison, microthrombotic events are slow, subtle, persistent,
recurring, frustrating, refractory.
They are non-obvious in origin unless you are familiar with their
spectrum of disease. So, remember the
tetrad: 1 – thrombosis or embolism;
2 – miscarriage; 3
– wound pathergy (including chronic ulcers);
4 – auto-immune
disorder; (& 5 – personal or family history). |
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Like anything else in medicine, proper diagnosis of a wound or
underlying disease starts with a history and physical exam, formulation of a
differential diagnosis if the exact diagnosis is not yet evident, then
resolution of the diagnosis by further testing. History was covered on the preceding
slide. This slide concerns what is apt
to be found on examination, both the initial physical plus subsequent
observations as treatment is managed. Hypercoagulable ulcers have features predominantly attributable
to ischemia and arterial insufficiency.
To the extent that they might have an associated immune component,
there may be inflammatory changes along with ischemic changes. However, for prototypical coagulopathic
ulceration, the pattern is one of thrombo-infarction rather than
inflammation-lysis. This means that
they have no unique nor pathognomonic features, but they do have an eminently
distinctive appearance. Features of gross appearance include: ischemic infarction (black desiccated
eschar), periwound vascular stasis (cyanotic plethora as opposed to the
scarlet hyperemia of inflammation), active ulceration (observable at the
margins where skin is dying, until the cause of ischemia has been corrected),
absence of edema, absence of gross inflammation, and a weak or absent wound
module. Unlike with classic arterial
diseases, patients will have these signs of arterial ischemia while still
having good pulses. If a patient has a
related condition, such as secondary venous disease caused by the chronic
hypercoagulopathy, then exam can be mixed with signs of the multiple
problems. However, for paradigm
hypercoagulable ulceration, the picture is one of localized arterial ischemia
in the face of good pulses. Observations over time and care, until definitive treatment is
rendered, can be summed up simply as “impaired wound behavior characteristic
of severe ischemia “. Wound behavior
is continuously pathological, with persistent active necrosis, pathergy, and
active ulceration. The wounds are
recalcitrant, with impaired dynamics and failure to make meaningful progress
until ischemic conditions are relieved.
Repetitive occult micro-thrombotic events result in rapid evolution
and slow resolution of the ulcers. If
wrong therapies are attempted based on wrong diagnosis, if no precautions are
taken to prevent or mitigate thrombosis and ischemia, then no results or
contrary results will happen. This is
especially problematic for attempted surgery which will fail due to pathergy,
necrosis, and dehiscence. Left upper: multifocal ankle infarcts in a patient with
protein C and anticardiolipin abnormalities.
Note the black eschar, absence of lytic ulceration and tissue
dissolution, and absence of generalized edema and panniculitis beyond the
immediate zone of the skin infarcts. Left center: distal leg ulcers in a patient with good
ankle pulses and anti-thrombin-3 deficiency.
Note dry black skin infarcts and eschar, vascular stasis and cyanosis,
absence of edema, in fact with wrinkles due to desiccation, all consistent
with severe micro-occlusive ischemia. Left lower: wound infarcts with acute black eschar, in
a forearm wound, in a patient with rheumatoid and proteins C & S
abnormalities. Right: ulceration of the
ankle after biopsy of a small lesion, in a patient with protein C
deficiency and positive cryoglobulins. Note absence of generalized edema and
inflammation, a caput medusa or venous “spider” consistent with prior
thrombosis and valvular reflux, and the histologic findings of thrombosis and
vascular necrosis. |
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Once a diagnosis of a hypercoagulable ulcer or hypercoagulable
state is suspected, the diagnosis can be refined or confirmed by laboratory
evaluation. There is a caveat here
though. We only have clinical tests
for perhaps a dozen or two chemical species involved in this problem, whereas
the problem can involve many dozens or hundreds of items. A positive diagnosis is not contingent on a
positive laboratory test. This is akin
to the evaluation of connective tissue disorders. Many such patients are sero-negative. If a patient comes in with crippling wrist,
hand, ankle, knee, and spine arthritis, characteristic deformities of ruptured
wrist extensors, MP severe ulnar deviation, tibio-talar dislocation, painful
effusions of the knee joints, severe morning stiffness, rheumatoid nodules,
and characteristic erosive changes on x-ray, but their rheumatoid factor is
negative, which are you going to believe?
That patient has rheumatoid arthritis.
The lab tests are not the answer. The same is true for the hypercoagulopathies. When they have it they have it. When a laboratory test is positive, then
your diagnosis and treatment are all the more certain, especially if the
clinical syndromic features were not conclusive by themselves. Knowing the specific faulty chemical can
also help guide therapy depending on which class of chemical is involved
(e.g. prethrombotic gene mutation versus antiphospholipid antibodies). Sometimes the lab confirmation comes not by
way of identifying the culprit, but by identifying the fallout, such as degradation
products of the hyperthrombotic state or else compensatory changes in other
chemicals reflecting up- or down-regulation in response to that state. What is crucial to appreciate is that hypercoagulable
ulcers are NOT diagnoses of exclusion.
These diagnoses can be made on specific criteria. When lab tests are positive, that always
helps, but history and physical exam are more important than the lab. Remember the essentially pathognomonic
tetrad which is the core of diagnosis for many of these patients: 1
– thrombosis or embolism; 2 – miscarriage; 3
– wound pathergy and ulcers; 4 – auto-immune disorder; (& 5
– personal or family history). It is worthwhile to have standard laboratory panels to order for
suspect situations. These should
include tests for thrombotic species and markers of closely allied or trigger
diseases: factor V Leiden, prothrombin
20210G, antithrombin III, protein C, protein S, APC resistance, fibrinogen,
D-dimer or fibrin degradation products, plasminogen, homocysteine, lupus
anticoagulant, anticardiolipin, cryoglobulins, cryofibrinogen, serum protein
electrophoresis, a screen for connective tissue disorders (ANA and related, rheumatoid
factor). This list is not exhaustive
and is a bit dated. Consult you own
clinical lab for the tests that are available to you. Other useful tests include measures of micro-vascular flow,
including tcpO2, laser doppler, and multispectral surface imaging. Vascular tests of large vessel flow, such
as pvr, ppg, and doppler & duplex are apt to be normal, unless the
patient coincidentally has atherosclerotic arterial disease, or not so
coincidentally has lupus angiopathy of the acral extremities. Histologic exam can be a gold mine of revelatory
changes and positive diagnosis, including findings of: microthrombi and aggregates, minimum acute inflammation,
microvasculopathies, concentric laminations of media due to repetitive
events, vascular fibrosis, vascular stenosis, acute vasculitis or
peri-vasculitis, and chronic peri-vasculitis with lymphocytes, eosinophils,
and plasma cells. Center: chronic thrombosis, vascular occlusion, and
re-organization, in a patient with rheumatoid and proteins C & S abnormalities
(same patient as left-lower on preceding slide). Right: chronic failed wounds and multiple
operations, and persistent skin ulcers following achilles tendon rupture, in
a patient with high fibrinogen, high anticardiolipins, and blind in one eye
due to retinal artery thrombosis. The
ankle is shown left with chronic skin dysplasia and ulceration before
treatment, and right with healed restored skin after diagnosis-specific
treatment. |
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When hypercoagulable patients present with chronic ulcers, some
of their histories can be otherwise quite benign. The wounds and their treatment can be slow,
subtle, persistent, recurring, frustrating, refractory, but a patient’s
general health and well-being are not in any immediate jeopardy – or are
they? Some such patients have
histories of serious prior events, such as blindness due to retinal artery
occlusion, strokes, limb loss from trauma, recurrent pulmonary “emboli”, and
other macro-vascular events. All hypercoagulable
patients have these potential risks.
With the appropriate trigger or generalized inflammatory or
hyper-thrombotic state, even the micro-vascular events can become extensive
and life-threatening. This slide shows
three patients who died from these conditions. Left
upper: this patient had heart
surgery, and a week or two after starting warfarin, he developed multiple
non-embolic skin and extremity infarcts.
Peripheral arteries were normal.
Lab studies confirmed low APC resistance and probable factor V
abnormality. The events were non-survivable. Lower: this patient had sigmoid resection for a
diverticular colo-vesical fistula.
Bowel necrosis resulted in progressive enterectomy, and with each
procedure, more of the abdominal wall died.
This view shows a necrotic ileostomy and abdominal fascia
infarcts. Lab studies confirmed APC deficiency. Histology confirmed diffuse primary
micro-thrombosis (i.e. not post-mortem changes, and absence of significant
inflammation pins the thrombosis as the primary event). The events were non-survivable. Right
upper: This patient had refractory
leg ulcers with active progressive infarcts during the period of
observation. Lab evaluation confirmed
primary low proteins C & S. She
died from a stroke shortly after making the diagnosis and planning treatment. These are non-trivial diagnoses, and their
management must include comprehensive and long term planning including the
role of anti-coagulation. |
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To brighten the mood, let us now look at some of the many
successes that accrue to proper diagnosis and treatment. Always keep in mind the key syndromic features
of hypercoagulability: 1 – thrombosis
or embolism 2– miscarriage 3 – wound
pathergy and ulcers 4 – auto-immune
or connective tissue disorder 5 – personal or
family history Imagine you have seen a patient with a suspicious wound and a
strong history. You try to confirm
your diagnosis with support from the lab.
Next you start the patient on anticoagulants, and then you implement
your plan to close the wound, be it surgery, biologics, wound
pharmaceuticals, or whatever. Problem
wounds of rapid progression or eons duration now heal. This slide shows three such stories. Left: a 29 year old man with long duration
refractory leg ulcers. History and
profile were suggestive, and the lab confirmed high anticardiolipins – an
antiphospholipid antibody syndrome – and the patient healed just by starting warfarin. Right
upper: a 43 year old woman,
otherwise healthy, but with many years of refractory leg ulcers, and a
history of multiple venous thrombosis and pulmonary embolism or
thrombosis. The lab confirmed low
proteins C&S and low tcpO2’s around the wounds. She healed with warfarin therapy and skin
reconstruction with a regenerative matrix.
She re-ulcerated after she stopped taking warfarin, but then rehealed
after resuming anticoagulation. Right lower: ulceration after skin biopsy in a patient
with cryoglobulins and low protein C (the same patient as “right” on slide
19). She healed with warfarin
anticoagulation and skin restoration with a regenerative matrix. |
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Summary of section 1-A The hypercoagulable disorders and ulcers are a major category of
chronic wounds and wound pathology.
They are under appreciated, but overly important. You will not recognize them until you start to incorporate them
into your differential diagnosis and start to ask the correct questions. Once you break out of the “classic 4”
mindset and start looking for these NON-atypical diagnoses, you just might be
surprised how many of these wounds are out there. More information on this subject is at the Arimedica website: http://www.arimedica.com/content/arimedica_hypercoagulable_annotated_(pages)_2005-1027.pdf http://www.arimedica.com/content/arimedica_hypercoagulable_(poster)_2006-0516.pdf |
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Section 1-B This section is a review of immune ulcers and classic immune
disorders. This section is probably
what most people might have expected in a talk advertised as “atypical
wounds”. As with the
hypercoagulopathies, this subject is not new, but it is still largely unknown
or under-appreciated by most practitioners.
This section will not be a comprehensive discussion of the subject,
and therapeutics will not be addressed.
The focus will be on issues of anatomical pathology, pathophysiology,
and clinical findings, enough to appreciate sections to follow concerning the
mechanisms of immunopathic ulceration.
To reiterate though, these are a MAJOR category of CAP wounds, and one
of extraordinary importance. As will
be developed in subsequent sections, these are the true diseases of wound
healing. [The trade card illustrated is another from the latter 19th
century. If you read its list of
particulars, it should have been good for many of these diseases. Featured is Lillie Langtry, 1853 - 1929,
stage actress and celebrity superstar of her day, lest you think that
celebrity endorsements and name-dropping salesmanship are something new.] |
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Illustrated are patients with wounds and ulcers in association
with classic connective tissue and collagen vascular diseases. All of these patients were sick to a
greater or lesser degree. Some have
since lived and done well for years.
Some died after prolonged chronic disease activity. Some died acutely from major
flare-ups. Some had a concomitant
hypercoagulopathy. None of them were
trivial or easy to manage nor heal.
These are bad diseases, hard enough to manage under any circumstances,
but harder yet when complicated by necrosis and ulcers. Left
upper: Sjögren’s with chronic
panniculitis and leg ulcers. Left middle: arteritis with skin ulcers and necrosis. Left
lower: chronic lupus with multiple
wound complications of trauma and surgery.
Center upper: acute lupus with extensive skin
necrosis. Center lower: Behçet’s
with multiple vasculitis, pathergy, thrombosis, and necrosis Right
upper: scleroderma-crest with
lupus angiopathy and multiple skin infarcts and ulcers. Right
lower: rheumatoid arthritis with a
hypercoagulopathy and extensive necrosis following back surgery. |
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Here are more examples of immunopathic patients and ulcers. All four patients are shown before and
after treatment of the disease and then skin reconstruction. Left
upper: lupus-rheumatoid-mixed
(mctd) with ulceration due to synovitis and panniculitis. Left
lower: rheumatoid arthritis, with
prototypical rheumatoid ulceration due to synovitis. Right
upper: another prototypical rheumatoid
ulceration due to synovitis. Right lower: Sjögren’s with chronic
panniculitis and leg ulcers. |
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The auto-immunopathies are a spectrum of disease with protean
manifestations. They can affect almost
any chemical, cell, tissue, organ, or system.
Their effects can be parochial and directed against very selective
targets (e.g. Hashimoto’s thyroiditis), or they can be nearly global in
expression (e.g. lupus). There are
various ways to categorize the auto-immune diseases, and this slide gives
several non-exhaustive lists of them: connective tissue disorders, e.g.
rheumatoid, lupus, sjögren’s, scleroderma, polymyositis, ankylosing
spondylitis, behçet’s, wegener’s, sarcoidosis, familial mediterranean fever; vasculitides,
e.g. polyarteritis nodosa, giant cell, thromboangiitis; panniculitis,
e.g. weber-christian, nodular & eosinophilic fasciitis, erythema nodosum,
necrobiosis lipoidica; inflammatory dermatoses, e.g. eczema,
pyoderma gangrenosum, pemphigus, bullous pemphigoid; miscellaneous,
e.g. crohn’s, ulcerative colitis, autoimmune hepatitis, multiple
sclerosis. Once you learn to recognize these diseases and take a thorough
history, you will appreciate that many patients with any of the nominal
primary diagnoses will have a variety of crossover symptoms. Many patients likewise cannot be readily categorized
into any one of the classic named diseases, yet they have strong features of
several of them. In a certain sense,
it is as though auto-immunopathy is a single disease in which, based on which
auto-immunizations and auto-antibodies you get dealt, that governs the
spectrum of signs, symptoms, and complications that you are apt to have. To account for these crossover and mix-and-match
profiles, patients can be assigned bread basket diagnoses: mctd (mixed connective tissue disorder),
uctd (undifferentiated connective tissue disorder), nctd (non-specific
connective tissue disorder). How many of these patients and diseases have wound
problems? Remember, as a wound
practitioner, you will see patients primarily because of their wounds, and
you WILL see all of these primary diagnoses come through your door. Conclusions anyone? Images, from left to
right: achilles (Wegener’s
granulomatosis); leg (leukocytoclastic
arteritis); abdomen (Weber-Christian);
leg (Crohn’s); finger (pyoderma gangrenosum). |
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To reiterate, as a wound practitioner, you will see patients
primarily because of their wounds.
When you suspect an immunopathic ulcer or patient, your history and
exam will be directed towards these diseases.
Do this enough times, and it becomes second nature, but until then,
you need a way to think about the multitude and multiplicity of signs,
symptoms, and sequelae that appertain.
Here are a few categorizations:
general and common findings,
e.g. malaise, arthralgias and arthropathies, rashes, sicca, ulcers,
neurological, abnormal serologies; findings by system, e.g.
musculoskeletal, renal, pulmonary, cardiac & vascular, blood &
lymphoreticular, cns & eye; distinctive and unique findings, e.g.
crst, sicca, pathergy, necrotizing synovitis, necrotizing vasculitis; findings
by disease, e.g. rheumatoid, lupus, scleroderma, Sjögren’s, polymyositis; disease
associations, e.g. hypercoagulability, venous, arterial disease,
neuro-psych, many misdiagnoses; other tip-offs, common and unusual
things, e.g. multiple allergies, drug hypersensitivity, photosensitivity,
malar rash, tendon rupture, nasal septal perforation. Left upper: rheumatoid arthritis, with acute
panniculitis and multifocal ulceration.
Note the inflammatory-lytic pattern of ulceration, skin dissolution
without infarcted eschar. Left middle: rheumatoid, with multifocal
inflammatory-lytic ulcers. Left lower: lupus or mixed ctd, with atrophie blanche,
dermal scarring from repetitive episodes of connective inflammation. Right
upper: lupus, with suppurative
synovitis. Right middle: scleroderma-crst,
with typical features of fingertip ulcers and necrosis, telangiectasias and
sclerodactyly. Right lower: lupus, with
atopic reaction to common dressing materials. |
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When it comes to examining the skin lesions and wounds due to
these disorders, keep in mind that appearances and features will change as
the injuries and ulcers evolve. First,
you will see a variety of features that occur during the early pre-ulcerative
phases of these lesions, when inflammation and infarction are starting, the
preludes to ulceration. Second, you
will see features characteristic of acute and early ulceration, as the acute
infarctive and inflammatory lesions progress to skin destruction. Third, you will see features of chronic and
late ulceration, as the primary events wind down (or not), and the ulcers
develop gross, histologic, biochemical, and behavioral features of wound
chronicity. This slide shows the
pre-ulcerative changes and features. Inflammatory
signs: Remember, ulceration is
caused by thrombosis-infarction and inflammation-lysis, so what you will see
in advance of actual necrosis and ulceration are the telltale signs of these
states. Because these diseases are
immune and inflammatory in nature, signs of inflammation are usually obvious,
either as dermatitis, panniculitis, cicatritis, inflammatory infiltrates in the
skin, edema, the classic and extended signs of local inflammation, and
systemic inflammatory signs and symptoms.
Vascular stasis signs: Immunopathic inflammation is more apt to
cause primary inflammatory signs, but as will be discussed in detail in subsequent
sections, inflammation triggers thrombosis, the auto-immune disorders
frequently accompany hypercoagulable states, and vessels and vasculitis are
specific targets of auto-immunopathy.
This means that thrombosis, vascular infarction, and stasis are integral
parts of the whole picture. You are
apt to signs of thrombosis and blood stasis, including congestion and
plethora, hemorrhage and skin staining (focal ecchymosis), cyanotic erythema
of these lesions (as opposed to the scarlet erythema of inflammation), skin
infarcts within these zones, ischemic pain in the lesions. Systemic
signs and symptoms: These are
indicative of the primary disease flaring up, and are due to a generalized
inflammatory state. These include
non-specific general symptoms such as malaise, pain, and other “flu-like”
complaints, along with more focal or tissue specific items such as arthralgias
and stiffness, neurolepsy, and the worsening of other disease- or person-specific
symptoms. Distribution of the pre-ulcerative lesions and other features
that would figure in the assessment of any dermatosis are also important,
such as whether they are single or multiple, focal or multifocal, blistered
or pemphigoid, macular, papular, suppurative, eczematous, acneform,
desquamative, sclerosing, etc. Left upper: Sweet’s neutrophilic dermatitis with acute
immunopathic neutrophilic abscesses affecting areas of old scar and prior
ulceration. These little abscesses are
the prelude to further focal skin destruction and ulceration. Left
lower: leukocytoclastic vasculitis
(2 patients) in acute phases of thrombosis, vascular stasis, and acute
inflammation, i.e. the beginnings of infarction and lysis with the risk of
ulceration within days. Right upper: lupus-crst, with sclerodactyly, telangiectasias,
Raynaud’s and angiopathy, prior amputations, contractures, and eczema. This hand obviously has high risk based on
the primary disease, but the eczema is an acute inflammatory condition which
will trigger the cascade to greater inflammation and ulceration. Right lower - right: Sjögren’s,
with acute panniculitis affecting the adipose fascias, a common early phase
indicator of disease flare up and potential progression to ulceration. Right
lower - left: In this ankle close-up
of a similar patient, note the ring of desquamation, a common indicator of
recent acute skin inflammation, now subsided with treatment, potential
ulceration averted. |
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This slide shows the features of acute and early ulcers. Since this is the phase of active ulceration,
you are witnessing the destruction as it happens, as the disease causes
thrombosis-infarction or immunity-inflammation-lysis. You are catching the culprit in the act, so
you are likely to see signs specific to the particular disease, along with
the generic signs of active inflammation and thrombosis, and of active
infarction, tissue lysis, and ulceration. Local findings: These are the features of the necrosis and
active ulceration, in the wounds themselves and in their immediate
surroundings. They may be focal or
multifocal, but when multiple or multifocal, this is usually a dependable
sign of autoimmune ulceration. There
may be inflammatory lysis and dissolution of tissue versus microthrombotic infarction,
which can give insights as to which diagnosis or mechanism of disease
predominates. Whether the periwound is
inflamed versus bland also tends to discriminate thrombo-occlusive lesions
from immune-inflammatory ones. Signs
of vasculitis, synovitis, panniculitis, dermatitis, cicatritis, and even arthritis
and serositis can reveal the autoimmune nature of the problem and imply which
specific disease or syndrome is active.
General and systemic findings: generalized inflammation, edema, dermatitis,
panniculitis, vascular stasis, systemic and disease-specific symptoms, pain,
malaise. Remember, during these acute
phases of ulceration the primary disease is active, so patients will often
have a multitude of symptoms. In the cases shown of early and developing wounds, note the
changes in the ulcers and surrounding tissues. They predominantly show an
inflammatory-lytic pattern of ulceration as opposed to thrombo-infarctive
necrosis. Top left: crst-mctd, dissolution of wound margins,
vascular stasis and cyanosis, acute dermatitis. Top
right: rheumatoid, multifocal
ulceration, periwound inflammation, dissolution of skin without dry eschar, panniculopathy. Bottom
left: rheumatoid, progressive
dissolution of skin and fascias, no eschar, involvement of old scar,
ulceration along tendon sheath and exposure of peroneus tendon. Bottom
center: rheumatoid, multifocal
ulceration, multifocal stasis and cyanosis in advance of infarcts and ulcers,
generalized panniculitis and edema, active necrosis and erosion at skin
margins, no eschar. Bottom right: Sjögren’s, loss of adipose panniculus,
active necrosis and ulceration at margins, exposure of peroneus muscle
(synovitis). This last example has
black necrosis and little inflammation in the periwound (no erythema nor
edema), making this mainly a thrombo-infarctive pattern of ulceration,
implying some type of micro-occlusive pathology. The patient has classic Sjögren’s, but she
also had a very high fibrinogen and low protein C, a good hypercoagulable
explanation for the thrombo-infarctive pattern of the wound. This is the same patient in the same
position (lower right) on the previous slide.
That was her opposite leg, with acute diffuse erythema-nodosum-like
panniculitis, along with generalized signs and symptoms of active
inflammation, immunity, and disease flare up.
As will be shown later, this duality of pathologies – inflammatory and
thrombotic – is common, and many patients will have mixed findings and
features in their wounds, both inflammation-lysis and thrombosis-infarction. |
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This slide shows the features of chronic and late ulceration. In chronic ulcers, the original cause of
the disease has subsided, and what is left is just the anatomical
defect. To the extent that the disease
is still active, there may be ongoing slow progression of the wound or persistence
of related findings and general symptoms.
To the extent that the disease is affecting wound repair, or that the
ulcer has entered a physiological and pathological state of chronicity, then
healing may be retarded or absent.
When looking at the wounds during these latter chronic phases, what
you will mainly see is just a generic chronic wound. Specific common features to observe include
the following. Persistent inflammation: If primary disease is quiet, then
inflammation may subside, but most such wounds are in a state of chronic
inflammation until treatment brings it under control. Some of it is likely to be a persistent
acute inflammation due to lack of care.
However, acute inflammation is a good stimulus to maintain the
pathological chronic inflammation of the disease, and these wounds rarely
break out of their pathological attractor until both the wound and the
general disease are explicitly treated.
Progressive ulceration: As chronic wounds, most of these ulcers
persist as is, often indefinitely.
However, after prolonged periods of stability they can also get better
or get worse. Many patients describe
prior ulcers which healed spontaneously, typically taking months, and healing
with treatment is the goal of all of this.
To the extent that primary disease or chronic inflammation in the
wound is sustained, there may be slow progressive necrosis or ulceration. Sudden rapid progressive ulceration and
enlargement is a good indicator of resurgence of the primary disease. Retarded
wound module, mixed wound module, and chaotic behavior: The immunopathic ulcers have a duality of
wound effects. Their afferent effect
on the wound is to make the ulcer.
Their efferent effect is to keep it from healing. There are very few types of pathology that
can arrest the wound module, and active auto-immunopathy is one of them. For most patients, wound healing is mixed,
both in space over the surface of the wound, and in time from one observation
to another. There may be qualitatively
normal proliferation in some areas.
There may be areas of appropriate suppression of wound healing by
acute inflammation. There can be zones
where the wound module is very weak or inactive due to the primary effects of
the auto-immunopathy, the effects of persistent allied disease states such as
hypercoagulability, and the effects of wound chronicity. There can be intermittent areas of new
ulceration due to persistent chronic disease activity. Even when the wounds look normal at first
glance, it is rare that such wounds are quantitatively normal with normal
kinetics. One of the hallmark features
of wound chronicity is chaotic behavior (as explained in subsequent slides)
in which the wound may wax and wane but never makes any real progress. Pain
& symptoms: There are only a
handful of generic causes of pain (mechanical, neuropathic, ischemia, cancer,
etc.), and inflammation is one of them.
Because these ulcers represent an inflammatory pathology, pain is a
common feature. For those who have a
concomitant thrombotic or micro-occlusive disorder, the pains are even
worse. Other symptoms of the primary
disease, and secondary symptoms or disabilities related to what is ulcerated
are also part of the picture of the chronic stages of auto-immune ulceration. In these cases, all wounds are chronic, of long duration, and
getting some basic topical wound care and treatment for their disease. Left
top: lupus with anticardiolipin
hypercoagulability, zones of granulation tissue, zones without, small active
infarcts at wound edges, persistent inflammation. Left
bottom: rheumatoid, active wound
module of deeper musculoskeletal structures, but no wound healing in
subcutaneous panniculus, active persistent erosions at wound margins, but
periwound inflammation is controlled. Left inner top: rheumatoid with coincidental
atherosclerosis, stable areas mixed with erosive areas, wound healing in
musculoskeletal structures but none in the adipose. Left
inner bottom: lupus-rheumatoid-mctd,
stable wounds, no periwound inflammation, healing of musculoskeletal
structures but not of adipose. Center lower: polyarteritis,
failed wound module, recurrent acute necrosis. Right
inner: lupus with
anticardiolipins, failed epithelialization, stalled edges, limited
contraction, weak angiogenesis/granulation.
Right top: rheumatoid and hypercoagulable, wound
module present at musculoskeletal base but not in subcutaneous fascias, no
contraction nor epithelialization, small surface infarcts even absent
periwound inflammation. Right bottom: rheumatoid, persistent unchanged wound over
a few weeks of observation and care, weak expression of wound module
elements, failed epithelialization and stalled edges. |
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Whether looking at the prodrome, acute, or chronic phases, many
of the wound features are generic findings of any inflammation, thrombosis,
or ulceration. However, immunopathic
ulcers can have some very distinctive features unlike wounds from other
primary diagnoses. Many of these
reflect specific effects of the given primary disease, such as necrotizing
synovitis from rheumatoid and lupus, and skin sclerosis and calcification
from scleroderma. These features include: ulceration along tendons, due to
synovitis; inflammation, lysis,
ulceration of old scars; ulceration
over small joints, due to synovitis; inflammation,
lysis, necrosis along recent incisions;
ulceration of the upper leg outside of the gaiter area, and ulceration
in a variety of other areas; skin
atrophy in affected areas, due to persistent inflammation and proteolysis; skin sclerosis in affected areas due to
scarring after inflammation; vascular
changes in skin and extremity; wound
pathergy, necrosis, and ulceration after injury and surgery; calcification and ossification in the
ulcers or surrounding panniculus. Left upper: rheumatoid, ulceration over and into small
joints. Left center: rheumatoid,
ulceration along old scar. Left lower: scleroderma, livedo reticularis, ulceration
along tendons (this ulcer is not under the metatarsal heads). Left
inner: rheumatoid, ulceration
along old scar and tendon. Right inner upper: rheumatoid, ulceration in unusual area
along tendons (thigh, hamstrings). Right inner lower: lupus-mctd, atrophie blanche dermal
scarring. Right upper: rheumatoid,
wound failure of unlikely location (abdomen).
Right lower: rheumatoid and hypercoagulable, wound
failure of unlikely location (forearm), ulceration along muscle and tendon, necrosis
around staples. |
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In examining and diagnosing immunopathic ulcers, or indeed ulcers
of any cause, it is crucial to observe what is not there. For instance, absence of pulses is a
crucial indicator of macro-arterial disease.
A wound patient without pulses does not necessarily have an arterial
ulcer — their atherosclerosis could be coincidental to their rheumatoid or
tibial abscess or open tendon or whatever they have, and proper evaluation
and diagnosis are required. However,
if good pulses are present, then macro-arterial disease is ruled out. If a suspect rheumatoid or lupus wound has
good pulses, then arterial disease is NOT there. What else is not there in immunopathic
ulceration? No arterial: no signs of
vascular disease, no claudication, no change in pulses or pressures or
dopplers. No venous: no signs of
venous disease, no dermato-liposclerosis, no hemosiderin pigment changes, no
venous varicosities nor reflux, no chronic edema nor phlegmasia. No
eschar: immunopathic ulceration is
more apt to be inflammatory-lytic in nature, not thrombo-infarctive, so dry
eschar is not apt to appear. No wound module: as will be explained in later slides, the
immunopathic disorders are the diseases of wound healing, and therefore the
proliferative wound module which does the healing is apt to be flawed or even
absent. Seeing wounds in which
underlying anatomical structures remain pristine visible for months, devoid of
angiogenesis and fibroplasia, is not an everyday occurrence, but nor is it
rare, usually occurring in severe metabolic wrecks or with the auto-immune
disorders. Age & risks: Various
ages and diseases are apt to cause certain types of wounds. Diabetes for instance causes very
characteristic syndromic wounds, such as malperforans ulcers. It is important to observe that a patient
or wound does not have those pathognomonic features of other disorders, nor
that there is a discrepancy between actual findings and demographic
expectations, all of which tend to rule out competing diagnoses. There are of course, in examining individual patients and
wounds, many exceptions to these generalities. The net of all observations is what is most
important, not just any single parameter.
In these cases, observe what is absent: Left
upper: rheumatoid, no edema, no
pigment changes, no liposclerosis, no chronic dermatitis. Left
middle: rheumatoid, no edema, no
pigment changes, no liposclerosis, no chronic dermatitis. Left
lower: rheumatoid, no edema, no
pigment changes, no liposclerosis, no chronic dermatitis, no subcutaneous
fascias (exposed muscle and tendon indicative of tenosynovitis). Center:
rheumatoid, no edema, no pigment
changes, no liposclerosis, no chronic dermatitis, no subcutaneous fascias
(exposed ligaments and tendons consistent with synovitis). Right
upper: severe acute lupus, no
peri-wound inflammation, no edema, no wound module (i.e. no healing). Right
middle: ulcerative colitis and
pyoderma, no generalized panniculitis or dermatitis, no involvement near
ankle, no pigment changes. Right lower: Sjögren’s, no pigment changes, no
generalized dermatitis, no generalized liposclerosis, no signs of arterial
disease, no venous varicosities. |
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In examining and diagnosing any ulcer or patient, it is crucial
to assess the entire person, their history, review of systems, and general
exam. Oftentimes the diagnosis will flow
directly from the history or spectrum of symptoms. It is important for wound practitioners to
become versed in the signs and symptoms of all of the relevant primary
diseases that underlie chronic and pathological ulcers, be it arterial ,
diabetes, hematological disorders, rheumatological diseases, and everything
else. The more you ask about these
relevant histories, the more you run an inventory of signs and symptoms, the
more automatic it becomes. Patient intake must include history and examination for all
facets of these diseases, but the following are key components or interesting
issues that will be frequent findings in a wound practice and are often key
features that establish the diagnosis on first encounter. History
& system review: disease history,
family history, treatment history, complications of trauma or surgery. General
physical exam: common signs of
immunopathy, signs of a general inflammatory state, arthropathies, sicca, neurolepsy
& other neurological changes, rashes, malaise & systemic
symptoms. Disease associations: vasculopathies,
hypercoagulopathy and hematological, neurological, renal, pulmonary, miscarriage,
venous disease, dermatoses, inflammatory bowel disease and other
organ-specific auto-immunopathies. Laboratory: serologies, hypercoagulation studies,
vascular assessments, wound histology. New patients with these diseases often have some extremely
common or else distinctive profiles on initial wound exams. The following few examples immediately give
away the auto-immunopathic cause of the ulcer, whether or not they had a
prior diagnosis. These profiles are
important to recognize and hard to overlook, unless the history is sloppy,
inexpert, or just ignored. Notice that
these profiles are based on general history and exam alone, not on anything
about the ulcers themselves. [1] – One very common profile is the
patient with rheumatoid or whatever who has had a recent adjustment in his
drugs. This is often someone doing
extremely well, enough that his chronic daily prednisone dose was lowered,
typically form 10 mg to 7 mg, or from 7 mg to 5 mg. Arthralgias, stiffness, and malaise flare
up, with leg panniculitis or synovitis causing skin ulceration. [2]
– Another common profile is the patient who comes with a typical leg ulcer. His hands have advanced rheumatoid
degeneration. He has complaints of
symmetrical polyarthralgias and morning stiffness. Are you smarter than a fifth grader? How could anyone have missed this? However, the patient has been explicitly
told that he does not have rheumatoid, and he has been denied treatment
because his rheumatoid factor and other serologies were negative. [3]
– Another profile, not so common but of immediate importance, is the patient
who comes in for a leg ulcer or whatever wound. Examination is hampered by a state of
neurolepsy, being apathetic, disoriented or disengaged, psychomotor retarded,
and just not “being there” or “out of it”.
The patient might also have some history of “seizures” or “MS” or
other central neuropathy refractory to treatment. He is plethoric, has malar rashes, and
signs of arthritis, synovitis, panniculitis, or sicca. This patient has lupus (or Sjögren’s or
rheumatoid or Behçet’s or mixed-ctd or whatever), and he needs steroids and
other treatment right now. It is most important to realize that the wound practitioner is
frequently going to be the first to make the diagnosis of the underlying
problem, or to correct a misdiagnosis that the patient has been given. If a rheumatoid patient goes to an orthopedic
surgeon’s office for an arthritis problem, odds are the patient already has
an established diagnosis, and if not, the orthopedist is likely to recognize
it. If a patient with lupus nephritis
is referred to a nephrologist for renal failure, odds are the diagnosis is
already known, or else the nephrologist will make it. For wounds, patients are referred to
somebody because there is a hole in the skin that is freaking somebody out. Patients rarely come with any insight as to
the diagnosis. Even if they have well
established diagnoses of rheumatoid, polymyositis, or whatever, their other
doctors have rarely drawn the connection to the wound. Sadly, when these patients show up to many
self-designated “wound specialists” who really are not, the ulcers and the
overt history of rheumatoid are never connected. However, there are also many patients with
wounds due to autoimmune and connective tissue disorders where the primary diagnosis
has never been made. Sometimes the
patients have subtle signs and symptoms of the disease. Sometimes they have gotten so used to
chronic symptoms of malaise and arthralgias that they hardly recognize that
they are systemically ill. Sometimes
new patients are seriously sick with underlying disease out of control. The patients may know that they feel lousy,
but they often have no other clue that there is a systemic problem, even in
the face of serious symptoms. To get
the wounds better, the disease has to be diagnosed and treated, and that
means you! Left upper: lupus-mctd, symptoms of neurolepsy,
arthralgias, stiffness, sicca, malaise.
Left lower: rheumatoid, typical hand changes, typical
histologic changes of chronic vasculitis.
Right upper & lower: two patients with rheumatoid and
hypercoagulable states, demonstrating the types of serious trauma and surgery
complications that can happen with these diseases. |
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Finally, the intake history for people with immunopathic wounds
must include a treatment history. Even
if the patient is not understanding of their own history and disease, their
medication list may betray that they are already being treated for connective
tissue disorders. Treatment history
may reveal that disease flared up and ulcers appeared when certain therapies
were started, stopped, or adjusted. Failed
and favorable responses to prior therapies are valuable in confirming
diagnosis and planning further treatment.
The responses to treatment may be considered as follows. Correct
responses: steroids, anti-immune, or
anti-inflammatory drugs were given to treat disease; the patient or wound had a positive
response to such drugs. No responses: failed or ineffective therapies for the
wound or disease; multiple failed therapies
with different agents or at different times; wound surgery failures such as skin grafts
which did not take. Adverse responses: disease or wound flare-ups due to treatment,
such lowering steroid doses; wound
pathergy and wound complications of surgery; atopic dermatitis or atopic vasculitis or
other allergic responses to treatments (common in many auto-immune patients
who have multiple drug allergies). Contrary responses: inflammation, wound infarction, and
progressive ulceration from treatments meant to improve the wound. Contrary wound responses can occur with
cytokines (e.g. pdgf, anti-tnf-α), living cell
therapies (engineered living skin equivalents), and immune competent
chemicals (e.g. monoclonal antibodies). Left upper: rheumatoid, 52 failed skin grafts (yes, he
counted them). Left lower: lupus-mctd,
resurgent ulceration after pdgf therapy.
Left inner: rheumatoid, healing induced after systemic
steroids and anti-rheumatoid drugs (plus typical topical wound care). Right
upper: rheumatoid and
hypercoagulable, inflammation arrested by steroids and warfarin, but wound
healing not induced. Right lower: Crohn’s disease of skin, ulcers healed
after intralesional steroids, new lesions prevented from ulcerating by prompt
steroid injection. |
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Summary of section 1-B The “rheumatoid” and immunopathic ulcers are a major category of chronic wounds and wound pathology, under appreciated, but
overly important. They are common, generally easy to recognize and diagnose, but
only if you are aware of them and conduct the proper patient interview. The wound practitioner will often be the
first one to make the diagnosis of a systemic connective tissue
disorder. Successful treatment of the
ulcers is contingent on proper diagnosis and treatment of the primary
disease. |
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Section 1-C Section 1-B explained immunopathic wounds with the implication
that the classic connective tissue or rheumatological diseases are behind all
of this. However, auto-immunopathy comes in a variety of flavors, and practitioners
from different specialties will have a different taste of the problem. This section will explain the generalities
and commonalities of these conditions. |
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Rheumatology practice will see the auto-immunopathies from the
point of view of the collagen vascular diseases and connective tissue
disorders. This is a diverse point of
view, but there are other auto-immune diseases that may not be so likely to
show up in a rheumatologist’s office, such as inflammatory bowel disease,
auto-immune thyroiditis, pemphigus, and multiple sclerosis. They will all show up in a wound practice. |
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The immune mediated dermatoses and panniculopathies are a large
category of illness, must likely to be seen by a dermatologist . . . and in a
wound practice. Dermatoses are common and are the face value stuff of
dermatology and dermatology textbooks.
Many skin problems will show up in a wound practice, and having some
familiarity with dermatology is important.
There are a few generic categories of dermatological disease that you
will see commonly, such as the eczemas, pemphigoid, atopic, and other
inflammatory dermatoses. Panniculitis and the panniculopathies are crucial to understand.
The “panniculus” refers to the subcutaneous adipose fascias. There are two subcutaneous layers, Camper’s
and Scarpa’s fascias, plus areas or layers of areolar adipose scattered
throughout the body. These fascias are
just generic stroma of fibroblasts and angiocytes playing host to adipocytes. The adipose panniculus is the prime target of a lot of
autoimmune attack. Many of the leg
ulcers you see start as inflammation in the panniculus, and ulceration occurs
as the overlying skin dies due to thrombosis of its supply vessels
underneath, or due to lysis from contiguous inflammation. While auto-immunopathy can result in
primary dermatitis, primary synovitis, primary fasciitis and ligamentitis,
and just about primary anything else, it is important to realize the crucial
role that the adipose fascias have in being the prime target and wellspring
of many of the skin ulcers that occur with immune and inflammatory diseases. As for so many of the dermatoses and related conditions, there
is a gargantuan nomenclature of the inflammatory dermatoses and likewise for
the panniculopathies. If you read a
dermatology textbook on the subject, the list of names and diagnoses will
take many columns. However, it is easy
to see that many are duplicates, or “blind-men-and-the-elephant” differing
perspectives on the same thing, or descriptive names based on physical
features rather than pathology (cf. “atrophie blanche” for dermal scarring),
or old names from bygone eras when the relevant physiology or pathology was
not understood. Some of the more
common or relevant disorders will be listed on slide 41. Regardless of all of the descriptive names
and legacy nomenclature, we are talking about a central pathology in which
immune, allergic, and inflammatory events are turned on against the host and
are causing damage and then impairing the ability of the body to repair that
damage. Left: simple postural stasis leading to secondary
panniculitis and an eczematous dermatitis,
Center: pyoderma gangrenosum in a patient with
subtle lupus-like symptoms. Right: necrotizing panniculitis of the thighs in a
patient with undifferentiated or mixed connective tissue disease. The subject of postural stasis needs some comment, since this is
one of the most common and commonly misunderstood and misdiagnosed entities
that a wound practice has to deal with.
This occurs due to the accumulation of dependent edema. It is common in people who sit and do
nothing all day with their legs down (typically obese sedentary older
people), in people with heart or lung disease who must sit up at all times
and sleep that way, and in the dependent part of the obese overhanging
panniculus of abdomen and thigh. Edema
and fluid stasis leads to leukocyte stasis which then triggers acute
inflammation. Panniculitis is the
primary event, with secondary eczema of the skin. These people simply need good compression
or other edema control, very short term anti-inflammatory therapy, and
non-specific wound and skin care. (This
care is extraordinarily simple in principle, and 100% effective, but
admittedly hard to implement or maintain in many of these people.) These are the patients who are often mislabeled
as “cellulitis” (an essentially meaningless term to begin with) and treated
with antibiotics and other irrelevant things while never getting any of the
correct care, turning a simple benign easy-to-fix problem into chaos and
complications. |
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Here are examples of inflammatory dermatoses and
panniculopathies causing skin ulcers.
Expect to see any and all of this in a wound practice. Left upper: pyoderma gangrenosum in an otherwise
healthy young woman (primary inflammation at dermal-hypodermal boundary). Left
middle: pyoderma gangrenosum in a
patient with ulcerative colitis (primary inflammation at dermal-hypodermal
boundary). Left lower: Crohn’s
disease, primary lesion in the skin (primary inflammation at
dermal-hypodermal boundary). Center upper: necrobiosis lipoidica in an otherwise
healthy woman (primary inflammation in the subcutaneous panniculus). Center
lower: postural stasis (primary
inflammation in the panniculus with secondary dermatitis). Right
upper: simple eczema and atopic
dermatitis (primary dermatitis). Right lower: bullous pemphigoid or eosinophilic
dermatitis (primary dermatitis). |
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Dermatology is a vast subject, and only a small part of it
involves wound related issues.
Likewise, wounds are a vast subject, and not all wounds involve the
skin, and only a portion are due to primary dermatoses and
panniculopathies. Yet dermatology and
wound practice have a very important area of overlap. These are the ulcerative dermatoses and
panniculopathies, and they are almost exclusively of
immune-allergic-inflammatory origin. There are many ways to mix, match, and rearrange them in a table
of nomenclatures, A few major
categorizations are given below. What
is common to all is that they represent a state of auto-sensitization or auto-immunization. They affect all ages. They have a spectrum of extent and
severity. They may or may not be
associated with some other major syndromic disorder (e.g. lupus or
inflammatory bowel disease). They are
all responsive to anti-inflammatory, anti-allergic, or anti-immune therapies,
and their steroid responsiveness is the cornerstone of acute and chronic
treatment. This list is far from complete – it is just a sampling of common
diagnoses that will be seen regularly in a wound practice, all within the
realm of the ulcerative and inflammatory dermatoses and
panniculopathies. Dermatoses: eczema, pyoderma,
pemphigus, pemphigoid, Sweet’s (neutrophilic dermatosis). Panniculopathies: Weber-Christian (and other lobular
panniculopathies), erythema nodosum (and other septal panniculopathies),
lipomembraneous panniculitis, necrobiosis lipoidica, nodular fasciitis, eosinophilic
fasciitis. Collagen-vascular and connective tissue disorders: lupus-rheumatoid-Sjögren’s, poly-dermatomyositis,
scleroderma-crst, Behçet’s, inflammatory bowel disease. Vasculitis: leukocytoclastic, polyarteritis nodosa, venous
vasculitis. Miscellaneous: uncategorized,
drug eruptions, contact eruptions, intertriginous dermatitis. |
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The rheumatologists see one aspect of autoimmune disorders. Dermatologists see another. In fact, doctors from almost any specialty
are going to see their own facet of autoimmune and inflammatory diseases. The following is a list of confirmed or
putative auto-immune disorders. If you
were a primary physician making referrals, they would go to many different
specialties (e.g. rheumatology, dermatology, allergy & immunology,
hematology gastroenterology, neurology, nephrology, endocrinology,
cardiology, pulmonary). As a wound
practitioner, you are in the one specialty that will see them all. Here is a sampling of these disorders, constrained by what would
fit on the slide, in no particular order:
classic connective tissue disorders, synovitis & arthropathies, dermatoses
& panniculopathies, inflammatory bowel disease, bowel associated dermatosis-arthritis
syndrome (badas), autoimmune hepatitis & cholangitis, autoimmune
thyroiditis, autoimmune aspects of diabetes, rheumatic carditis and rheumatic
fever, autoimmune neuropathies, autoimmune myopathies, myasthenia gravis, multiple
sclerosis, sarcoidosis, granulomatous disorders, autoimmune arteritides, venous
vasculitis, autoimmune sialoadenitis, autoimmune nephritis, polyserositis,
mixed connective tissue disorders (mctd-nctd-uctd). Keep in mind that many of these patients and disorders will have
a mix-and-match set of signs and symptoms, and these crossover profiles have
necessitated the use of generic terms like mixed and undifferentiated
connective tissue disorder. The more
thorough you are in taking a history and inventory of symptoms, the more you
will find. In a sense, it is as though
auto-immunopathy is just as single generic disease, presenting different
profiles, symptoms, and sequelae based on which specific antibodies appear
and which specific cells or tissues get targeted. |
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Summary of section 1-C The autoimmune disorders are a broad class of disease that will
be seen, in one form or another, by physicians from almost all
specialties. Autoimmune disorders are often
manifest in a variety of common and distinctive syndromic patterns, and they
are thus classified by an accepted nosological nomenclature (e.g. major names
like lupus or rheumatoid or eczema).
However, these nomenclatures are artifice and an alias for the real
pathologies that underlie a state of auto-sensitization or auto-immunization.. They all tend to have a variety of crossover features or
symptoms, and in a sense they are conceptually all a single disease. All carry some risk of wound problems, and
all such diagnoses will be seen in a busy wound practice. |
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Section 1-D The main goal of this presentation is to discuss the auto-immune
connective tissue disorders as the true intrinsic diseases of wound
healing. To do so though, some
prefatory topics need to be reviewed.
In the past few sections, we have discussed the generalities of
chronic and pathological wounds, the subject of hypercoagulability and
hematological ulcers, and the subject of the auto-immune disorders. The focus so far has been on basic clinical
knowledge, and we have not yet drawn the connections of how these diseases
cause ulcers and disrupt wound healing.
Before doing so, one last prefatory subject must be reviewed – normal
wound healing and the wound module. |
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In the photographs, a normal healthy wound goes through the
natural process of healing until it is closed, i.e. epithelialized. Histologically, all of the reparative
events taking place in the wound have a well organized and recognizable
anatomy, and each of the features seen microscopically correlates with
something that is happening or can be observed grossly. What is that anatomy and organization? What is the sequence, and how do we
recognize these events? The basic biology of wound healing can be epitomized in one
concept, the Wound Module of post-inflammatory
proliferative repair. This term was
coined by Dr. Thomas K. Hunt, San Francisco surgeon-scientist and pre-eminent
wound researcher of the latter 20th century. It is the core anatomy and physiology of
wound healing, the same as bronchi and alveoli to the lung doctor, the same
as the myocardium and valves to the heart doctor. What you observe on physical examination of
the wound correlates with some distinctive event or element in the cellular physiology
of wound healing. It is the orderly
appearance, interaction, and assembly of these elements that constitutes the
wound module. While the whole process
has bazillions of individual chemicals and interactions (the stuff of
everyday laboratory wound research across the globe), the process is
conceptually quite streamlined and easy to abstract. In this short discussion, the process will
be reduced to 7 key items, 7 physiological events with 7 clinically observable
correlates, the quintessential “seven clinical signs of wound healing”. 0 – Injury and inflammation: Wound healing is a reserve physiology, the
wound module an ad hoc organ. They
appear when injury disrupts the integrity of the body. The body’s response to any injury is
inflammation. Inflammation is the protective
and destructive response that defends the body during injury, then cleans up
the debris, then initiates the healing process. Without an initial injury and then
inflammation, wound healing is not there.
However, the process is a bit complex, because while inflammation
triggers the healing process, it also suppresses healing. This is a way to ensure that resources are
not wasted, delaying repair and not permitting it to run fully until the
field is sufficiently stabilized and cleaned up. Recrudescence of injury and acute
neutrophilic inflammation will put wound healing down again. Injury and inflammation are the predicates
to healing. They get the process
going, but only as they themselves are leaving. If significant inflammation is present, grossly
or histologically, the wound remains in acute phases, and healing does not
appear. 1 – Inflammation
subsides: The first sign of wound
healing is that inflammation subsides.
As an inhibitor of the wound module, high levels of inflammation must
wane before the wound module will accelerate.
Clinically, there will be subsidence of erythema, edema, warmth and
hyperemia, pain and tenderness, drainage, necrosis, and other markers of
injury and acute response. If this
does not happen, the wound module will not progress. If these changes do subside, that is the
harbinger of proliferative repair events. 2 – Macrophages,
eschar separation, and cytokines:
Macrophages arrive in the wound as blood borne monocytes. Inflammatory mediators such as pdgf transform
these cells into the macrophage. As
acute inflammation and other leukocytes clear out of the wound, these cells
remain to do the keystone job in the integrated inflammation-repair process. Macrophages actually have two major roles
in the wound. Their afferent task is as phagocytic cells
to remove debris. Whatever is dead or
damaged and needs to be cleared, they do it.
(An ancillary role in this regard is to present antigen to lymphocytes
as part of immune recognition and defense against xeno-pathogens, stuff that
they find as they mop up. This
function is tangential or irrelevant to the wound module and normal wound
healing per se. However, in chronic
pathological wounds, this becomes the basis of the auto-immunization which
perpetuates wound chronicity, which will be discussed at length in later
sections.) Clinically, the afferent
function of the macrophage is recognized by eschar separation – dead stuff is
cleaved from the living stuff, and the dead stuff bit by bit falls off and
disappears. Their efferent task is to initiate the repair process. The local repair cells need something to
flip the switch to “on”, and it is the transformative and stimulatory cytokines
and growth factors made by the macrophages which do this. They include bfgf, pdgf, vegf, igf, and
others, all of which act to stimulate local vascular and fibrous cells. Clinically, the efferent effect of
macrophage wound stimulation is recognized because all of the subsequent
items on this list begin to appear. 3 – Ground
substance and mucus: The purpose of wound
healing and the wound module is to reconstitute a basic stroma that holds the
body together and provides a foundation for epithelial growth. Native stroma and repaired stroma have
collagen and other connective proteins as the structural matrix. However, early cells in the wound need a
place to live and do their thing as they make the new connective matrix. Architects and builders must create some
form of staging on which construction workers can stand, so that they can lay
the bricks and mortar, the stones and steel of some new building. Plasma proteins constitute the topmost
layer of the wound, where acute inflammatory cells do their work. Below that is a zone of glycosaminoglycans
(gag’s), ground substance, where the early repair cells, angiocytes and
fibroblasts, can live and do their job.
The aminoglycan layer is the construction staging. The gag’s are created by inflammatory and
arriving mesenchymal cells. One of the
earliest signs that the wound is entering the proliferative phase, clinically
it is recognized by mucus and light reflex on the wound. 4 – “Granulation
tissue” and angiogenesis: This is
the most obvious positive wound finding to naïve observers, the red pebbly
carpet of new blood vessels that appears, eventually covering the entire
surface in any wound that is properly healing. This tissue is new blood vessels forming in
the aminoglycan matrix. The angiocytes
that make the new vessels are being attracted from old vessels below by
angiogenic cytokines made by macrophages above. Vascular density is much higher than in
normal tissues, hence why it is so red.
Once these new vessels are established, they create the favorable
environment in which fibroplasia can then occur. 5 – Histioblasts,
fibroblasts, and fibroplasia:
Once angiocytes have formed vessels within the aminoglycan layer,
there is now an environment hospitable to other cells. The other cell which has a restorative
function is the histioblast-fibroblast.
In this presentation, “histioblasts” will refer to the earlier
incarnation of these cells, the uncommitted pluripotent stem or reserve cell
line that will spawn new fibroblasts when needed. The “fibroblast” is the more mature
version, making and embedding itself into the new connective protein
matrix. The matrix starts as amorphous
fibrillar collagen, and as it becomes denser and more mature, it becomes more
fibrous with its characteristic mechanical properties. Clinically, thus us observed as stiffness
in the wound, less mechanical compliance. 6 – Myofibroblasts
and contraction: Wound closure ultimately
is defined by the restoration of an epithelial boundary which sequesters the
mesenchyme from the ambient world.
However, to lighten the load on the epithelium, nature has another trick,
wound contraction, which reduces the size of the wound. To do this, some fibroblasts develop muscle
proteins and become contractile. The
function of these myofibroblasts is to ratchet the wound together: tug with
the muscle proteins, then cement with the connective proteins, then tug with
the muscle proteins, then cement with the connective proteins . . . Clinically, this is recognized by
in-curling of the wound edges, smoothing of the wound contours, and
progressive reduction in wound width and size. 7 – Epithelialization: Epithelialization that separates insides
from outsides is the final step. For
epithelium to grow across the wound, all other components of the wound module
must be in place. Epithelium will only
start to grow where “granulation tissue” is in contact with the wound
edges. Once the process starts, thin
new epidermis (or any epithelium) outgrows across the surface until the whole
thing has been “painted”, a process very easy to observe clinically. 8 – Maturation: The seven events and clinical signs of
wound healing and the wound module have now been witnessed: inflammation subsides >>
macrophages & eschar separation
>> ground substance &
mucus >> angiogenesis & granulation tissue >>
fibroblasts & fibroplasia
>> myofibroblasts &
contraction >> epithelialization. The wound is now nominally closed. However, wound healing is not over. The newly restored stroma is excessively
dense with new connective proteins and vessels, and the mechanics of the
tissue and functions of the epithelium are far from mature. Over a period of months or years, the new
scar will be reworked and remodeled back to something akin to natural dermis
or fascia. Those slow changes also
have their clinical observations, mainly improved color and compliance. This slide presented the general functions of the wound module
and what you will see clinically that correlates with these events. The next seven slides will focus on wound
anatomy, what you will see under the microscope, which likewise directly
correlates with wound module events and the 7 clinical signs of active wound
healing. These following slides are an
abbreviated version of a larger presentation on normal wound healing. You can read more and get the thorough
story on the Arimedica website: http://www.arimedica.com/content/integra%20histogenesis_gottlieb-me_v2003.htm http://www.arimedica.com/content/arimedica_integra%20histogenesis_gottlieb-me_v2003.pdf |
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The wound module has several distinct
generic events or dynamics, and these have clinical signs and
correlations. Wound anatomy, which
must be observed histologically, also has its own distinctive features, and
these too correlate nicely with the physiologic and clinical features of the
wound module. This slide looks at that
wound anatomy. Just like the dynamical
wound module has certain well defined events, wound anatomy has certain
well-defined strata. On the left of
this slide is a completely healthy wound which is healing properly, seen here
with basic hematoxylin and eosin stain.
It is sliced into 6 strata. Zone 1 – Inflammatory or plasma
protein layer: This is constituted of plasma proteins,
leaked from vessels underneath, serving as the substance and environment in
which acute leukocytic inflammatory cells muster to defend the host. This zone varies with the degree to which
topical care and hygiene have controlled desiccation, injury, bioburden, etc. With scrupulously good care it can become
rather negligible (and the opposite with no care). There is also platelet aggregation here,
and this is the zone in which platelet-derived and other transformative
cytokines convert blood-borne monocytes into tissue macrophages. Zone 2 – GAG and
angio-attraction layer: This is the upper part of the aminoglycan
layer, at the boundary of the topmost plasma protein layer. Cell density is relatively sparse, and
there are no connective proteins here whatsoever. There are still neutrophils here (acute
inflammation), but not nearly in the numbers as above. There are three distinctive key elements at
this level. (1) The “space” is all glycosaminoglycans,
made by inflammatory and stromal cells, serving as the “ether” in which the
other cells operate until they can make an actual fibrous matrix. (2) Large mononuclear cells can be found
here, monocytes and macrophages, making the proliferative cytokines which
induce the local repair cells. (3)
“Planktonic” or migratory angiocytes, generally individualized and spindle
shaped as they stream from established vessels below toward the source of
chemotactic stimulation above. They
can also be seen starting to reorganize, becoming ovoid again as they start
to reassemble with others of their kind. Zone 3 – GAG and
angio-organization layer: This is the deeper part of the aminoglycan
layer. Neutrophils can still be found
here, but mostly in scant numbers, representing inflammatory chemoattraction
and migration rather than any type of injury or assault. Connective proteins are still missing. The distinctive feature of this level are
the angiogenic cords, reflecting angio-organization and the reformation of
tubular blood vessels. The angioid
cells and their cohesion are still a bit loose and immature, the cells still
big and unsettled, but they have found their positions, conducting channels
are open, and erythrocytes are present in the lumens. The new vessels have a distinctive look of
long radial or vertical cords traversing the gag layer. This establishes the environment in which
other cells can appear and do their functions. Zone 4 – GAG-connective histio-attraction layer: This is the layer where
collagen and matrigenesis begin.
Aminoglycans are still present, but they are being displaced by young
fibrillar collagen. Neutrophils are
completely absent. Vessels are better organized, some mature, and some are of
greater diameter, indicating that they are now supplying a downstream
angiosome of vessels organizing in the upper layers. There are two distinctive key elements at
this level. (1) Histioblasts have been
stimulated into activity from mature vessels underneath, and therefore young
fibroblasts have appeared and are proliferating. They appear like small round uniform cells
scattered between the nurturing angiogenic cords and young vessels. They are migratory, and they have little or
no organization, yet to be trapped in the collagen they are making . . . (2) but
they are making collagen. The young
collagen is amorphous, relatively pasty or homogeneous, and presumably still
fibrillar. Zone 5 – Amorphous collagen layer: In this layer, collagen
is getting denser. There are no
neutrophils. Vessels are mature, some
of greater diameter and mural thickness reflecting a mature hemo-conducting
network. Fibroblasts have become very numerous
and dense. They are no longer
migratory, and some are becoming trapped, but they are still more young and
round rather than mature and flattened.
Young collagen fills most of the space, the aminoglycans having been almost
completely displaced. The collagen
matrix is starting to look more fibrous, but it is still immature. This can be considered young scar, but the overall
architecture is still more wound than scar. Zone 6 – Fibrous collagen layer: Collagen has become not
only dense, but highly fibrous and well organized into lamellae or sheaf-like
bundles. Fibroblasts are mature,
trapped and flattened, settling in for a lifetime of collagen turnover and
remodeling. Arteries, veins, and
lymphatics can all be discriminated.
This layer can be considered real scar, and the end of the mesenchymal
component of wound healing. All of this has taken place within a
depth of 1 – 2 mm (the depth will vary, greater or lesser, with location and
the circumstances of each wound). Now,
look at the two vertical images on the right.
These are also prototypical healthy wounds properly healing. [1]
The light blue stain is Alcian blue.
H&E histology allows the location of the glycosaminoglycans to be
inferred, but it does not directly stain the gag’s. Alcian blue is the opposite, staining only
the tissue gag’s (it stains the carboxylated and sulfated aminoglycans of the
“ground substance” such as chondroitin, hyaluronan, dermatan). The dense blue stain is present in the
sub-inflammatory angio-attraction and angio-organization layers, the zones of
angiocyte streaming and vascular reassembly.
This beautifully reveals the vertical architecture of the angiogenic
cords and young vessels. The plasma
protein layer above and the collagen layers below do not stain, and cell
populations and densities can be easily discerned by the red counter stain. [2]
The H&E stain on the right is of a wound that has been well cared
for, regular daily bathing and dressings with silver sulfadiazine. It is devoid of inflammatory cells – almost
zero neutrophils. That is why proper
wound care is so important. If
environmental injury and challenges can be subdued, then nothing but pure
wound healing is happening. Look at
what is present. The plasma protein
layer is there. Even without
inflammation, this layer exists by default, a consequence of leaky vessels underneath
where angiocytes are reorganizing – this is normal. It is easy to observe the pink plasma,
coming from the dis- or loosely organized vessels, intermixing with the pale
purple aminoglycans at the boundary of these layers. Note that there are cells in the upper
plasma layer, all large and migratory, all mononuclear cells, macrophages,
and possibly arriving angioid cells.
Below that are the other layers, angio-attraction and
angio-organization, shown down to the boundary with the histio-attraction
layer where fibroblasts and faint collagen are just appearing. |
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0 -
injury, inflammation 1 -
inflammation, subsides 2 -
macrophages, eschar separation, cytokines 3 -
ground substance, mucus The seven events (and corresponding
clinical signs) of the wound module will be looked at more closely in these
next few slides. The first three
events – subsidence of inflammation, macrophages, and ground substance – will
be ganged together as the preparatory or pre-matrix phase, when things are
cleaned up and readied for the formation of new stroma. Macrophages, derived from blood borne
monocytes, initiate the repair process by making cytokines which stimulate the
local repair cells. Two cell lines
must be triggered, angiogenic cells and fibroblasts. Left: This view shows the upper inflammatory and
plasma protein layer, and the subjacent gag and angio-attraction layer. There are typical plasma exudates at the
top hosting acute inflammatory cells and large mononuclear cells. In the subjacent gag layer, neutrophils are
sparse, but streaming angiocytes are abundant, Reorganized vessels are deeper, just
appearing near the bottom. Right: A close up view near the top of the
wound. There are mononuclear cells
(monocyte-macrophage) and angioid cells.
The organized cluster of cells is an angiogenic cord, reassembling a
vessel from individual angiocytes. These
angiocytes have zoomed up from vessels below, aiming directly at the source
of chemotactic stimulation, the angiogenic cytokines made by the macrophages. There is no normal fibrous stroma to give
structure to all of this (that is the job of these cells, to remake the
stroma), so a medium is needed for these cells to work in, and that is the
aminoglycan ground substance. |
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4 -
“granulation”, angiogenesis “Granulation tissue” is the one sign
of a healing wound that the average physician can recognize or label. It is recognizable because of its pink
color, due to blood in proliferative new vessels. The vessels form from angiocytes derived
from other angiocytes or angiopericytes in vessels deeper down. This proliferation and reassembly of blood
vessels establishes the crucial supply network that then permits
histioblasts-fibroblasts to flourish and make connective proteins. Right:
Streaming angioblasts are highly organized, forming vessels reaching
nearly to the plasma protein inflammatory layer. The vessels here all show a directional
orientation, reaching through the aminoglycan layer toward the macrophages
that are stimulating them, coming originally from old established vessels at
the base of the wound (and later on from newer more superficial vessels
established more recently in the life of the wound). Pink staining erythrocytes amongst these
cords attest that these vessels are still immature and quite leaky. In the lower third of the image, the vessels
are getting thicker and more mature, but the angiocytes are still large and
“unwound”, not yet tightly assembled into a solid luminal cylinders. In the bottom right corner is a perfectly
mature tight-junctioned vessel made of flattened angiocytes. Left: An example of granulation tissue that is
densely packed with vessels. This
specimen was harvested from within a hollow wound chamber implanted
explicitly for the sake of raising a crop of wound activated cells. At two weeks after chamber implantation,
this tissue has almost exclusively angiocytes and erythrocytes, with no
inflammatory cells and only a few young fibroblasts or histioblasts. Fibroblasts and fibroplasia will follow,
but without the vessels there first, nothing else can grow and be productive. |
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5 -
histioblasts, fibroblasts, fibroplasia Angiocytes make vessels and establish
an environment in which other cells can proliferate. After that, many new cells appear which
will mature into the fibroblasts and myofibroblasts which deposit proteins to
make the connective matrix and then contract the wound. As with angiocytes, these cells are sourced
from vascular pericytes or other pluripotent angioid cells in the vascular
loci below. Clinically, fibroplasia is
generally evidenced by changes in wound mechanics, compliance and stiffness, Left photo: Fibroplasia can be seen visually as the
final skin scar, but it is usually not visible in open wounds, since the
fibroblastic layers are deep to the granulation tissue and other superficial
layers. However, in this photo (an
abdominal wound after trauma), angiogenic granulation tissue is very thin, allowing
the deeper layer of fibrosis to be seen.
Left histo: At the top is the macrophage transformation
zone, and below this the angiocyte streaming zone. Just above the middle are some organized
vessels, and between them are small cells with round nuclei. These cells are the young fibroblasts, becoming
denser and more numerous going toward the bottom. Layers and events deeper to this are shown
in the three images on the right. Right upper: This image corresponds to the bottom of the
long image on the left. The
fibroblasts are interspersed among organized vessels. They are numerous and small, but they are starting
to elongate into the spindle shape of the more familiar mature fibrocyte. While the matrix is still largely
aminoglycans (non-staining areas and pale purple reticulum), thin strands of
eosinophilic young collagen are starting to appear. Right middle: This view is a bit deeper. There are vessels at bottom and upper
right, and between them histioblasts and young spindled fibroblasts are quite
dense. More of the space is occupied
by pale pink collagen. Right lower: This is deeper yet. Young fibroblasts remain dense. the space is almost completely filled by
young disorganized collagen. The cells
are, in general, less round, more spindled, and starting to take on some
organization in the form of stratification or lamellations. |
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6 -
myofibroblasts, contraction The previous slide focused on the
histio-fibroblasts. This one focuses
on their end product, the fibrous scar.
Throughout this discussion, collagen alone is referenced for
convenience, but the process involves all of the connective proteins, such as
elastin and fibronectins, which have greater or lesser roles in this process
depending on various circumstances. Right middle: Just below the zones shown on the last
slide, the randomly arranged young fibroblasts are starting to become flatter
and layered. They are stratified
between maturing bundles of wavy pink collagen. Right lower: At yet a deeper layer, the stratification,
organization, and packing of the scar is obvious. The scar bundles are thick, and different
bundles criss-cross in different directions. Right upper: This image is from the wound margin
subjacent to an infolding skin edge. It
shows a zone of fibroblast and collagen condensation which is denser,
straighter, and more lamellar than other areas of fibroplasia around it. This is the “rubber band” of myofibroblast
activity and wound and scar contraction. Left:
Scar is the glue that cements the wound together. While it is crucial to restore the
mechanical integrity of the injured part, the dense pack of collagen as seen
on the right leads to undesirable properties.
here are photos of scar complications.
[1] - an anterior ankle
burn scar, hypertrophied due to tensile loads (Wolff’s Law), resulting in a
non-compliant leash that fractures with plantar flexion, triggering more
inflammation and scar. [2] - circumferential scars cause
stenosis and non-compliance of tubular structures, in this case of the
esophagus after lye ingestion. [3] - scar contractures across joints
result in flexion deformities that cannot be corrected except by surgery. |
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7 -
epithelialization Closure of the wound means
sequestration of the mesenchymal elements underneath from the ambient world
by a layer of epithelium. Complete
epithelialization is the nominal endpoint of wound healing for the sake of
practical everyday wound management. Top:
On the right, active epithelial ingrowth is occurring from all wound
margins, covering granulation tissue that has already formed. This process will continue until its growth
is inhibited by contact with itself, and the wound is then closed. At left and center is a small wound that
has healed exclusively by epithelialization rather than contraction. The margins of the ulcerated dermis are
clearly seen, even after it is healed, due to epithelial growth over the
edges and down into the crater. Bottom:
This is epidermis at the edge of an open wound. What were normal basal cells and
acanthocytes have become primitive and migratory, streaming outward toward a
wound margin that has a suitable wound module underneath, especially close capillaries. Migrating epithelium bears little
resemblance to its mature form, but the cells maintain contact with each
other as they spread superficially and tangentially in an elongated flattened
form. |
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8 -
maturation Wound and scar maturation is what
happens after the wound is fully epithelialized. This is the long term involution of the
scar. As seen in the preceding slides,
the early healed wound has a dense excess of collagen, fibroblasts, and new
blood vessels, over abundant compared to normal dermis, fascias, and other
connective tissues. As the healed
wound ages, the excess materials are removed, and gradually the scar takes on
characteristics closer to normal skin and fascias. Left:
The photo shows a set of scars from an area having had multiple
operations. Some of the scars are old
and mature, being pale and flat, soft and compliant. Some of the scars are young, being thick
and stiff from excess collagen and connective matrix, and discolored from excess
vascularity and hyperemia. Right upper: Fibroblasts, collagen, and new blood
vessels are seen at the peak of proliferative repair. Right second: This is a skin scar after it is fully
epithelialized and acute reparative activities have settled down. Vascular density seems to be less, and
cellularity in the collagen also seems less, compared to their peak density
in the top image. The timeframe for
this is within weeks of full epithelialization. Right third: As a scar becomes progressively mature,
collagen bundles become wavy and springy, with tangential spaces or planes opening
between bundles. Fibrocyte density is
much decreased. Vessel morphology
returns to normal, and the number of vessels diminishes back to normal vascular
density, meaning that clinically the red color fades. The timeframe for this is within months of
full epithelialization. Right lower: In the fully matured scar, herringbone
patterns attest to a final collagen configuration that is once again compliant
and mobile. Vessels are sparse, and
fibrocyte density is at a minimum.
While not looking exactly like normal dermis or musculotendinous fascias,
it looks very similar. The timeframe
for this is within years of full epithelialization. |
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Summary
of 1-D This
was an overview of normal wound healing biology. The anatomy of this process is the
proliferative wound module of post-inflammatory repair. There are 4 specific cells required to heal
the wound: monocyte-macrophages to
initiate repair, histio-fibroblasts & vascular angiocytes to make the
stroma, and keratinocytes or other epithelium to complete the process. The key point to understand, for the
purposes of this presentation about CAP wounds, is that the mesenchymal
component of this process depends on just 2 cells, the fibroblasts and
angiocytes. These are the only 2 cells
which create, constitute, and repair the generic stroma of the whole
body. After injury, they get called
into action to create new stromal tissue to replace what is injured or
missing. |
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Section 2 – The connections between autoimmunopathy
and connective tissue disorders Sections
2 and 3 will make the connections between autoimmunopathy, connective tissue
disorders, and wound healing. When we
think about the “connective tissue diseases”, it is all about the autoimmune
disorders that are typically within the purview of the specialty of
rheumatology. Why are the “connective
tissue disorders” related or due to autoimmune states? Why are they not related to some other general
class of pathology? Why are there no
common diseases of the fascias, connective tissues, and general stroma
related to metabolic alterations or genetic deficiencies? Section 2 will explain the connection
between autoimmune states and the resulting connective tissue disorders,
first (2-A) how it is that the autoimmune diseases affect the connective
tissues, and second (2-B) how it is that autoimmunopathy arises and is
directed against the connective tissues. |
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Section 2-A This
section will show the effects and tissue pathology that result from the
autoimmune collagen-vascular & connective-tissue disorders. It will show why these diseases have those
names, because of their effects on connective and stromal tissues. |
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Why are these called “collagen-vascular diseases” and
“connective tissue disorders”? First,
let us clarify some basic terminology about the soft and connective
tissues. The connective tissues are
the general stroma or support structure of the body. They are all basically a structural matrix
of collagen fibers. The chemical
composition is of course more complex than just collagen, but the collagen
structural matrix is the basic fabric of all connective tissues. Of course, the matrix has to be made by
some sort of cell, and that is the fibroblast. However, nothing lives without substrate
supply, and this depends on a vascular distribution system – blood vessels –
created by angiocytes. These are the
two constituent cells of the general connective stroma of the body – fibroblasts
and angiocytes – period. These
structures can play host to other cells, such as adipocytes, but the fibrous
stroma of the body depends on just fibroblasts and angiocytes. The term “histioblast” will also be used
here to denote tissue forming progenitor cells that spawn the
fibroblasts. Recall that all of these
cells are part of the mesenchyme, the tissues derived from the embryonic
mesoderm. Illustrated are two prototypical
examples of basic stromal or connective tissue. On the left
is scar from a healthy trauma wound in early phases of maturation. On the right
is normal muscular fascia. Depending
on the specific tissue and circumstances, the collagen architecture may
differ in expected and predictable ways, but aside from that, there are only
two structures, blood vessels in collagen matrix, and two cells, angiocytes
and fibroblasts. |
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The stromal tissues, engineered by the mesenchymal cells of the
mesoderm, predominantly histioblasts-fibroblasts and angiocytes, are composed
of collagen and connective proteins, traversed by blood vessels and vascular
structures. Diseases which affect the
mesenchymal stroma therefore affect these cells and structures. It is predominantly the autoimmune
disorders which do this. Why are these
cells and structures the target of auto-immunopathy? To begin the answer, this slide shows what
that targeted pathology looks like. Bottom left: acute leukocytoclastic vasculitis. This is arteritis in its acute phases, with
intense neutrophil infiltration with necrosis and myxoid degeneration of the
vessel wall. Vessels are clearly an
explicit target of this event. Bottom right: rheumatoid synovitis, likewise with
neutrophilic acute inflammation and myxoid changes in a tissue that is
nothing but loose fibrous stroma with fibroblasts. Top
left: chronic vasculitis or
peri-arteritis (from a patient with long-standing ulcers and infarcts due to
a combined coagulopathic and auto-immune disorder mainly consistent with
polyarteritis nodosa). Neutrophils
have disappeared, and instead, chronic inflammation has ensued, consisting of
lymphocytes, plasma cells, and eosinophils.
Note how the pathology is confined to the vascular locus, without
inflammation in the surrounding connective matrix. Note also the chronic thrombosis in the
damaged vessels. In anticipation of
explanations soon to come, ask yourself this crucial question: what came first, the thrombosis or the
inflammation? |
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The
consequence of auto-immune attack is to kill cells and trigger inflammation. Inflammation is a destructive process by
intent, so when triggered, there is progressive damage to the affected
tissues. Inflammation also begets
wound repair, so fibrosis and related consequences of the wound module also
appear. The net effect is acute and
chronic damage to mesenchymal, musculoskeletal, and stromal structures. This slide shows the anatomical and
clinical effects that result form auto-immunopathy and inflammation of the
collagen-vascular connective tissue stroma.
Top left: fibrosis develops in blood vessels after
vasculitis, leading to stenosis and obstruction; these angiogram shows
paradigm “lupus angiopathy” which occurs most commonly in lupus and
scleroderma. Bottom left: a
cross-section view of a dermal artery from a scleroderma patient showing the
mural fibrosis and stenosis; this patient’s skin was also highly fibrotic
from repetitive inflammation and scarring of the dermis, confirming both
“collagen” and “vascular” targets of his disease. Bottom
middle: prototypical late stage
rheumatoid hands; these deformities are the biomechanical consequences of
destruction of tendons and joint ligaments, destroyed by chronic active
inflammation triggered by autoimmunity targeted against synovium. Top
middle: earlier stage rheumatoid
synovitis during a flare up; the leg has become ulcerated because of global
anti-connective tissue effects affecting more than just synovium. Top
right: atrophie blanche, a classic
morphological feature of skin in some of these disorders, representing areas
of residual normal skin interspersed with dermal scarring due to repetitive
dermatitis-fibrositis. Bottom-right: “string-of-beads” ulceration characteristic
of autoimmune synovitis; in the hand, rheumatoid synovitis is apt to cause
tendon rupture, whereas in the lower extremity, it is apt to lyse skin; the
upper photo is a lupus patient during acute phases of synovial suppuration
and skin ulceration; the lower photo is a rheumatoid with chronic ulceration
after the synovitis flared and has now subsided. |
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The
autoimmune disorders can affect nearly any cell or tissue in the body – e.g.
immune thyroiditis, hepato-biliary disease, inflammatory bowel disease,
hidradenitis, etc. However, when the
mesodermal/mesenchymal connective and vascular stroma of the body is the
target of auto-immunopathy, then the tissues affected are those of the
fascias and musculoskeletal system, as seen on the last slide. Depending on which antibodies or cells and
tissues are predominantly targeted, the patient may have a syndromic set of
signs and symptoms that fit into standard nosological categories. Synovitis dominant disease is likely to fit
diagnostic criteria for rheumatoid arthritis.
Dominant involvement of the adipose fascias is apt to be recognized as
Weber-Christian, erythema nodosum, and related panniculopathies. Muscle involvement may prompt a diagnosis
of polymyositis. Serositis dominant
disease might be called lupus or Weber-Christian. Complications of fresh wounds and old scars
are apt to fit with lupus. Other
distinctive events, such as uveitis, spondylitis, secretory adenitis,
urethritis, cerebritis, central vasculitis, mediastinitis, etc. will all
betray certain syndromic diseases and classifications, such as Reiter’s,
ankylosing spondylitis, Sjögren’s, Behçet’s, Wegener’s, Takayasu’s, etc. Many patients of course will have mix and
match findings necessitating the use of “mixed”, “undifferentiated”, and
“non-specific” to describe the connective tissue disorder. One thing that is common to all is that
because connective and vascular tissues are involved or targeted, therefore
skin ulcers, wound pathergy, and similar soft tissue events are common |
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Summary
of 2-A This
section has shown the effects and tissue pathology that result from the autoimmune
collagen-vascular & connective-tissue disorders. We can now answer why these are called
“collagen-vascular diseases” and “connective tissue disorders”. They are so called because the immune
events and their targets affect the mesenchymal cells which constitute the
stroma of all tissues, the connective tissues and blood vessels, composed
predominantly of fibroblasts & angiocytes. The gross anatomical pathology and the
clinical sequelae of these diseases are due to (1) active inflammation
damaging connective and other tissues, such as acute synovitis and
panniculitis, (2) anatomical changes resulting from that destruction, such as
tendon and ligament rupture, joint deformity, and skin ulcers, and (3) the
effects of scar, such as vascular stenosis. |
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Section 2-B So
far, you have been asked to accept on faith and common basic knowledge that
auto-immunity is the cause of the connective tissue disorders. We have just shown the anatomical pathology
that results from the auto-immune state and thus why they are called
collagen-vascular diseases. The next
big question – a two-parter – is (1)
what are the origins of autoimmunity in the first place, and (2) why does
autoimmunity target these tissues?
This is what will be answered in Section 2-B. |
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The
origins of rheumatoid, lupus, and auto-immunopathy have had various theories
and debates. Infections, repetitive
trauma, and other inflammatory states have all been implicated. None of these is explicitly correct, but
what they all share is a state of chronic inflammation. What you will see here is how a chronic
inflammatory state of any primary cause can lead to auto-immunization. Start by considering two other auto-immunopathies
where the origins of the auto-immunity is understood. (1) Rheumatic fever and rheumatic heart
disease occur because strep throat, scarlet fever, or other streptococcal
disease induces immunity to streptococcal antigens. Key to this is the streptococcal PARF
antigen (“peptide associated with rheumatic fever”), which binds to human
collagen. When immune cells become
sensitized to the bacterial antigen, they also develop immunity to the
conjoined collagen, and now you have an auto-immune connective tissue
disorder. (2) Spina bifida and
myelomeningocele have a high incidence of allergy to latex. Now how odd is that? A meningocele exposes neuroectodermal
tissues to the general circulation and mesenchyme, where inflammatory cells
can meet them. The CNS is rich in a
variety of phospholipids, so some type of low level sensitization to these
chemicals occurs. Latex, raw rubber,
is a micellular suspension of isoprene monomer globules suspended in
phospholipid membranes – phospholipids, the same stuff as in the CNS. Exposure to latex probably acts as a
secondary sensitizer, a booster shot if you will for auto-immunity which is
already present to some degree. Latex
then further acts as a trigger for acute responses. The response is more allergic than immune,
but it is nonetheless an example of sensitization developing to auto-antigens. In the rheumatic fever case,
auto-immunization occurs because human collagen is in the way, at the wrong
place at the wrong time, caught up in the melee as immunity develops to an
exogenous immunogen. In the spina
bifida case, auto-immunization occurs because non-mesenchymal antigens
normally hidden from the immune system become exposed. How does this relate to the common
connective tissue disorders and the problems that frequent a wound practice? The
clinical lab has various tools to assess auto-immunity, such as antibody
assays. Anti-nuclear antibodies are
the most prevalent, and serve as a basic screen. If positive, further testing can reveal
others. The table on the right shows
some tests and panels available from a large commercial lab. The antibodies and assays that are tested
for include those against nuclear chromatin and DNA, nucleoli, centromeres,
endoplasmic reticulum, ribosomes, golgi complex, and mitochondria. Do you see a pattern? These are all directed against intra-cellular
structures. Consider another disease,
hidradenitis suppurativa. A type of
acne affecting apocrine glands, the disease includes a lymphocyte mediated
inflammation with antibody fixation.
Everybody gets overly focused on the suppurative abscesses in the
obstructed glands, but the real problem that obstructs the glands is the
autoimmunity. How does this
develop? When the cysts themselves
inflame and rupture, epithelial endocellular debris and sebaceous chemicals
that should NEVER be present on the underside of the basement membrane get
exposed to the mesenchyme, allowing immune sensitization to occur. Similar events presumably explain the
uveitis that occurs in the eye (as with Behçet’s and Reiter’s), and perhaps
as well antigens in the secretory lacrimal and salivary glands (Sjögren’s),
and so on. So, how is it that the body
develops immunity to these chemicals?
Is it that they are caught up in the fracas of some acute inflammatory
event, as occurs with streptococcus-induced rheumatic fever? Or is that they were never meant to meet a
lymphocyte in real life, but the ramparts tumbled or they were shanghaied to
a tough neighborhood as occurs with spins bifida and latex cross-over
allergy? For the diseases that are apt
to show up in a wound practice, we can find strong compelling evidence of
both mechanisms. |
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This
slide will show you the some of basis whereby nuclear auto-immunization
occurs. Left lower: a normal
specimen from a “healthy” chronic wound.
The angiocytes of the blood vessels are all hyperplastic and
disorganized, a normal effect of angiogenic cytokines in the proliferating
wound, i.e. normal and healthy. There
is stasis and migration of polymorphonuclear leukocytes – completely normal
behavior after any injury or thrombosis – completely proper reactive inflammation. In addition to well-formed poly’s, you will
also see dark spots that look like the size and shape of individual lobes of
a neutrophil’s nucleus – because they are.
This is “nuclear debris”, aka “poly dust”. As neutrophils conclude their business and
do the apoptosis thing, nuclear remnants are left, waiting to be cleaned up
by macrophages or other degenerative mechanisms. The more intense the inflammation, the more
concentrated the nuclear or cytoplasmic material becomes. In specimens with intense necrosis and
suppuration, there is always a generalized purple basophilia reflecting the
high load of loose endocellular material.
Right upper: a specimen from an unhealthy wound, a
patient with polyarteritis nodosa. There is vascular disorganization with
fibrin exudates, heavily infiltrated with poly’s, and a substantial amount of
poly dust. The vessels are the target
of acute inflammation, but unlike a short term inflammatory state after
trauma, this inflammation is repetitive and sustained. The increased load of nuclear debris and
increased time of exposure increases the chances of antigenic
recognition. Right lower: a specimen
from long standing pressure ulcer.
This type of wound is presumably non-pathological, just a matter of
pressure and trauma, but nonetheless chronic.
The vessels and stroma high in the wound are normal, and there are
poly’s and poly dust as you would expect, but there is also immunogenic
inflammation – eosinophils and plasma cells.
Why would the body be acting as though it is immunized and making
immunoglobulins against itself in this chronic seemingly benign wound? You can start to see how auto-immunization
occurs. All of that nuclear debris is
freely exposed in the tissue. What
should be protected antigens sequestered inside cells are being exposed where
immune processing cells can pick them up.
The more the material, the longer it is exposed, the greater the
chance of recognition and sensitization.
And not only are the sequestered antigens at risk (like happens with
spina bifida and latex), but even chemicals normally exposed in the area risk
being picked up and carried along on the immunization ride (like for
rheumatic fever). And what normal
chemicals or structures risk being carried along? Those associated with the matrix or its
resident cells and structures – fibroblasts, angiocytes, vascular structures,
and connective structures. |
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This
starts a series of slides that demonstrate a fascinating and crucial
connection in this story – the relationship of hypercoagulable disorders to
auto-immune disorders. Recall in our
basic review of hypercoagulable states and ulcers that there is a
recognizable, nearly pathognomonic tetrad / pentad that nails the diagnosis
of a hypercoagulable disorder: (1)
thrombotic or embolic event, (2) miscarriage, (3) wound pathergy event, and
(4) a connective tissue disorder, with (5) either a personal or family
history. Why the connection between
these two major disease categories?
Left: a woman with scleroderma-crest.
History and wound behavior suggested a hypercoagulable state,
confirmed by laboratory, and she ultimately died from pulmonary embolism or
thrombosis. Note the significant
multifactorial markers of both autoimmunopathy and hypercoagulability. Right: a man with clinically active lupus
with multiple wounds and wound complications due to minor trauma and
surgery. Wound specimens confirmed
thrombi, the lab confirmed antiphospholipid antibodies, and he healed
promptly with warfarin. Why did both
patients have unequivocal evidence of both disorders? |
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You
might think that the two patients on the preceding slide just had an unhappy
coincidence of dual diseases. You
might, until you see this and the next few slides. On this slide are three patients presenting
with obvious pathological ulcers, including active necrosis, inflammation,
and progressive ulceration. One of
them had no prior documented history, and the other two had confirmed histories
of polycythemia or other blood cell disorders. Laboratory evaluation using customary
panels for autoimmune and hypercoagulable disorders showed evidence of both
in all three of these patients. None
of them had a clinical history of autoimmunopathy or connective tissue
disease, but on symptom inventory and review of systems they had a variety of
typical complaints such as arthralgias or sicca syndrome. The profile of the 54 year old man is
especially noteworthy. In addition to
autoimmune markers, he has a dual type of coagulopathy: factor V Leiden
indicates an intrinsic pre-thrombotic hypercoagulopathy, and he also has a
strong antiphospholipid antibody elevation, both lupus anticoagulant and
anticardiolipin. You cannot cheat on a
gene test - factor V Leiden is an inborn error, a built in hypercoagulable
disorder. So isn’t one coagulation
defect enough for one person? Well,
not for him, but why - why would he then also get auto-immune procoagulant
antibodies? No, it’s not coincidence. |
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More
of the same, three more examples of mixed laboratory findings in patients
with clinical profiles that likewise indicate dual disease, both
coagulopathic and immunopathic. On the
left, 2 patients with a priori clinical diagnoses of a connective tissue disorder,
where the ulcers behaved equally coagulopathic, confirmed in the lab. Both healed with a customary program of
anticoagulation and skin reconstruction with a regenerative matrix. On the right, a patient with no antecedent
diagnosis, but presenting with a prototypical acute pathological wound. The features are more thrombo-infarctive
than inflammatory-lytic, but there are elements of both, both grossly and by
laboratory assay. |
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And
another one . . . These three patients
had clinical histories of active immunopathy plus acute ulcers behaving more
thrombo-infarctive rather than inflammatory-lytic. The duality of the problem was confirmed on
laboratory profiles. Note that the
rheumatoid patient has markers that cannot be mistaken – clinical and
pathological rheumatoid for which she just had her back operated on, and
genetically inborn factor V Leiden.
(Notice that plasminogen, a natural thrombolysin, and protein C, a
natural anticoagulant, are both elevated, a typical reflex up-regulation of
these compounds in response to a continuing state of thrombosis.) I could keep showing you more of the same
thing, lots more . . . Are you
convinced now that these are not coincidences? I have yet to do a formal retrospective
(nor prospective) data analysis of our experience with these patients and
profiles. However, having paid
attention to these issues for the past 14 years, and having observed them in
hundreds of patients, I have a general sense about the incidence of these
correlations. Remember, all of these
patients come to our practice because of the wounds, not because of a
characteristic rheumatological or hematological complaint. (1)
For patients presenting with a primary hypercoagulopathy, i.e. where the
wounds and history and laboratory profile are strongly “hematological”, more
thrombo-infarctive in nature, then the incidence of laboratory cross-over
with positive auto-immune markers seems to be well over 50%, perhaps as high
as 85%. (2) For patients whose
clinical profiles are strongly “rheumatological”, with overt history or
symptoms, and with inflammatory-lytic ulcers, the presence of hypercoagulable
markers seems to be in the range of about 25% to 50%. For a long time, we have been drawing both
sets of blood panels on our primary coagulopathic patients, so the “data” and
experience are more thorough for those patients. Only recently have we started drawing
“hypercoag” panels on our primary “rheumatoid” patients, and as we do more,
the real values for this set should become clearer. There are also plenty of patients who come
with ulcer profiles and clinical histories that make both sets of disease
obvious from the outset, and it is not surprising that their lab workups have
mixed markers. |
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Why? Why do so many of these patients have
markers of two major categories of disease?
The findings may be occult or overt, subtle or dramatic, but they are
there when you look for them. The
explanation is not so mysterious, and it relates to the basic mutual
interaction of thrombosis and inflammation.
Recall the quintessential roles and functions of inflammation and
thrombosis. How is an injury
recognized? How is it cleaned up? How is the repair process started? There are several pathways of injury
recognition, and one of them is platelet activation and thrombosis. Once these events occur, they then initiate
inflammation, so the body can handle the defenses, do damage control, and
then clean up. Thrombosis triggers
inflammation. However, inflammation
also creates a milieu that promotes thrombosis via prothrombotic chemicals,
leukocyte and platelet trapping, changes in vessels and blood viscosity,
etc. Inflammation triggers
thrombosis. They trigger each
other. This complex non-linear system
is self-amplifying. In the case of a
one-shot incidental injury, such as trauma, this thrombosis-inflammation
coupling ensures a swift ramp up of defensive changes, but then the process
subsides and settles, paving the way for repair. However, when there is some sort of
repetitive or sustained injury, then new thrombosis and inflammation keep
getting triggered, keeping the process alive.
For the technically savvy, it is very much analogous to an oscillatory
system in mechanics or electricity. A
one-shot trigger in a spring or vibrator circuit may oscillate briefly as it falls
back to zero, but if you keep kicking in a bit of energy at the resonant
frequency, enough to replenish internal energy losses, then you can sustain
the oscillation and make cool things work, like a radio or a clock. Trauma induced thrombosis-inflammation is a
one-shot. Thrombosis-inflammation
triggered by chronic sustained thrombotic or immune disorders and activities
keeps the system running – to the detriment of the host. What
triggers abnormal or sustained thrombosis and inflammation? Immunopathies and coagulopathies do, i.e.
intrinsic disorders of these primary events.
Also, angiopathies and panniculopathies, diseases of the host
structures which can trigger thrombosis and inflammation. They have complex interactions, but when
these chronic alterations or disorders are present, then the
thrombosis-inflammation cycle can become sustained. And what is caught in the middle? The health of the host tissue – necrosis
and ulceration. If the thrombotic
events predominate, then thrombo-infarctive necrosis is more apt to be
seen. If the inflammatory events
predominate, then lysis and ulceration are more apt to be seen. It should be no surprise though that many
wounds and patients will have features of both events, both grossly and in
the laboratory. In
the world of wound pathology, there are several highly interconnected events
and responses of paramount importance to health and disease, the connections
between:
injury-thrombosis-inflammation;
pathergy-necrosis-ulceration;
inflammation-immunity;
coagulopathy-immunopathy-angiopathy-panniculopathy. Patients with pathological wounds have
aberrations of these chains, and because they are highly inter-dependent
there are frequently multiple such abnormalities, e.g. auto-immunopathy
generally accompanies hypercoagulable disorders. The common pathways all come down to
thrombosis and inflammation, with infarction and lysis, affecting stromal
tissues made of vessels and collagen, angiocytes and fibroblasts. The final step in this section is now to
show why there is such a strong association of autoimmunopathy with the
hypercoagulable states. |
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Here are two slides from two patients with hypercoagulable
disorders. The specimens came from
wound debridements, meaning that there was already established ulceration
(the views are of nearby zones, not directly in the ulcers themselves). What do you see? Both show a vascular locus, a zone of
vessels and angioid tissue within a dermal or connective matrix. Within the vascular locus, vessels have
chronic thrombi and reorganization.
The specimen on the left shows migratory spindle shaped
disorganization of the angiocytes consistent with a state of chronic
inflammation and wound healing. Both
specimens have diffuse infiltration of the vascular locus with chronic inflammatory
cells. Recall that whereas acute
inflammation is neutrophilic, chronic inflammation shows predominantly
lymphocytes, plasma cells, and eosinophils.
The left specimen is infiltrated with almost pure lymphocytes. The right specimen is infiltrated with
mostly all plasma cells and eosinophils.
There are few neutrophils, and the surrounding collagen matrix shows
normal fibroblasts without inflammatory changes. Why are these vessels in a state of chronic
immunogenic inflammation? On slide 56 we asked what came first, thrombosis or
inflammation? The answer is that the
thrombosis came first. These patients
have a chronic coagulopathic state, always making microthrombi. This triggers chronic repetitive
micro-inflammation. As the
thrombo-inflammatory state persists and becomes prolonged, there will be an
ever increasing load of cellular debris and endocellular antigens,
intermingled with an ever increasing parade of inflammatory cells. Just like for spina bifida and for
hidradenitis, sequestered or endocellular material that should remain hidden
from lymphoid cells is getting exposed.
Because these events are happening amongst angiocytes and fibroblasts,
it is not just acute inflammatory cells that are being exposed, but also
these stromal cells. And because these
events are taking place within the stromal tissue, supporting chemicals of
the vascular structures and connective matrix are also present, many of which
are being digested by the matrix proteases that are part of the acute
inflammation. To the extent that these
normal exposed proteins, their sub-fragments, and other chemicals are caught
up in the war zone, to the extent that sequestered antigens or other opsonins
or inverse-haptens might bind to these matrix chemicals and take them for a ride,
they too might become the target of auto-immunization, just like for
rheumatic fever. In normal incidental one-shot inflammation, macrophages in the
wound clean up debris. They have a
vital role to present antigen to lymphocytes, in the event that they find
viruses or fungi or other xeno-pathogens, thereby leading to immunity against
the invaders. But lymphocytes are not
prominent players in one shot incidental inflammation. They and macrophages
have only a limited amount of shared time on the stage or at the party. But what happens when inflammation becomes
more chronic, and more lymphocytes show up while macrophages are cleaning up
ever more endocellular debris and opsonized-haptenized matrix proteins? The chances go up that sooner or later a macrophage
and a lymphocyte get confused, that one of your own chemicals gets fingered,
that the activated lymphocyte then returns to the hive, and your own “stuff”
is now on the most wanted list. What
stuff? The stuff that’s there in that
zone of chronic inflammation. The
chronicity of the inflammation is being maintained or renewed because of the
primary pathology, the repetitive micro-thrombosis due to a
hypercoagulopathy. The stuff that is
being damaged, degraded, exposed, and processed is nothing more than the
materials of the general stroma: vessels, matrix, angiocytes, fibroblasts. As time goes by, you are becoming immunized
to your own stromal cells and matrix. The
thrombotic condition comes first, and the auto-immune state is an induced
reaction. That is why so many
hypercoagulable patients have auto-immune disorders, be it an overt classifiable
clinical syndrome, or else a mixed set of autoimmune symptoms, or else just
positive laboratory serologies. When
patients with factor V Leiden or prothrombin 20210G genetic mutations have
rip-roaring rheumatoid or lupus, the cause-and-effect connection is real. |
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With the hypercoagulable states, low level continuous thrombosis
leads to continuous or repetitive inflammation (with or without micro-infarcts
due to the ischemia; the inflammation
in turn helps maintain a thrombotic state).
This all causes continuing exposure of sequestered antigens as cells
degrade. Also occurring is the degradation
of normally non-antigenic matrix chemicals into antigenic fragments (either
directly antigenic or else after opsonization or inverse haptenization with
normally hidden antigens). This debris
is all derived from acute inflammatory leukocytes and from the host stroma
itself, i.e. vessels and connective matrix, angiocytes and fibroblasts. The debris must be cleaned up, a function of
macrophages (transformed from mononuclear leukocytes). Another normal part of macrophage function is
the presentation of antigen to immune competent lymphocytes. This creates the risk that normal
extracellular matrix chemicals and normally sequestered intracellular
chemicals will become the subject of antigenic recognition and
auto-immunization. This risk increases
as the chronicity of the inflammation puts more lymphoid cells into the
picture, increasing the mutual exposure of macrophages and lymphocytes. The connective tissue disorders are due to
autoimmunity against generic stroma, vessels and matrix, and it is easy to
see why this occurs when the locus of primary inflammation is the vessels
themselves. The causes of auto-immunization can now be generalized. Primary hypercoagulability creates
conditions of chronic inflammation directly around blood vessels, and thus
vessels and surrounding matrix are not only the prime casualties, the prime
targets of necrosis and ulceration, but also the prime targets of erroneous
immune recognition and sensitization.
However, any primary condition causing chronic inflammation could do
the same, especially if sequestered and novel chemicals are being
unmasked. The chronic inflammation may
be reactive, a normal response to a primary injury, such as trauma or
infection. It may be induced
inflammation, such as that triggered by primary thrombosis. The inflammation may represent several types
of host defense, including suppurative states (neutrophilic), allergic or
atopic states (granular leukocytes), and immune states (lymphoid). The problem may be amplified or sensitized
by ancillary genetic or metabolic factors, such as the association of
autoimmune disorders with HLA-B27 (ankylosing spondylitis) and HLS-B51
(Behçet’s). The system is very
complex, but at it’s heart, any chronic inflammatory state induced by some
primary non-autoimmune pathology risks sensitizing the body to itself. It can easily be appreciated how it is over
many years that various authors have implicated chronic infections,
allergies, injuries as the cause of auto-immune connective tissue
disorders. It is not the primary
injury which is specific to the process, but rather a state of chronic primary
non-immune inflammation which leads to auto-immunization. These concepts can be illustrated via hidradenitis
suppurativa. The auto-immune component
of that disease is long recognized as it relates to the pathology of the apocrinitis
itself. It is not surprising that
auto-immunity might occur, since these micro-abscesses will expose sebaceous
and other epithelial antigens repetitively and chronically. This is just like hypercoagulability in
that it creates the perfect chronic mix of debris, antigens, acute inflammation
and macrophages, and chronic inflammation and lymphocytes. For hypercoagulable states, sensitization
occurs against vessels, leading to further arteritis. For hidradenitis, sensitization is against
the glandular epithelium, leading to chronic apocrinitis and persistence of
the acneform state. What is interesting
though is that once auto-immunization occurs, it can have global
effects. The patient shown had active
untreated disease for over thirty years.
Excision of the affected areas cured the problem. In so doing, many other symptoms that she
had lived with for years suddenly resolved.
Along with general malaise, she had symmetrical large joint
polyarthralgias, sore wrists and hands, morning stiffness, and sicca
syndrome. All of this evaporated as
the post-excisional wounds healed.
This story is not unique, neither among hidradenitis patients nor
among any patient with a chronic inflammatory state. In summary, a chronic repetitive sustained state of primary
inflammation will lead to sensitization and auto-immunization against those
structures that are the target of primary inflammation. In a sense it is just the whole immune
system behaving the way it is meant to, but it gets confused about who the
enemy is when primary acute inflammation is sustained rather than being a
one-shot. Once auto-immunized,
whatever structure was once the locus of acute reactive leukocytic
inflammation now becomes the target of chronic immune lymphoid
inflammation. When vessels and
connective matrix are the targets, then patients will have disorders of the
generalized stroma, meaning the classic connective tissue disorders, but
also, as we are now about to see, disorders of the wound healing process. |
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Summary of 2-B Autoimmunity occurs when the immune system “sees” antigens that
it should never have seen, either endo-cellular or other sequestered antigens,
or else open matrix chemicals that are altered or presented by the occult
antigens. Angiocyte and fibroblast,
vessel and matrix antigens are prominent in this sensitization, immunizing
the patient to the connective tissue and vascular cells which constitute the stroma
of all tissues. This pathology results
from any number of underlying primary disorders which result in a chronic
inflammatory state which leads to the unmasking and presentation of the occult
antigens. Once someone is auto-immunized,
protean clinical sequelae ensue. |
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Epilogue to
Section 2 At the beginning of Section 2 we asked why the connective tissue
disorders are due to autoimmune states as opposed to some other general class
of pathology. Throughout this section
we have established the connection between autoimmunity and the diseases of
the general stroma. However, we have
yet to answer the other side of that question: why are there no common
diseases of the fascias, connective tissues, and general stroma related to
metabolic alterations or genetic deficiencies? The full annotated answer is beyond the
scope of this presentation, but a few basics can be explained, partly here,
and partly in the epilogue to section 3-A after slide 76. The stromal cells, fibroblasts and angiocytes, represent
evolutionary and phylogenetically ancient cells. Multicellular life appeared about 1 billion
years ago, as single celled life learned that there is strength and survival
advantage in cooperative association and the division and specialization of
labor. There are two quintessential
constructs needed to permit multicellular association and function: some system
for holding everything together in a stable functional anatomical form, and
some sort of distribution system to permit the interchange of nutrients,
metabolites, and information. In
animals, the system that evolved for holding things together is based on
connective proteins, the most abundant of which is collagen. Collagen structures and anatomy became
increasingly complex as life advanced, but collagen is present even in the
most primitive of multicellular organisms, the Porifera, the sponges. Evidence of a bulk transport system – a
vascular system – is also seen in some sponges, and it is permanently
established by the Cnidaria, the hydras and jellyfish. Primitive invertebrates do not have a blood
circulatory system. Instead, their gut
has extensions into all parts of the organism to directly deliver food, a
gastrovascular cavity that handles both digestion and distribution. Nonetheless, this is a vascular
distribution network, and our blood circulatory vascular system is a direct
evolutionary descendant of the gastrovascular cavities of the Cnidaria. Only one gene and its product are required
to govern the formation and morphology of this vascular distribution system,
and that gene is VEGF (vascular endothelial growth factor; well, actually 2
genes, VEGF and VEGFR, its receptor). Genetic
sequencing allows us to recognize the specific nucleotide “spelling” of each
gene, and jellyfish and human VEGF and VEGFR are highly homologous, spelled almost
exactly the same. Also, the observable
functions of VEGF on vascular cells and structures are identical for
jellyfish and humans. As life evolved,
many new genes appeared, old ones disappeared, and many morphed and
changed. But, over eons of
multicellular evolution, VEGF and its functions are unchanged. Why? Why has VEGF remained unchanged?
Because multicellular life is wholly contingent on a bulk transport
vascular distribution system. Without
it, complex multicellular life is categorically impossible. Once this core infrastructure element of
life had been written, it needed no revision, because it worked so well. What this means is that for the few
quintessential genes that permit multicellular life, there is little room for
mutation. VEGF is so crucially
essential for life that without it, an embryo unconditionally cannot develop
– period - exclamation. (In some
experiments, VEGF knockout is categorically lethal; in other experiments,
other angiogenic factors can keep a conceptus alive, but with significant
developmental defects.) Whatever VEGF mutation
might occur in a gamete, it cannot be propagated, because a conceptus simply
cannot develop beyond just a few cells (the gastrula stage). The basic stromal structure of
multicellular life – connective matrix and vascular distribution system – was
worked out from the beginning, 1 billion years ago. The formation and function of these
structures and cells has been thoroughly tested and debugged, meaning they
are essentially error free. These core
infrastructure functions of multicellular life are so consistently conserved
and dependable, so thoroughly robust, that there are no major genetic or metabolic
disorders of the stroma, and consequently none of the mesenchymal component
of wound healing. Because these cells
and structures have extraordinarily few intrinsic disorders, when wound
healing goes bad it reflects some sort of exogenous disorder or damage, some
sort of deprivation or attack affecting these cells and structures. That includes non-specific non-targeted
conditions such as trauma, ischemia, toxicities, and severe
metabolic-nutritional inadequacy. It
also includes targeted damage directed against these cells and structures,
and as we have seen in this section, that means the auto-immune disorders. |
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Section 3 – The connections between autoimmunopathy,
connective tissue disorders, and altered wound healing Sections 2 made the connection between autoimmunopathy and
connective tissue disorders. Section 3
will now tie them to impaired wound healing.
Section 3-A will look at how wound healing is altered in the presence
of the autoimmune connective diseases.
Section 3-B will put these premises together to show why wound healing
is altered and impaired in these disorders. |
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Section 3-A In the last section, it was shown why the autoimmune disorders
are directed against the basic stroma.
Wound healing is just the process of the stroma putting itself back
together after disruption. Therefore,
if the autoimmune disorders affect the connective and vascular stroma, then
they should likewise be affecting wound healing. We have already seen that this is true, but
in this section the connection between connective tissue pathology and wound
healing will be more explicitly developed.
Section 3-A will begin with a look at how wound healing is altered in
the presence of these diseases. |
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This and the next few slides are a brief gallery showing CAP and
immunopathic wounds and their histological variances from a normal wound
module. (What is listed are features
that were obvious for each patient, but since space limitations preclude
putting up dozens of images, you might not be able to discern some of the
items mentioned.) This first slide is of an 85 year old woman with polyarteritis
nodosa. The specimens are from the
edges of the ulcers. Features to
observe include: neutrophilic
arteritis and peri-arteritis, acute and chronic thrombosis, arterial stenosis,
vascular necrosis or fibrinoid degeneration, vascular disruption and disorganization,
diffuse plasma exudates, chronic peri-arterial inflammation with plasma cells
and eosinophils, dense poly dust and other basophilic cellular debris, an
absent or impoverished aminoglycan layer, abortive neo-angiogenesis. One of the problems in looking at the histology of CAP wounds is
that it can be hard to discriminate between active disease and impaired wound
healing. During active acute
inflammation-thrombosis-necrosis-lysis everything looks bad, and reparative
processes are appropriately suppressed.
Ideally, one should look at acute phase specimens when trying to
establish a causative disease, because that is when the primary disease is
active. One should then look at late
phase specimens, after acute inflammation and necrosis are subsided, because
that is when chronic wound healing impairments will be more manifest. Note in the image on this slide that the
multiple ulcers are largely free from peri-wound inflammation, and edema is
gone. This is a latter phase image
where basic care has controlled acute changes, and wound healing should be
active but is weak. That is one of the core issues of CAP and immunopathic wounds,
that latter phase impaired wound healing cannot be separated from acute phase
active injury. The ongoing active
injury is the chronic inflammation, triggered by autoimmunity against
cellular components (which was first created by prolonged inflammation and
necrosis due to a primary inflammation-inducing disease). The inflammation and immunity are targeted
against the stromal elements, meaning ipso facto that they are targeted
against the wound healing machinery.
Thus, in the autoimmune wounds, impaired wound healing and chronic
inflammation are conjoined, with or without some acute inflammation, and with
varying degrees of chronic inflammation and varying levels of expression of
the reparative wound module and its elements. |
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This 35 year old woman had years of intermittent slowly healing
leg ulcers, recurrent lower extremity panniculitis, and finally a popliteal
ulcer. Immunopathic ulceration was
suspected, but could not be confirmed by serologies or other tests. Popliteal ulcers can be hard to resolve in
the healthiest of people due to mechanical effects, but in this case, it
persisted over three years before healing, in spite of various approaches to
care with splints, surgery, and various physical, topical, and wound
stimulatory modalities. Histology
shows features of many CAP and immunopathic wounds: neutrophilic per-arteritis (in a grossly
bland uninflamed wound), plasma cell and eosinophil infiltrates, vascular
disorganization, narrow or thin zones of aminoglycans and angio-organization,
insignificant or disorganized fibroplasia, dense nuclear debris. What is especially interesting are the mitoses, visible near the
centers of the two lower images. In
this specimen, there were mitoses in most high power fields, sometimes 2 or
3, almost what you could expect to see with anaplastic cancers. These are angioid cells, proliferating as
they would in any healthy wound, but with bizarrely excessive turnover. This was a wound where the “granulation
tissue” was grossly thin and “anemic”, and where it was largely absent
histologically. In cancers, new cells
appear and accumulate. Here, they were
rapidly generating then wholly disappearing.
Perhaps they were disappearing by apoptosis, perhaps by immune
mediated lysis (antibody-complement), perhaps by some other mechanism. It is bizarre, but immunopathic and other
CAP wounds can have bizarre pathological wound histology. The mitotic rate aside, the presence of chronic
inflammatory cells, peri-vasculitis, altered behaviors of angioid and fibrous
cells, and corruption of normal wound strata makes this a typical
pathological wound, almost certainly of auto-immunopathic origin. |
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These images are from an 31 year old woman with a primary
hypercoagulable disorder and ankle ulcer, along with miscellaneous
immunopathic symptoms. Laboratory
evaluation confirmed low protein C and low APC resistance (likely the primary
problems), a positive lupus anticoagulant (probably secondary due to induced
auto-immunity) and low factor IX (indirect evidence of a thrombotic state,
due to compensatory down-regulation of a prothrombotic element). The specimens are from the base and edge of
the ulcer. Features that can be
observed include: acute and chronic
inflammation, acute and chronic thrombosis, vascular necrosis or fibrinoid
degeneration, vascular disruption and disorganization, dense peri-vascular plasma
cell infiltration, cellular debris and basophilia deeper than expected for
healthy wounds, cellular debris and basophilia along angiogenic cords, scant
or disorganized fibroplasia. As seen in the gross picture, there is active inflammation and necrosis
in spite of treatment, representing
persistence of the pathological state. Histologically, the overall architecture of
the wound module is relatively correct, but numerous features are altered
from normality. In this case, the
primary hypercoagulable state is responsible for the persistent state of
active infarctive and inflammatory pathology, which will in turn inhibit and
delay wound healing. Recognizing an
auto-immune component of delayed or disrupted healing becomes easier only
after non-immune acute events have been controlled. However, in this case, the active
pathological state was not controlled by anticoagulants and topical care
alone, and persistent auto-immune inflammation may have been the persistent
promoter of continued micro-thrombosis.
As discussed in the first of these three cases, untangling the interconnections
of acute inflammation, chronic inflammation, thrombosis, and their effects on
subsequent wound healing becomes
difficult, because this whole mess IS the disease of wound healing. |
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Nearly every other organ and tissue has a systematized set of histopathological
findings that pathologists recognize as disease states. Chronic and pathological wounds also have
alterations from normal histology. The
problem is that “wound pathology”, as a discipline of organized academic histopathology,
does not exist. If you work closely
with pathologists you will appreciate that they tend to view wounds as a
normal reaction to injury, inflammation, and many other primary
pathologies. The idea that
inflammation and wound healing themselves go wrong is missing. There are endless chapters and textbooks on
the nuanced differences of breast disease and thyroid disease and placental
disease. But just like in surgery
textbooks, these subjects, which are the biological foundations of everything
else that goes on, get only cursory and perfunctory treatment, on the
assumption that, although they are a vital reaction to things that go wrong,
that they themselves do not go wrong.
This assumption is forgivable to a degree because of the issues
discussed in the Section 2 epilogue a few slides back concerning the
evolution of these cells. These
infrastructure functions of repair and stromal restoration are indeed robust,
and intrinsic diseases are infrequent or non-existent. So, pathologists tend to see “a wound is a
wound”, and there is never anything discriminating or diagnostic contained in
a wound histology report. However, as
wound doctors, we recognize wound pathologies all of the time, and there are
indeed histologic changes that occur in problem wounds. Features that are frequently seen that vary
from a normal wound include: acute
inflammation, chronic inflammation, plasma cell and lymphoid infiltrates,
acute leukocytoclastic vasculitis, chronic vasculitis, acute and chronic peri-vasculitis,
acute and chronic and organizing microthrombi, vascular necrosis, vascular
hyalinization or fibrinoid degeneration, vascular disorganization, fibrous
disorganization, excessive mitosis, epithelial arrest, variations in
anatomical depth of wound, variations in physical depth of wound, and missing
or corrupted wound strata (proliferative zones). And this list is only what can be seen
using classic colored stains such as hematoxylin and eosin or trichrome. Immuno-staining techniques open up a vast
world of even greater peculiarities, perversions, and pathologies of the
wound healing system. |
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Summary of 3-A Wound healing is impaired inpatients with immunopathic
ulcers. Histologic examination of
immunopathic and other pathological wounds reveals variances from normal wound
healing in which chronic and acute inflammation are associated with chronic
vasculitis, fasciitis-fibrositis, and panniculitis, with abnormal
angiogenesis and fibroplasia, and abnormal organization and integration of
these elements. In these wounds, the wound
healing process itself is altered and impaired. |
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Epilogue to
Section 3-A Let us reiterate the statement at the end of slide 74,
“Recognizing an auto-immune component of delayed or disrupted healing becomes
easier only after non-immune acute events have been controlled. However, . . . untangling the
interconnections of acute inflammation, chronic inflammation, thrombosis, and
their effects on subsequent wound healing
becomes difficult, because this whole mess IS the disease of wound
healing.” Wounds are intrinsically
pathological when these core events in stromal biology and pathology get
entangled to the point that the normal wound module cannot function
properly. Wound chronicity occurs
because this entanglement gets locked into a pathological attractor, a
clinically undesirable but dynamically stable state from which it cannot
escape without deliberate therapies. Compare this to a benign wound, a simple trauma or surgical
wound. The response to one-time injury
is a one-shot response. Inflammation
(defense and cleanup) explodes, then decays and extinguishes as the tissues
stabilize. Wound healing (repair) then
ramps up and does it thing. These two
general events are crucially contingent, wound healing being triggered by the
inflammation, one rising as the other settles. However, in a simple wound, each general
event has its own focus of activity and its own locus in time. This is not the case in CAP wounds. In the chronic intrinsically pathological
wound, injury and inflammation never subside, and healing never fully rises,
because they feedback and sustain or suppress each other. The agents of acute inflammation provoke
repair, but the induced agents of wound healing (and their debris) can
provoke auto-sensitization and thus more inflammation. In turn, this continued inflammation
suppresses wound healing as sensitized inflammatory-defensive agents turn and
attack the repair elements. When a
wound becomes intrinsically pathological and wound healing is disrupted, we
are really dealing with three general events:
acute inflammation, the wound module, and chronic inflammation. Acute inflammation and repair are meant to
be sequential and self-limited, and lymphoid cells (chronic inflammation) and
stromal cells (wound module) are hardly meant to mingle, yet under
pathological circumstances they become perpetually intermixed, and the
orderly progression of a healthy one-shot wound module can never develop and
run its course. The interplay or tension between reparative events and
inflammatory events is crucial to understand.
Do any of these events ever get the upper hand? Do they go back and forth? Do the wounds ever heal? If you take care of these wounds, then you
already know the answers – anything goes.
The wounds can suddenly get better, suddenly get worse, hold the line
for prolonged periods, or wax and wane from visit to visit. Are these dynamics predictable or
controllable? Day-to-day dynamics are
not predictable, but the overall principles of these systems are completely
understandable. This little discussion
is meant to give some casual insight and understanding of this situation, the
dynamics of what happens when inflammatory and repair elements become
mutually unbalanced. I do not want to go too far afield in these discussions, but
this section is at the core of why chronic intrinsically pathological wounds
exist. First, consider congestive
heart failure. Its overall
pathophysiology is a vast subject, but its quintessence is that the heart
becomes an inadequate pump. Consider
acute renal failure, likewise vast, but centered on the principle that the
kidney cannot filter blood through the glomerulo-tubular apparatus. For pulmonary failure, the lung is an
inadequate bellows (ventilation) and/or an impaired diffusion membrane (respiration). So, what is the quintessential derangement
of intrinsic wound pathology and chronicity? The answer is that it is a dynamical
disorder, a logistical and self-organizational problem of interacting cell
populations. [1] Logistical problems are a classic
introductory issue in non-linear dynamics (the behavior of complex systems)
related to population dynamics. In
this case, we are dealing with the interactive populations of inflammation
and wound module. To understand this,
consider a generic population in which food can be supplied at a steady
invariant rate, or that liveable space is fixed, and the amount of space or
food per year will sustain a certain maximum population. If the population starts small and is
allowed to evolve, there is an equation to describe its rise to the
maximum. It is the Verhulst equation,
also known as the logistical equation, which is a proper equation of calculus
and algebra (linear, continuous, differentiable) which will tell you the
population as a function of time. But
now consider this next scenario. There
is a field full of green grass, and sheep are introduced. The system is closed, with a fixed biomass
divided between sheep and grass. The
sheep eat the grass, grow strong and fecund, and beget more sheep. The grass mass decreases as sheep mass
increases, and eventually, the sheep outgrow the available grass. The sheep population will then start to
decline, and as it does, grass mass again increases. In this scenario, the grass is not supplied
at a fixed rate. The grass is an
active population itself, just like the sheep, and it can be depleted but
then it can rebound. Sheep and grass
are two mutually interlocked populations, at times supportive, at times
confrontational. Nutrition,
starvation, predation, cultivation are the intertwined dynamics. The problem gets even hairier if you then
throw in a third element such as wolves to eat the sheep. In this scenario, can we calculate the
population of sheep or grass as a matter of time? Not so easily. The Verhulst logistical equation still
applies in principle, but now it must be applied to two populations, and
those two are contingent on the other!
The balance between two interactive populations cannot be calculated
by a continuous linear equation, because this has now become what is known as
a “non-linear” problem, the heart and soul of real world complex
systems. There is no way to calculate,
as a direct analytical function, how many sheep or how much grass is there,
neither one as a function of the other [ sheep = f (grass) ], nor
parametrically in time [ grass = f (t); sheep = f (t) ]. Nonetheless, this problem can be solved,
but as for any non-linear complex system (aka non-linear dynamics) the
problem is solved by recursive iterations, using the iterative form of the
Verhulst equation, the “logistic difference equation” xn+1
!
Axn(1-xn).
It turns out that the dynamics of this system, the amount of sheep or
grass, has a very strange and wonderful set of back-and-forth numbers year by
year. The main message is that in
these complex systems of interacting populations, the dynamics can be
strange, seemingly unpredictable, and at times locked in to “attractors”,
states of being, from which it is hard to break away. The “logistic map” as it is known is a
foundational subject in non-linear dynamics, and you can easily learn more by
searching for non-linear dynamics,
chaos, logistical map. What does this all have to do with our main subject? Everything.
Inflammation (and its host of various cells and chemicals) and wound
healing (and its entourage) are interactive populations very similar to sheep
and grass. They support and promote
each other, and at the same time deprive and degrade each other. In normal wound healing, incidental injury
invokes a one-shot response. This
one-shot has two compartments, inflammation and wound module. Inflammation rises then extinguishes, its
uprise partly based on linear Verhulst logistics (with some
auto-amplification thrown in), its decline being a first-order exponential
decay (as Verhulst style substrate disappears and the system must
extinguish). The wound module,
triggered into existence by inflammation, has similar dynamics as it rises
then falls. The inflammation
compartment evolves and extinguishes over a time frame of hours-to-days; the wound module compartment exists over a
time frame of days-to-weeks. In
chronic and pathological wounds, this sequential evolution of two linear
compartments gets perverted by the appearance of another population - chronic
inflammation (with an entirely different cohort of cells and chemicals). Also, the wound module’s alter ego of
pathological repair is unmasked, further changing the dynamics and mutual
interactivity of the situation. Normally, acute inflammation (ai) has an inducing or
proliferative effect on the wound module (wm), ai gÉ
wm. In a normal wound, that
is all there is to it, acute inflammation turns on wound healing, and each
phase runs its own course. (Normal
healing does not have a lot of direct inhibitory feedback on
inflammation. Instead, inflammation
runs its course and extinguishes itself if there is no further injury as
repair ramps up. To the extent though
that repair keeps the tissues in a “good state” that inflammation is not
alerted to, then the wound module can be seen as having some inhibitory
feedback on acute inflammation, ai Vf wm.)
In the chronic pathological wound, chronic inflammation (ci) joins the
mix. Chronic inflammation has an
effect to suppress or upset the wound module, disorganizing it or retarding
its kinetics, ci gV wm.
The altered wound module in turn is creating auto-sensitizers and
exposed antigens which fuel the chronic inflammation ci Éf
wm. Note the symmetries in
these dynamics: acute inflammation
begets wound module; chronic
inflammation suppresses wound module; normal
wound module suppresses acute inflammation;
altered wound module promotes chronic inflammation. Thus, we have a system of mutual feedback,
mutual promotion and inhibition, mutual predation and deprivation, mutual
induction and suppression. These are
the same types of population dynamics that affected grass and sheep. And not to belabor the point, but we must if we are to truly understand
intrinsic wound disease, return to slide 67 and the interdependence of
inflammation and thrombosis. Normal
events provoke a one-shot uprise and then decay of thrombosis (time frame minutes-to-hours)
which then triggers an uprise then decay of inflammation (time frame
hours-to-days). Without being overly
specific, you should be able to see that the same type of exponential or
Verhulst style dynamics will apply to this system, the same as inflammation
and wound healing. If the system is
healthy, then thrombosis and inflammation should be relatively
sequential. However, if they get
locked into an attractor where both perpetually sustain and promote each
other, then you have the destructive loop shown on slide 67. This is just like the chronic inflammation
and impaired wound module loop that we are discussing here. So, inflammation is to thrombosis as sheep
are to grass, and wound module is to inflammation as wolves are to sheep,
giving us a three tier system with even greater complexity in its timewise
dynamics. Thrombosis will be a part of
this no matter what, but when thrombosis is normal, then one-shot sequential
linear dynamics occur, all the way through from initial injury to healed
wound. However, when thrombosis is
faulty and it becomes the primary alteration that keeps renewing or
replenishing the abnormal state, then the thrombosis-inflammation loop
becomes non-linear and perpetuated, and in turn so does the
inflammation-module loop, especially as inflammation transgresses from acute
to chronic. It is grass-sheep-wolves
until some external force can interrupt some component of population or
predation. We have focused on
hyperthrombotic states as a cause of all of this, because those are real
diseases of real wounds and they are easy to demonstrate histologically, but
the same applies to any other primary pathogen in this system that triggers
persistent and chronic inflammation: chronic trauma, chronic allergy-atopy,
chronic infection. The wound situation is not 100% reducible to population
logistics, because some other dynamics can also be defined here, such as
other promoter-inhibitor models, and even [pseudo] harmonic feedback and
amplification models as discussed on slide 67. However, the principles of non-linear
dynamics and inferences about how these systems will behave remain
unaltered. There is a reason that
chronic and pathological wounds act “locked in”, now a bit better, now a bit
worse, but fundamentally unaltered over long periods. They are locked into a dynamical attractor
where chronic inflammation and an altered wound module compete and promote
and can not easily escape. [2] The whole wound healing system represents
another concept in dynamics – it is a class of self-organizing automata.
Cellular automata are another foundational concept in non-linear
dynamics. They are systems in which individual
elements, cells, have a set of strict deterministic rules governing their
behavior and how they must interact with other cells. If you throw them all into a pot, they will
sort themselves out, generally ending up with complex highly organized structures
based on just their few instructions.
That is what normal healthy acute wound healing is all about. Each cell – monocyte, angiocyte,
fibroblast, keratinocyte – has an assigned job, and if they can just do it,
the wound self-organizes back to a stable stroma. When you look at a chronic and pathological
wound, productive self-organization is not happening. However, from the point of view of a single
plasma cell, monocyte, or fibroblast, there may be nothing really wrong, just
“life in the ‘hood”. They have no
insight or collective concept of what they are trying to build. Instead, as long as they are alive, they
just do their own thing, day-by-day, reacting as programmed to local stimuli. And as long as local cells can indeed do
their own thing, then the wound and stroma reorganize without problem. Problems happen when you throw a cadre of
chronic inflammatory cells into the neighborhood. Are they good cops, bad cops, street thugs
and bullies, misguided vigilantes, officially sanctioned law enforcement,
civil defense, or sanitation workers to clean up the mess? It depends on your point of view, but if
you are a neighborhood angiocyte, then that lymphocyte who doesn’t live on
your street is probably going to beat you up.
Although each cell is alive and functioning correctly, the collective
system and its set of cells fails to organize. In summary, when you look at an intrinsically pathological
wound, chronic, difficult to heal, perpetually a bit better then a bit worse
in spite of treatment, you are seeing the same logistical dynamics that you
would see when looking at the grassy field and its sheep. Competition between wound module and
chronic inflammation keeps the wound module from fully self-organizing. The linear dynamics of a one-shot perturbation
and response to a single trauma in a healthy subject, i.e. normal wound
healing does not exist in the chronic pathological wound. Instead, the chronic pathological wound exhibits
typical non-linear dynamics, meaning chaos, orbits, and clinically
undesirable but dynamically stable attractors that keep the wound module from
getting to the finish line. Chronic
wounds are simply behaving as complex natural systems are expected to behave
when their normal balance or attractor is stressed by added populations,
promoters, or inhibitors. What causes dynamical disruption of these populations and makes
them misbehave? In abstract theory,
anything could. In reality, these
systems are robust and resilient, and the main pathology is when auto-immune
sensitization against one of these populations (wound module) induces another
population (chronic inflammation).
Recall what was said at the end of slide 70 about the evolutionary
genesis of this system, “ . . . there are no major genetic or metabolic
disorders of the stroma, and consequently none of the mesenchymal component
of wound healing . . . when wound healing goes bad it reflects some sort of
exogenous deprivation or attack . . .”
When the wound module is left to itself, it very reliably self-organizes
back to a stable re-epithelialized stroma.
However, to do its own thing, it needs protection from exposure to the
ambient world. The inflammatory and
immune host defense systems provide this protection, perfect shelter for the
repair process underneath. So, in
principle, since the wound module elements themselves are essentially
error-free, and since they are protected from exogenous attack, then wound
healing should work perfectly . . . and it does, except for its Achilles
heel. The only thing that can and does
goes wrong is the unexpected auto-attack, when the defender system turns and
attacks the repair system. This attack
from a misdirected population is what disrupts self-organization. The effects of cardiovascular disease are easy to understand if
you know some rudimentary fluid dynamics.
The effects of respiratory disease are easy to understand if you know
the basic physics of gases . . . mechanics for musculoskeletal disease,
optics for eye disease, acoustics for ear disease, electricity for
neuromuscular disease, and so on. What
are the physics of the wound? The
wound is not a pump and pipes like the heart, not a diffusion membrane like
the lung, not a structural member like a bone, not a light collector like the
eye, nor a sound transducer like the ear, nor a conductive network like
nerves. It is a collection of mutually
interactive self-organizing cell populations.
Once you learn to appreciate the core anatomy and physiology of this
special ad hoc reserve organ, the wound module, then its pathology becomes
understandable – dynamical disorder of complex populations. (See slide 83 for a bit more on the subject
of dysdynamia and its effects on the complex wound system.) (To learn the basics of this subject, one need only read about
the logistic map and cellular automata in any introductory textbook about
non-linear dynamics. If you find it
interesting, you can easily experiment with the logistic equation for
yourself, as it is very easy to set this up on a spreadsheet, e.g. Microsoft
Excel or OpenOffice SCalc. Also, see the
Arimedica website for more information about the wound as a control system
and the behavior of non-linear systems and the non-linear wound: “The Wound as a Non-Linear Control System”,
May, 2006. http://www.arimedica.com/content/arimedica_wounds_control_(poster)_2006-0516.pdf
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Section 3-B In section 2-A we looked at the anatomical and tissue
pathologies that result from the autoimmune diseases, and how they affect
primarily the fibrous and vascular stroma, and thus why they are called
“collagen-vascular diseases” and “connective tissue disorders”. In section 2-B we looked at why
autoimmunity develops in the first place and why it targets the
connective-vascular stroma. This
occurs because a chronic inflammatory state unmasks immunogenic antigens in
the connective and vascular stroma. The
last section 3-A demonstrated that autoimmune wounds have altered histological
findings, confirming that wound healing itself is pathological, that it is
sick. This section 3-B will take the
final step of putting these premises together and showing why wound healing
is sick in these disorders. |
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Understanding how the auto-immunopathies affect wound healing is
based on a few simple chains of reasoning.
(1) All mesenchymal stroma, the connective tissues, are composed of 2 cell
types, fibroblasts and angiocytes. (2)
The mesenchymal portion of wound healing, depends on the same 2 cell types, fibroblasts,
angiocytes, because wound healing is nothing more than the general stroma
trying to reconstitute itself. (3) The
targets of mesenchymal autoimmune attack are the stromal soft tissues with
their 2 cell types, fibroblasts and angiocytes. (4) These predicates lead to this basic
syllogism: (a) Because they are both made of fibroblasts and angiocytes,
diseases that affect collagen-vascular connective stroma ipso facto are
diseases of the mesenchymal wound module (predicates 1 & 2) (b) The autoimmune connective tissue disorders are the diseases
that affect the collagen-vascular stroma (predicate 3). (c) Therefore, the autoimmune connective tissue disorders are
the diseases of wound healing. The tissues that are the targets of the collagen-vascular
diseases are therefore the casualties of wound disorder, the places where
skin ulcers and musculoskeletal ruptures occur, the places where surgery is
likely to have complications, the places where wound healing is retarded or
incompetent. The adverse effects can
be seen on both sides of the wound healing divide: effects on the open ulcers
before they are healed, and then effects on the resulting scars after they
seem to be healed. Perhaps the most
pernicious aspect of the auto-immunopathies and connective tissue disorders
is the duality of their effects. They
have an afferent effect on wounds to cause them, and then an efferent effect
to keep them from healing. |
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We have made the case that the autoimmune connective tissue
disorders are the true intrinsic diseases of wound healing. For those who have never formally studied
wounds, who only have the cursory awareness of the commonly appreciated
wounds (trauma wounds and the “classic 4”), this may sound surprising, But it should not be. If wounds are made of fibroblasts and
angiocytes, then diseases of fibroblasts and angiocytes are the wound
diseases. If you have not been seeing
these wounds and diseases, it is because you have not been looking, merely
ascribing all wounds to a limited set of commonly known diagnoses. All effective care starts with diagnosis
specific therapies, and that means making the correct diagnosis. As stated in slide 11, it is time for those
who would be expert in wounds to understand the full spectrum of relevant
pathologies and diagnoses. Once you
start to recognize these wounds, and start to get the good results that come
from specific therapies, the straightforward validity of the syllogism above
will be evident. |
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Healing rates
and times. In support of this
thesis, one need look only at the healing rates or healing times of various
wound diagnoses. The graph on the
slide shows data from my clinic looking at days until healed stratified by
diagnosis. The rheumatoid and other
autoimmune diagnoses take longer to heal.
This is because wound healing is broken in these disorders. For the other diagnoses, generic wound
healing throughout the body is intact, and wounds heal once local
pathologies, injuries, and inhibitors are removed. For the auto-immune disorders, wound
healing itself is impaired. Another
diagnosis where wound healing is intrinsically impaired is radiation injury,
but the cause is always known, and this is just a small fraction of all
ulcers. In contrast, the autoimmune
chronic and pathological ulcers are a very big group of wounds. Again, if you have not appreciated this, it
is because you have not been looking nor being discriminating and exact about
your diagnoses. The pernicious effect of immunopathy on wound healing is also demonstrated
in the table below. This is Table 4
from the paper Gottlieb ME, Furman
J: Successful Management and Surgical
Closure of Chronic and Pathological Wounds Using Integra®. Journal of Burns & Surgical Wound Care,
3:2, 2004. (The journal is now Eplasty,
the Open Access Journal of Plastic Surgery, at www.eplasty.com. The paper can also be read at the Arimedica
website.). Integra® collagen-gag
matrix is an artificial skin and regenerative scaffold that has many uses in
reconstructive plastic surgery and chronic wound care. This table shows length of treatment time
for 95 patients with chronic wounds, stratified by diagnosis. Integra® is a two-step process: (1) the matrix is placed on the wound and
allowed to regenerate, then (2) skin grafts are placed on the regenerated
neo-dermis. The first set of data, “Integra-to-skin
grafts”, shows the average regeneration time in weeks, the time between
placing the material then placing the skin grafts. It should be noted that Integra® has an
effect to suppress normal wound healing, and instead turn on an embryonic
model of dermis formation. The length
of this phase, overall average 5.3
weeks, is largely independent of diagnosis, and immunopathy had no effect on
this process. However, skin grafts
were not always completely successful, necessitating additional topical care
or secondary skin grafts. This latter
phase of additional care was a matter of normal wound healing and wound
care. The second set of data shows the
time to full healing, full epidermal restitution. The average time to full healing was
roughly 5 – 6 months for most diagnoses, but it was nearly 10 months for
immunopathic and radiation ulcers, the two diagnoses where the local stromal
cells and wound healing are rendered incompetent and intrinsically
dysfunctional. Table
4. Length of treatment Primary diagnosis Integra
– to – skin grafts (weeks) Integra – to – healed (months) . No.
pts mean std No. pts mean std range Macro-arterial 22 5.3 1.2 16 5.0 2.5 1 - 9 Immunopathic 21 5.4 1.6 12 9.6 5.3 2 - 18 Venous / lymphatic 17 4.6 1.3 11 6.2 3.2 2 - 11 Hypercoagulable 6 5.3 2.0 7 5.8 2.1 4 - 9 Mechanical / anatomical 8 5.0 1.3 6 5.2 1.5 3 - 7 Radiation / malignancy 6 7.4 3.9 4 9.8 4.3 5 - 15 Diabetes 5 4.3 1.1 3 6.5 2.1 5 - 8 Unknown 5 4.1 1.4 4 7.0 0.8 6 - 8 Micro-occlusive 1 6.0 - - - 1 4 - - - - - - Trauma and surgery 2 4.6 1.5 1 3 - - - - - - Granulomatous / infectious 2 4.1 1.6 1 2 - - - - - - Total 95 5.3 2.0 66 7.2 4.3 1 - 19 Wound
chronicity. This slide seems to be a
good place for some ancillary items.
The long healing times mean that by the time these ulcers settle in
for the long haul of treatment, they have become “chronic”, and this has
greater implications than just the common use of that term. We have been discussing CAP wounds, chronic
and pathological, and so far the detailed focus has been on
“pathological”. Let us focus on
“chronic” for a moment. Remember from
slide 29 and following that these problems have pre-ulcerative, then
active-early ulcerative, then chronic-late features. During early ulceration, you are apt to see
disease specific findings, such as synovitis or panniculitis or cicatritis. As the acute events wind down, the ulcers
develop gross, histologic, biochemical, and behavioral features of wound
chronicity. These chronic features
characterize CAP wounds as being distinctly different than acute healthy
wounds. [1] Gross findings of chronicity are more or less the same for CAP
wounds of any cause. This is analogous
to the end stage liver or kidney – each organ has a generic final
pathological appearance regardless of a priori causes. The gross features of chronic non-healing
wounds are obviously very familiar to anyone caring for them. [2] Biochemical
features of chronicity may not be as familiar to many practitioners, but this
subject has garnered major attention from wound research bioscientists over
the past decade. There are many characterizations
of chronic wound chemistry, and in the past few years we have started seeing
an explosion of this work as gene chip analysis lets us look directly at what
genes are on or off. What has been
learned in a short time is that chronic and acute wound biochemistry and
genomics are dramatically different, reflecting two entirely different
dynamical attractors. (Hopefully the
concept of “dynamical attractors” makes sense now after reading through the
past several slides.) [3]
Histologic features of chronicity have also been addressed in the
past few slides. The appearance of
chronic inflammation and alterations in the wound module are easily observed
and reflect fundamental differences between healthy and pathological, and
between acute and chronic. [4]
Behavioral features of chronicity are self evident – if it is not
healing, it is chronic. However, in
the past few slides we have seen why chronicity develops, because the core
physics of wound chronicity is the altered dynamical behavior of a collection
of mutually interactive cell populations. Research needs. While this presentation is not discussing
therapies and management, this slide is a good moment to mention a serious
clinical research need in wound practice, the need to tailor therapies to
specific flavors of immunopathy. Just
as rheumatology research has identified which of many anti-inflammatory and
anti-immune therapies are best suited for specific nosological diagnoses, so
too we in wounds have a need to match specific immunopathies, dermatoses, and
wound profiles to the most effective anti-immune drugs for healing those
wounds. Localized
versus systemic auto-immunity.
This is also a good place to mention auto-immune wounds versus
generalized auto-immune states. If a
patient becomes sensitized to components of the connective stroma, then a
global connective tissue disorder and inflammatory state could occur. That is certainly the case with acute
rheumatic fever, acute lupus, acute and chronic rheumatoid arthritis,
etc. For patients with chronic wounds,
some do have active generalized inflammatory states or classic
rheumatological diagnoses. However,
some seem to have clinical effects just on wounds and wound healing. It is quite likely that for many of them,
they are sensitized or immunized to occult antigens that appear only locally
and incidentally in the wound itself.
These would be antigens unmasked during conditions of acute injury,
inflammation, or wound healing, antigens related to localized thrombosis,
inflammation, vascular and matrix degradation, and the proliferation and
degradation of angiocytes and fibroblasts.
For the research-minded among the wound healing brotherhood, there is
a lot of work to be done to identify the details of all of this. |
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Summary of 3-B In this section, we have made the case that the autoimmune
connective tissue disorders are the true intrinsic diseases of wound
healing. This is because the primary
targets of the immunopathic connective tissue disorders, the mesenchymal
stroma and its cells, the fibroblasts and angiocytes, are also the principal
agents of wound healing. Inasmuch as
these disorders affect the primary agents of wound healing, wound healing is
more impaired than for other chronic wound causes and diagnoses which are
extrinsic to the primary process. The autoimmune and CTD-CVD ulcers are a major category of chronic
wounds and wound pathology, historically under-appreciated, but clinically
and pathologically of paramount importance. |
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Section 4 – Epilogue
and summary Some loose ends and ancillary subjects will be discussed, and
the major points and theses will be summarized. |
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Section 4 Immunopathy, Autoimmunity, & Diseases of Wound Healing, an Epilogue. This is where we wrap up. The trade card illustrated is from the latter 19th
century, at the epitome of the “patent medicine” experience. In an era when electricity was beginning to
become important, it was an easy bit of hucksterism to promote Dr. Thomas’
Eclectric Oil, which was “capital for burns, bruises, cuts, and sprains”. While we may sneer at fraudulent or
unsubstantiated products, the truth is that proper care of any problem is
only as good as the diagnosis. If a
wound diagnosis is incorrect, then the legitimacy of any one product is
irrelevant if it is the wrong agent for the wrong purpose. |
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We have been discussing autoimmunity and the targeted disorders
of angiocytes and fibroblasts as the intrinsic diseases of wound
healing. While that story is true, it
is not quite complete. These cells are
just two elements of a complex inter-operative system. Wound healing also depends on its
ento-ectodermal component, the restoration of epithelium, and that has its
own problems. Then there are a
bazillion individual micro-structures and chemicals that create and support
the nuts-and-bolts operations of the major elements. In spite of this, there are extremely few
major diseases of the stroma, for the evolutionary reasons discussed after
slide 70. But there is another set of
problems that we see regularly when looking at impaired wound behaviors, and
that is dysfunction of the major cell populations in the wound and the
dysfunction of the coordinated inter-operations of the whole system. We have already talked a bit about this in
the epilogue after slide 76, concerning population logistics and self-organizing
automata. Wound healing is “complex system”. In physics, “complexity” has specific
meanings beyond the everyday use of that word. The functioning of complex systems is
described by the science of non-linear dynamics (NLD). While this too is beyond the scope of this
presentation, a major point or two are worth understanding. (1) Technically speaking, complexity is any
system with three or more mutually inter-acting elements. (2) Mutual interactions means that there
are controls on the system, the ability of the system to recognize and
respond to out-of-bounds conditions and try to hold to an allowable state. (3) Complex systems tend to settle into
stable states or “attractors” which can maintain their own stability; complex systems can also “orbit” and meander
through different states. (4) In
complex systems, minute changes can have huge impacts on the system
state. As introduced in the
bioengineering article that is cited, the 21st century is the
century of the system, when we start to look at complex systems as a whole,
not at just individual small components.
Our main method of technical mathematics and engineering for the past
300 years, Newton’s calculus, cannot solve problems related to complex
systems, but we can solve them with modern iterative techniques that require
automated computation. That is why
complexity and NLD have become sciences of just the past 30 years. What does this all have to do with wounds? In reference to the 4 points in the last
paragraph: (1) Wound healing is a
complex system of dozens or hundreds or more mutually interacting chemicals,
structures, and cells. (2) Wounds are
a control system, a highly regulated feedback loop that corrects errors in
the integrity of the body. The main
control loop is shown. (3) The wound
control system has three major attractors, (a) actively ulcerating, (b)
actively closing, and (c) orbiting through states that may seem a bit better
then a bit worse, but never really making any substantive changes
(undoubtedly you have seen such wounds).
(4) Seemingly petty changes of health status or care can have large
effects on re-ulceration or healing of a chronic and pathological wound. “Dynamical disorders” are getting attention
from people who study a variety of complex systems in biology, because they
affect cardiovascular functions, neurological functions, endocrine and
nutritional functions, even population and herd dynamics, and everything
else. The connective tissue disorders
are the diseases which affect the intrinsic elements and individual
components of the wound healing system.
Dysdynamia is the disorder which affects the inter-operations and
collective function of the wound healing system as a whole. |
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Summary CAP wounds – chronic and pathological – have a variety of categories. In addition to the “classic 4” are a
variety of common and uncommon causes, many of which are under-appreciated by
most practitioners (even those that are common and easily managed, such as
mechanical ulcers). A few of them most
directly or adversely affect the intrinsic elements of the wound healing
machinery, the stromal structures and cells, meaning vessels and connective
matrix, angiocytes and fibroblasts. These
are the diseases of blood and lymphoreticular systems, of immunity and coagulation. Hypercoagulable states and autoimmune
states have been reviewed as the paradigms of micro-scale pathology that lead
to the thrombo-infarctive and inflammatory-lytic patterns of necrosis and
ulceration. The intimate entanglement
of thrombosis and inflammation is the engine that drives this pathology in
the face of repetitive or sustained injury.
As we have seen, patients with one of these diseases, hypercoagulable
or autoimmune, is likely to have the other as well, and histological
examination of tissues demonstrates why.
Primary chronic thrombosis leads to chronic inflammation around these
stromal structures, eventually leading to auto-immunization. Connective tissue auto-immunization can be
considered the truest most intrinsic disease of the mesenchymal component of
the wound healing process. The auto-immunopathic connective tissue & collagen vascular
diseases are a major category of chronic wounds. These diseases have two pernicious
effects. They cause ulceration via
thrombo-infarctive and inflammatory lytic pathways, and they prevent healing
by disruptive effects on the functions of the general connective stroma and
the wound module via their targeting of fibroblasts and angiocytes or the
structures that they make. Because
wound healing is thus “broken”, immunopathic ulcers are a challenge to treat. Hopefully it can now be appreciated that so called “atypical
wounds” are not atypical at all. They
are typical, in fact prototypical. And
their significance is not just related to the severity of the problem or
difficulty treating these ulcers. It
relates to their prevalence. Granted,
these are significant problems because they are associated with nasty
underlying diseases and they are hard to get healed. However it is not as though they are rare
wounds that get our attention only because of their severity. They are common. If someone has not noticed these wounds, it
is not because they haven’t seen them, it is because they haven’t recognized
them. Too many practitioners are still
tied to the anachronism of “the classic 4”.
All good outcomes start with a proper diagnosis so that proper care
can be selected. For these patients
and ulcers, comprehensive management of both the wound and the underlying
disease is generally rewarded with good albeit slow results. The challenge of our day is to refine our understanding of these
non-atypical ulcers. Obvious
opportunities for meaningful clinical research and therapeutic advances are
in these areas: dissemination of
knowledge and professional education about this subject; development of relevant clinical sciences,
such as correlating disease and prognosis with histologic findings, blood
serologies, and gene chip analysis;
cross-correlating specific diseases or wound and patient profiles
against (a) the various pharmaceuticals used to control the underlying
immune-inflammatory state, and (b) the various wound stimulatory or
regulatory therapies that are evolving and appearing on the market. All of this needs to be done with the goals
of increasing healing rates and accelerating times to closure. |
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While our
summary has been made, this presentation will end on the soapbox, with a
reprise of an “Editorial about modern wound practice.” 1 Chronic and
pathological wounds (CAP wounds) represent a distinctive class of disease and
clinical activity. 2 There is a
non-expert misunderstanding of wounds that focuses only on trauma and the several
classic wound types. 3 Legitimate
practitioners of this specialty must have the professional knowledge required
to master these diseases, starting with relevant pathologies and clinical
skills. 4 What are
dismissed as "atypical wounds" are not atypical at all. They are the core of chronic and
pathological wounds, far more abundant and significant than most perceive. |
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Addendum In the original presentation given on September 26, 2009, I
threw in an extra slide at the last minute to illustrate how TYPICAL these
wounds are (slide 95 below). This was
a new patient seen for the first time just 2 days before the presentation, so
it seemed timely, to show how just how ordinary and common these cases can be
when you see lots of wound patients. I
decided to throw in this addendum to follow up and to emphasize with some
graphical drama a few of the main points. |
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As we have seen, auto-immunopathic states disorganize the wound
module and break wound healing. This
results in prolonged healing times compared to other wound diagnoses which
are extrinsic to the wound healing process.
What does broken wound healing look like? That is, what does it look like when it is
REALLY genuinely broken? On this and
the next slide, you will see 5 patients in whom wound healing is busted to
the point that the mesenchymal components of the wound module simply do not
exist to any meaningful or recognizable degree. Left top: the thigh in a patient with acute lupus
(see slide 33). The skin necrosis is
more thrombo-infarctive in nature, rather than inflammatory-lytic, and she
had hypercoagulable markers along with the immune markers, meaning that both
pathologies are present. Note the
appearance of the femoral fascia.
Fascia fibers and subcutaneous adipose are still visible weeks after
these wound occurred, with only the slightest hint of a pink blush to
indicate some abortive angiogenesis. Left bottom: the ankle in a patient with chronic
overlooked rheumatoid (see slides 26 and 33).
This wound had been present several years, and there is essential zero
wound proliferation – you are looking at native anatomy as though the tissues
had been excised just yesterday. Right: the dorsal foot in a patient with
rheumatoid (see slide 31). Over an
interval of a few weeks of basic care, areolar fascias and tendon sheaths are
still visible, with no wound proliferation over them. |
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Here are two more patients with auto-immunopathic diseases and
ulcers in whom wound healing is broken and a wound module has failed to
appear. Left: the buttock in a
woman with rheumatoid, 6 months following some injury or ulcerative
event. While there is a pale pink
blush of angiogenesis, all of the fat lobules of the subcutaneous adipose
maintain their native anatomy, texture, and mechanics as though the wound had
been created just 3 or 4 days ago in a normal person. Right: the leg in a woman with severe polymyositis
following minor household trauma (bumping into a bed frame). We have all seen wounds like this, but they
are usually acute. If the injury had
occurred just a week ago, and if care had been neglected, and she then showed
up in the emergency room, nobody would be surprised that an otherwise normal
injury and wound looks this way under those circumstances. However, this wound did have basic hygienic
care, and it occurred 4 months ago.
Wound module events are so impaired that even eschar is not fully
separated yet. |
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Now that we have seen a few cases of broken wound healing in
immunopathic (and/or coagulopathic) patients, let us look at a few cases
showing the microscopic anatomy of what is happening. Left: a wound from a 35 year old man with a
primary hypercoagulable disorder, with multiple coagulopathic markers,
various immune markers, severe venous disease, and femoro-tibial
arteriosclerosis. He had a large leg
wound that was refractory to years of topical care, compression, and
operative revascularization. The
vascular locus is peppered with plasma cells and lymphocytes, i.e. chronic
inflammation, the key event that seems to disrupt proper proliferation and
self-organization of the new stromal elements. Right: refractory leg ulcers in a 53 year old man
with rheumatoid. The tissues are dense
with plasma cells, vessels and angiocytes are failing to coalesce and
stabilize, and there is stasis and leukocyte trapping within the
vessels. All three dynamical
populations are here: acute
inflammation, chronic inflammation, and wound module, and not one of them is
behaving the way a healthy wound behaves. |
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These two images come from the same subject, a man
with rheumatoid and leg ulcers.
Left: the close up shows numerous plasma cells
intermixed with the angiocytes and fibroblasts of the developing (or not
developing) stroma. Right: the broader view shows that these
activities predominate in the vascular locus, leading to disorganized and
non-coalescent vessels. |
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Left: A patient with hypercoagulopathic and
immune markers. The hypercoagulopathy
was considered to be the primary state.
This is from the patient shown on slide 97. There is chronic thrombosis and
reorganization seen on this specimen, with vascular stasis and
hemorrhage. The vascular locus is
filled with plasma cells and eosinophils.
Right: another chronic leg ulcer in a
hypercoagulable patient. Here, the
vascular locus is filled with lymphocytes. |
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This is from a scalp wound in a patient with a chronic radiation
ulcer. We think we understand the
pathophysiology of radiation wounds fairly well. Photonic energy damages DNA and nuclear
machinery, by design. Cell kill is
latent, and becomes manifest during attempted mitosis. Highly proliferative dividing cells such as
cancers die quickly. Cells which have
no normal need to divide, such as mature stromal cells, can carry on
vegetative functions and survive.
However, when such cells are asked to divide, such as for wound
healing, the process dies with the cells.
Radiation injury is another example of where the intrinsic machinery
of healing is broken (although radiation wounds are just a tiny fraction of
all chronic wounds). However, a slide like this suggests that the problem may be more
complex. Radiation may be the primary
event that causes the wound and invokes acute inflammation, just like
hypercoagulable microthrombosis does, but once the wound becomes chronic,
then the same events occur that sensitize or immunize the patient to the stroma. Since the leukocytes and lymphoid cells are
marrow-derived and blood-borne, they have not been impaired by the
radiation. Left: plasma cells in the
vascular locus. They surround a
vessel, which while of fascinating morphology, is nonetheless strange and
presumably not entirely healthy. Right: another area of the wound, looking like a
rock concert for plasmacytes.
Something in this chronic wound has provoked the body to make
immunoglobulins against its own stroma. |
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Left: from a chronic sacral pressure ulcer. Pressure ulcers are due to a trauma. The cause of the wound is strictly
extrinsic to the wound healing process, and such wounds are expected to have
normal wound healing kinetics as long as pressure and other adverse mechanics
and contact conditions are relieved. This
is generally true, but there is also nothing unusual about a chronic pressure
ulcer that seems to defy these expectations, acting impaired and difficult to
heal even after topical conditions are completely relieved. These patients obviously have globally
normal wound healing, and you can do surgery elsewhere on their bodies
without problems, but the primary wounds seem to be misbehaved. The key element in this adverse
transformation to an impaired wound may just be the state of chronicity
itself, giving the wound a chance to develop some degree of
lymphocyte-mediated auto-sensitization and disruption of the dynamical
integrity of the wound module. This
specimen is from the angio-attraction and angio-organization aminoglycan
strata of the wound, and it would appear fairly normal except for one thing –
the intense plasma cell infiltration along the vascular locus and elsewhere
where angiocytes are streaming. Right: a chronic leg ulcer from a woman with
rheumatoid. In the center, there is
intense lymphocyte infiltration in the vascular locus. The vessels are disorganized, with chronic
thrombosis and reorganization, implying that microthrombosis, either primary
or secondary, is a key component of the process. At right center are areas of non-lymphoid non-vascular
cells lining up or chained together.
This morphology may well be strictly coincidental or random, but it is
somewhat suggestive of the palisading seen in rheumatoid nodules, implying
that chronic cell degradation with macrophage-histiocyte cleanup is going
on. If real and not artifactual, then
we are seeing an example of intense lymphoid and macrophage admixture,
presumably a key step in the process of auto-immunization and the
transformation from acute to chronic wound status. |
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These two images come from the same wound, a leg ulcer in a 31
year old woman with a primary coagulopathic disorder and secondary
immunopathy. This is the subject from
slide 74. Left: A close view shows
the angio-attraction zone with numerous streaming angiocytes. There is little evidence of
angio-organization, in part because this view may be too high or superficial
in the wound, but in part because of the diffuse admixture with plasma cells. These cells presumably are attacking or
degrading something in the local matrix or cell set, preventing proper wound
module dynamics and self-organization.
Of interest are the large macrophages with ingested red cells. Loose erythrocytes, i.e. “hemorrhage” are
normal and expected in this stratum, because organizing uncoalesced vessels
are still quite open and leaky. In
healthy wounds, a lot of this degrades and disappears. However, in some wounds macrophages
sequester the erythrocytes, degrade them within, and then they remain in situ
as long term hemosiderin staining.
This is typical of venous ulcers and various others, and it should be
no surprise after looking at the intense vascular stasis and congestion seen
on slide 74. Whether this is relevant
to the issue of chronicity and auto-sensitization is unclear, but it does
reveal that macrophage activity is significant in this wound, and may be part
of the long term immune recognition and sensitization that has obviously
taken place, as evidenced by the plasmacytes.
Right: a wider view from a somewhat deeper zone in
the same wound. Cylindrical vascular
structures have formed, the largest one conducting blood, but they are poorly
organized, and overall expected wound architecture is disorganized and
imprecise. The entire field is infiltrated
with plasma cells and some lymphocytes. |
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This 71 year old man presented just 2 days before this lecture
was given, very timely, since his story, disease, and ulcers are paradigms of
the issues being discussed. He has had
rheumatoid for 20 years, poorly treated.
Ankle ulcers have been present for 2 years. His hands and wrists are a mess. He lives in a perpetual state of arthralgias
and stiffness, and it has become such a way of life for him that he has
forgotten what normal is. The ulcers
have obviously had some sort of basic competent topical care, keeping them
clean, hygienic, and free of gross complications and acute inflammation, but
they have not changed much in 2 years.
Intralesional triamcinolone was given, and the patient was started on
prednisone. This slide was shown at
the meeting to demonstrate an extraordinarily typical “atypical” ulcer,
pathognomonic of ulceration with rheumatoid, lupus, and other classic
connective tissue disorders. This
story continues on slide 96 . . . |
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When the patient was next seen 10 days later, I got one of the
most sincere and emphatic thank you’s I have had in a while. Within those 10 days, pain and symptoms
were eliminated from the wounds, and generalized pain and stiffness were
almost fully abated from his joints.
His wrists went from just a few degrees of motion to about 40-50
degrees combined volar and dorsiflexion.
MP and IP synovitis had subsided dramatically. Other major joint groups had become more
mobile and less painful. The ulcers
already showed improvements. At 3
weeks, the medial ankle ulcers were nearly healed, and the larger lateral
wounds had decreased in measured area by 35%.
This summary is being written at just 4 weeks, so more of the story
and more pictures are yet to unfold.
However, the key message should be clear. Chronic inflammation is a potent inhibitor
or disruptor of the wound module.
Control the inflammation, and wound dynamics should tend toward
normal. |
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This is another timely patient, seen just one month before this
lecture was given. She is a 51 year
old woman with a 5 year history of mixed connective tissue disorder. Scleroderma-crest signs and symptoms are
the most overt, but she has also been designated as lupus, rheumatoid, and
mctd. She has had episodes of large
vein thrombosis in leg and arm, and anticardiolipin antibodies are
confirmed. History also includes
multiple severe drug allergies and anti-drug antibodies. The medial malleolar ulcer resulted from a
minor household injury. It has
persisted as is, inflamed and painful for 7 months without response to
various treatments. Her auto-immune
symptoms are active and have been for the past year. Steroids were the key to successful treatment. The patient reported good control of disease
when she was on methylprednisolone.
However, she was switched to prednisone about a year ago because of
Cushingoid symptoms, which is when disease symptoms became active. The patient is on warfarin already for the
thrombotic history. Note that the appearance
of the ulcer and periwound is inflammatory-lytic, not thrombo-infarctive. Between exam and history, the
immune-inflammatory state is likely to be the predominant pathology. In addition to basic hygienic topical care
and some light compression, the only treatment was an adjustment of her
steroids back to an effective agent and dose.
She was started on methylprednisolone 12 mg daily. As the pictures demonstrate, periwound
inflammation was settled within one week, wound proliferation was evident at
2 weeks, and the wound was nearly healed on latest exam at 1o weeks. All other systemic immunopathy symptoms
have improved. This case reiterates
the message that chronic inflammation and autoimmunopathy are potent
inhibitors or disruptors of the wound module.
Control the inflammation and the underlying disease, and wound
dynamics should tend toward normal. |
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This is the same patient as on slide 91-left, a 25 year old
woman with hypercoagulopathic and immune markers. The hypercoagulopathy was considered to be
the primary state. She presented with
multifocal vascular stasis and skin infarcts and ulcers. The patterns of injury, ulceration, and
diffuse skin changes were predominantly thrombo-infarctive. Histology showed chronic periarteritis, but
no signs of primary leukocytoclastic arteritis or polyarteritis nodosa. For two years, we treated her with warfarin
anticoagulation. This tended to keep
disease quiet, and the various ulcers and skin changes healed at times. However, disease was never completely quiet,
and she would periodically have recurrent events. After two years, disease activity
accelerated. The addition of steroids
was helpful, but not curative. To the
extent that it did help, prednisone doses crept up, but the patient developed
a variety of hyper-cortisolism side effects.
A switch to auto-immune drugs was tried, but azothioprine and others
were ineffective. However, as soon as
the patient was put on cyclophosphamide, the disease was put to sleep, and
she healed. Steroids were withdrawn,
and the process has stayed quiet. Top left (1): The problem at the beginning of the third
year, when disease and ulceration accelerated and became unresponsive to just
anticoagulants. Note the gross
inflammatory signs of dermatitis and panniculitis. Top
right: (2): A few weeks later, the
scene in image 1 is settled a bit with steroids, but not cured. Bottom
left (3): Three months later, the
patient had an intense resurgence of disease with diffuse focal ulceration,
severe pain, and related thrombotic and inflammatory changes in the skin and
lesions. This is when therapy became
more aggressive. Bottom right (4): Seven
months later, a few months into cyclophosphamide therapy, the legs are
completely healed, all inflammatory changes are gone, all thrombo-infarctive
and vascular stasis changes are gone, and general status is improving
including involution of Cushingoid changes. Regardless of what the original primary pathology was, she
ultimately got better only with a potent antimetabolite that is used to
arrest the proliferation of reticuloendothelial and lymphoid cells. This means that in the end the active
pathology and the impaired wound healing were attributable to the chronic
inflammatory state. You saw the
problem on slides 91-left and 68-right, a chronic plasmacytic (lymphoid)
perivasculitis. This was not an acute
or neutrophilic vasculitis as one might ordinarily think about the connective
tissue disorders and the classic arteritides.
This is the chronic
pathological wound in all of its perverse dynamical misbehavior, with chronic
inflammation disrupting the wound module. |
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End |
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Abstract (as submitted in advance of the meeting) (NOT) ATYPICAL ULCERS Marc E. Gottlieb, MD, FACS Phoenix, AZ meg99az@cox.net arimedica.com This is a simple conspectus of the
presentation that will be given. The
final presentation will be posted at the website arimedica.com. You can view the presentation and annotations
there. The main concepts presented are: 1
- Chronic and pathological
wounds (CAP wounds) represent a distinctive class of disease and clinical
activity. 2
- There is a non-expert legacy
understanding-misunderstanding of wounds that focuses only on trauma and a
few standard categories of CAP wounds - arterial, venous, pressure, diabetes. 3
- Legitimate purveyors,
professors, practitioners, and professionals of the specialty of wounds must
understand the professional level of knowledge that appertains to understanding
these diseases. Like all specialties,
that starts with an understanding of the full spectrum of relevant
pathologies. 4
- What are often dismissed as
"atypical wounds" are not atypical at all. In fact, they are the core of chronic and
pathological wounds, and they are far more abundant and significant than
non-experts perceive. 5
- The subject of CAP wounds is
encyclopedic, both in scope and in established knowledge and experience, and
a comprehensive summary will not be made. 6
- Relevant concepts will be
briefly illustrated by two of the most common types of misunderstood,
under-appreciated, and overlooked problem wounds: mechanical ulcers and coagulopathic ulcers. 7
- Relevant concepts will then
be further illustrated by a more detailed review of immunopathic ulcers and
diseases. 8
- The talk culminates in
understanding one crucial concept - that the autoimmune connective tissue
disorders are the true intrinsic diseases of wound healing. 9
- Emphasis will be drawn to the
prevalence and significance of immunopathic ulceration, then to the caveats
and all-too-common poor outcomes attributable to improper diagnosis and
uninformed care of these all-too-typical ulcers. Regarding items #6 & 7,
concerning hematological and immunopathic ulcers, the following key points
will be illustrated and explained: -
Wound and soft tissue pathology is vitally contingent on several core,
highly interconnected, non-linear auto-amplifying combinations of events and
responses: coagulopathy
- immunopathy - angiopathy - panniculopathy injury
- inflammation - thrombosis pathergy
- necrosis - ulceration -
Understanding these chains is crucial to understanding and
anticipating the behavior of the causative diseases and the resulting wounds,
and then to applying effective care. -
Patients presenting with pathological wounds not only have some
aberration of these chains, but they almost invariably have multiple such
abnormalities, e.g. markers of auto-immunopathy almost invariably accompany
the hypercoagulable disorders. Regarding item #8, that the
autoimmune connective tissue disorders are the true intrinsic diseases of
wound healing, the following key points will be illustrated and explained: -
The mesenchymal component of wound healing has just two intrinsic
proliferative cells, angiocytes and fibroblasts, which are likewise the only
two cells which constitute the generalized stroma of the body. -
The connective tissue disorders, aka collagen vascular diseases affect
these cells. Thus the collagen
vascular diseases affect wound healing. -
While this syllogism might seen overly simple, it is not. It is the core paradigm of pathology that
disrupts the functioning of these cells, preventing them from re-establishing
a continuous stroma. -
Key to understanding this relationship is in understanding that the connective
tissue disorders are auto-immunopathic. -
The origins of autoimmunopathy against apocryphal and sequestered
antigens will be explained, as a function of chronic primary inflammation and
micro-thrombosis. -
The subsequent effects of autoimmunopathy on the functioning of the
proliferative wound module can then be understood. -
Immunopathic disorders are a two-edged sword: they both cause ulceration and then impair
subsequent healing. As the true
diseases of wound healing, clinical management is prone to frustrations,
failures, and prolonged healing times. In summary, what naives call
"atypical wounds" are not.
They are common and ordinary, and they constitute the core of chronic
and pathological CAP wounds - they are typical. Among the several interconnected primary
pathologies that cause them, the autoimmune connective tissue disorders are
the important archetype, and they are in fact the true intrinsic diseases of
wound healing. |
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AUTOIMMUNOPATHY
AND CONNECTIVE TISSUE DISORDERS THE TRUE
INTRINSIC DISEASES OF WOUND HEALING Original presentation September 26, 2009, Miami, at the 4th Annual Wound Symposium of Baptist Health South Florida The presentation and related materials are accessible at: arimedica.com Content may be used for non-commercial educational purposes. Content may not be published or used for commercial purposes
without prior license or permission. Contact information is on the slide. Copyright © 2009, Marc E. Gottlieb, MD Revision 10b, November 5,
2009 |
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