Fibrin Cuffs Research Articles

Evaluation of pericapillary fibrin cuffs by confocal microscopy

Evaluation of pericapillary fibrin cuffs by confocal microscopy

Presidential address: Venous disorders—Reflections of the past three decades

Presidential address: Venous disorders—Reflections of the past three decades

Pericapillary fibrin cuffs in venous disease. A reappraisal.

Over the last several years, a number of hypotheses have been proposed to explain the pathogenesis of venous ulceration. According to an early model suggested by Browse and Burnand, pericapillary fibrin cuffs, developing as a result of venous hypertension and extravasation of fibrinogen, act as a barrier to the diffusion of oxygen and nutrients; ultimately, tissue anoxia, cell death, and ulceration would follow. More recent hypotheses include the idea that macromolecules leaking from the vasculature trap growth factors and adhesion molecules, and the notion that white blood cells adhere to and damage endothelial cells in the microcirculation. To review the available evidence for or against a pathogenic role of fibrin cuffs, and hope to provide a useful perspective for this controversial topic. We have reviewed the different hypotheses for venous ulceration and the evidence for and against fibrin cuffs acting as a barrier. Venous ulceration is likely to be the result of a number of distinct pathogenic events. Pericapillary fibrin cuffs remain a prominent feature, whether they act as a barrier, a marker for endothelial cell damage, or as part of an overall mechanism of macromolecular leakage and trapping.

Pathophysiology of venous leg ulceration--an update.

The microcirculatory component of the pathophysiology of venous ulceration is now attracting considerable research interests, but is still far from fully elucidated. Currently, the central role is filled by the inappropriately activated white cell and its interaction with the endothelium. Interstitial oedema, pericapillary fibrin cuff and capillary microthromboses could all fit in with this hypothesis. However, there are other demonstrated changes, for instance in lymphatic drainage, intrinsic fibrinolysis and hemorheological changes which also need to be taken into account. The interaction between the microcirculatory changes is an obvious target for the systemic pharmacotherapy of venous ulceration.

Chronic venous insufficiency: Mechanisms and management

CVI is a common disease with significant morbidity that results from venous hypertension of the extremities. Increased perfusion pressure probably traps excessive numbers of white blood cells in the capillaries. Activated leukocytes subsequently damage capillary endothelium, increase capillary permeability, and cause ischemia of the overlying skin as a result of leakage of fibrinogen and formation of a fibrin cuff. Diagnosis of CVI is not difficult because its clinical manifestations are usually evident. Vascular compression therapy remains the foundation of medical management for CVI. Refractory cases may require a combined medical and operative approach.

Microcirculation in venous disease

Microcirculation in venous disease P. D. Coleridge Smith, Austin, Tex., 1995, RG Landes, 199 pages, $89.95. The aims of this book are to present a comprehensive review of the mechanisms responsible for the development of venous ulceration and the experimental work that indicates that it is a series of inflammatory processes rather than hypoxia that leads to tissue necrosis. An overview of historical aspects and present day beliefs of association between venous hemodynamics, microcirculation, fibrin cuff theory, white blood cell trapping theory, and venous ulceration is presented in chapter 1. Chapter 2 provides a review of theories relating to arteriovenous fistulas as a cause. The experimental work that has been undertaken to investigate the gas diffusion problems produced by the alleged fibrin cuffs and the pitfalls in the interpretation of such data are summarized in chapters 3 and 4. The effects of venous hypertension on the microcirculation and the methods of investigation with capillary microscopy and laser Doppler fluximetry are presented in chapter 5. The phenomenon of white blood cell trapping in the skin microcirculation and the experimental work that demonstrates the mechanism and consequence of neutrophil attraction in response to venous hypertension are dealt with in chapters 7 and 8. The clinical studies demonstrating the effect and efficacy of compression and pharmacologic therapy together with comprehensive review of recent work on the place of antibiotics, zinc, diuretics, hydroxyratosides, fibrinolytic therapy, prostacycline, pentoxifylline, and combined (compression plus pharmacotherapy) therapy are the subject of chapters 9 and 10. This is a much-needed book that fills a gap in a field of recent rapid developments. These developments and the detail of the experimental work presented form an excellent guide for the clinician who wants to be up-to-date and those who want to embark on further research in this field.

Relation between aetiology and treatment of leg ulcers

The author's leg ulcer unit has been involved in compression methods for 45 years1. During this time views expressed by its clinicians on compression and its relevance to the aetiology of ulceration have developed in parallel. This differs from the situation in other centres, where the cause of such lesions has so far been examined in detail only in the ulcerated leg itself. The situation found in such limbs includes ‘venostasis’, leg oedema, arteriovenous shunts, free radicals, pericapillary fibrin cuffs, micro-oedema, and vessel plugging by leucocytes and microthrombi. By contrast the author's unit has approached the problem from the perspective of the normal limb. The physiological vulnerability of any limb has been used as a model for the vulnerability of the varicose limb. A compression treatment regimen counteracts two simple gross determinants of ulceration; first, the pressure amplitude changes during exercise and, second, the pressure gradient. This broad conceptual approach has allowed the identification of important relationships which have long since been buried beneath the wealth of what the author believes to be a secondary phenomenon recorded in the literature.

Anticardiolipin antibodies and ulcerations of the leg.

ACA appeared to be significantly associated with venous ulcerations of the leg but not with ulcerations associated with isolated arteritis. None of the patients had typical signs of APS. As for the relation between ACA and venous ulcerations, several hypotheses can be proposed. First, the causes of arteritis-associated and venous ulcers are clearly different; t he former is most frequently related to atherosclerosis.S 8 Venous ulcers have been reported to develop as a consequence of fibrin cuff formation or leukocyte trapping.?' 10 In the first model decreased fibrinolytic activity favors the formation of pericapillary fibrin cuffs impairing the diffusion of oxygen and nutrients. Although ACA could lead to anomalies of the coagulation cascade, a direct role ofsuch antibodies and their appearance as a consequence of the vascular alterations induced by cuff formation seem unlikely in this model. The formation of ACA could more likely be triggered in the leukocyte trapping model. This hypothesis sugThe leg ulcers described in the antiphospholipid syndrome (APS)!' 2 mimic pyoderma gangrenosum or appear as superficial ulcerations surrounded by a purple halo.3, 4 These painful, treatment-resistant lesions occur mostly in young patients with systemic lupus erythematosus. Clinically different types of ulcerations of the leg occur commonly in elderly patients with no clinical or biologic signs of systemic lupus erythematosus.l

Venous hypertension of the hand caused by hemodialysis shunt: immunofluorescence studies of pericapillary cuffs.

Venous hypertension of the hand is an unusual complication of an arteriovenous shunt in patients receiving dialysis. We investigated whether in venous hypertension of the hand pericapillary cuffs are present and whether they consist of fibrin and other components. Biopsy specimens were taken from three patients with a side-to-side shunt and venous hypertension of the hand, from three patients with an end-to-side shunt without venous hypertension, and from three control subjects. The specimens were stained with antibodies against fibrinogen, fibrin, plasminogen activator inhibitor-I, factor VIII-related antigen, and collagen type IV. Pericapillary cuffs consisting of fibrin only were observed in patients with venous hypertension of the hand. In this fibrin network, factor VIII-related antigen and collagen type IV were also present. The finding of plasminogen activator inhibitor-I in the pericapillary cuff in the patient with the most severe signs of venous hypertension may indicate that breakdown of this fibrin cuff is impaired. Pericapillary cuffs may be of pathogenetic significance in venous hypertension of the hand.

Proteolytic enzymes in wound healing: the role of enzymatic debridement.

Proteolytic enzymes are a family of proteins that serve to degrade necrotic debris derived from cell breakdown. They are produced endogenously often as precursor proteins whose activation is precisely regulated. These activated enzymes serve many functions in normal as well as pathological situations. In particular they are involved in the regulation of cell maturation and multiplication; collagen synthesis and turnover; the development and removal of the perivascular fibrin cuffs found in venous insufficiency and leg ulceration as well as the removal of dead tissues following inflammation. As a limited number of enzymes perform all these functions, it is difficult to predict the effects of applying synthetic proteolytic enzymes to a wound. Many such enzymes are currently commercially available and being promoted as alternatives to surgical wound debridement. It is important for their use to be considered in the context of their interaction with endogenous proteases, their physiological role in tissue, their ability to reach a desired target and the stage of wound healing at the time they are applied.

Overview of wound healing in a moist environment

Maintaining a moist wound environment facilitates the wound-healing process. The beneficial effects of a moist versus a dry wound environment include: prevention of tissue dehydration and cell death, accelerated angiogenesis, increased breakdown of dead tissue and fibrin, i.e., pericapillary fibrin cuffs, and potentiating the interaction of growth factors with their target cells. In addition, pain is significantly reduced when wounds are covered with an occlusive dressing. Concerns that moisture in wounds would increase the risk of clinical infection over traditional therapies are unfounded. The use of hydrocolloid occlusive dressings in maintaining a moist wound environment has proved to be a useful adjunct in facilitating wound healing.

Etiology of venous ulceration.

The etiology of venous ulceration is far more complex than Homans' theory of stagnation and hypo-oxygenation. Indeed, studies have shown that flow in lipodermatosclerotic limbs is actually faster than normal. We suggest, therefore, that the terms "stasis dermatitis" and "stasis ulcer" be dropped from medical parlance. The term "lipodermatosclerosis with ulceration" as used by the British, or simply "venous ulcer," would seem more appropriate. Venous hypertension, produced by incompetence of deep and communicating vein valves and thrombosis of segments of the deep system, is closely correlated with the development of venous ulcers. Precisely how this venous hypertension translates into ulceration is unclear. Burnand et al showed that fibrin cuffs are deposited around the capillaries in lipodermatosclerotic limbs. These cuffs may serve as barriers to the diffusion of oxygen, leading to local ischemia and epidermal necrosis. Others suggest that trapped leukocytes in the microcirculation alter capillary permeability by releasing various inflammatory mediators that hasten the flow of fibrinogen across the capillary membrane and promote the formation of fibrin cuffs. Proof of this hypothesis is still lacking, but may eventually come from using radioactive WBC tagging procedures. A synthesis of these two theories may in fact explain the etiology of venous ulceration.

Leg ulceration in venous disease

We have given a brief summary of the scale of the problem caused by venous ulceration in the UK, and have then reviewed the various theories of causation, including a historical survey, and presented the evidence for and against the two main current theories of fibrin cuffs and white cell trapping. We also outline previous hypotheses of the aetiology of venous ulceration, including arteriovenous microanastomoses, stasis and oedema. The contribution of superficial venous incompetence in the pathogenesis of ulceration is also examined.

Pericapillary fibrin cuffs in venous ulceration. Persistence with treatment and during ulcer healing.

A recent hypothesis suggests that venous hypertension leads to ulceration through the formation of pericapillary fibrin cuffs, which are presumed to impede the exchange of oxygen and other nutrients. In this report, we evaluated by direct immunofluorescence the presence of pericapillary fibrin at the edge of venous ulcers during the course of treatment with elastic compression. In an initial group of 23 patients studied at baseline, pericapillary fibrin cuffs were detected in 20 (91%) of 22 patients. The intensity of fibrin staining, rated blindly on a scale of 0 to 3, could not be correlated with several baseline parameters, including the clinical presence and extent of lipodermatosclerosis, ulcer size, venous recovery time, and transcutaneous oxygen measurements (TcPO2) taken next to the ulcer. Eleven of this initial group of 23 patients were randomly selected to receive elastic compression treatment, and were evaluated for the persistence of pericapillary fibrin at 60 and 120 days. Although a reduction (mean +/- SD = 50.2% +/- 25.7) in ulcer size occurred in 10 of the 11 patients, pericapillary fibrin was still present at the ulcer edge and with undiminished intensity. We conclude that pericapillary fibrin cuffs in venous ulcers persist with compression treatment and in spite of healing, and are unlikely to be directly related to the development of ulceration.

The Efficacy of Fibrinolytic Enhancement with Stanozolol in the Treatment of Venous Insufficiency

Pericapillary fibrin cuffs have been demonstrated in patients with chronic venous insufficiency. It has been suggested that this fibrin deposition is responsible for an oxygen diffusion block, leading to local hypoxia and resulting in ulceration. Fibrinolysis is depressed in patients with venous insufficiency and therefore pharmacological enhancement of this factor might be expected to produce clinical improvement. A total of 60 patients with lipodermatosclerosis were entered into a prospective, double-blind, placebo-controlled, randomized trial. Stanozolol 5 mg or a placebo tablet was given twice daily for a period of 6 months. All patients were supplied with below knee German/Swiss specification class 2 compression stockings. The area of lipodermatosclerosis was measured at monthly intervals and transcutaneous oxygen tension within the liposclerotic area was measured at 3-monthly intervals. The control group showed a mean reduction in area of lipodermatosclerosis of 14% (95% confidence interval −2.6%−31%) compared with a 28% reduction in area in the active treatment group (95% confidence interval 5.3%–46%; P < 0.007). Transcutaneous oxygen measurements showed no change in either group. Side-effects were significantly more common in the active treatment group ( P < 0.002 χ2). Though fibrinolytic enhancement caused a reduction in the area of lipodermatosclerosis, no evidence of any effect on a possible oxygen diffusion block was demonstrated.

Detection of undegraded fibrin and tumor necrosis factor-α in venous leg ulcers

The pathogenesis of venous leg ulcers is based on the leakage of fibrinogen leading to pericapillary fibrin cuff and plugging of capillaries by white blood cells. Eight patients with venous leg ulcers have been studied with a panel of antibodies reactive for fibrinogen, fibrin, fibrin degradation products, and various cell-associated markers for polymorphonuclear cells, monocytes, and B and T lymphocytes. Our results showed that pericapillary fibrin cuff was mainly composed of undegraded fibrin and that, in the granulation tissue, tumor necrosis factor-alpha and elastase activities were detectable in monocytes and polymorphonuclear cells, respectively. Only few activated lymphocytes were present. On the basis of these results, it is assumed that inflammation generated by activated white blood cells that accumulate under unrelieved pressure is the key event. Tumor necrosis factor-alpha synthesized by activated monocytes may therefore induce the formation of pericapillary fibrin cuffs. Pericapillary fibrin cuffs and toxic metabolites released by polymorphonuclear cells may explain the absence of wound repair.

Heterogeneity in Oxygen Diffusion Around Venous Ulcers

The pathogenesis of venous ulceration is thought to involve the formation of fibrin cuffs around dermal capillaries. Consistent with a barrier effect of fibrin, it has been shown that the dermal diffusion of oxygen, as measured by transcutaneous oxygen pressure (TcPO2), is decreased in limbs affected by venous ulcer. However, it is unknown whether oxygen diffusion around the perimeter of venous ulcers is uniformly affected. In this study, we investigated TcPO2 values at four different quadrants around the ulcers of 14 patients, the contralateral leg of five patients with unilateral ulcers, and the leg of six normal individuals. These values were also compared to TcPO2 measurements at the chest. Our results indicate that, whereas TcPO2 values in limbs affected by venous ulcers are much lower than normal, there is a great deal of variability in oxygen diffusion around individual ulcers. These findings may represent a heterogeneity in the disease process affecting the leg.

EFFICACY OF FIBRINOLYTlC ENHANCEMENT WITH STANOZOLOL IN THE TREATMENT OF VENOUS INSUFFICIENCY

Pericapillary fibrin cuffs have been shown in patients with chronic venous insufficiency. It has been suggested that this fibrin deposition is responsible for an oxygen diffusion block, leading to local hypoxia and resulting in ulceration. Fibrinolysis is depressed in patients with venous insufficiency and therefore pharmacological enhancement of this factor might be expected to produce clinical improvement in this condition. Sixty patients with lipodermatoscelerosis were entered into a prospective, double-blind, placebo-controlled, randomized trial. Stanozolol 5 mg or a placebo tablet was given twice daily for 6 months. All patients were supplied with below knee German/Swiss specification class 2 graduated compression stockings. The area of lipodermatosclerosis was measured at monthly intervals and transcutaneous oxygen tension within the liposclerotic area was measured at 3-monthly intervals. The control group showed a mean reduction in area of lipodermatosclerosis of 14% (95% c.i.: -2.6-31%) compared with a 28% reduction in area in the active treatment group (95% c.i.: 5.3-46%). Transcutaneous oxygen measurements showed no change in either group. Side effects were significantly more common in the active treatment group (P less than 0.02, Chi-squared). Although fibrinolytic enhancement caused a reduction in area of lipodermatosclerosis, no evidence of any effect on a possible oxygen diffusion block was indicated.

Pericapillary fibrin cuff: a histological sign of venous leg ulceration

The incidence of pericapillary fibrin cuffs was investigated in 49 biopsies of venous leg ulcers and 67 biopsies of leg ulcers of non-venous etiology. Pericapillary fibrin cuffs were seen in 28 biopsies (57.1%) of venous leg ulcers, but only in 11 biopsies (16.4%) of non-venous leg ulcers. In the venous leg ulcers pericapillary fibrin cuffs occurred predominantly near the ulcer surface and around dilated capillaries. Dilation of the capillaries and inflammation probably contribute more to the pathogenesis of pericapillary fibrin cuffs than venous hypertension.

Tissue Oxygenation, Venous Ulcers and Fibrin Cuffs

Skin oxygen tension (TcPO2) was measured at 43 degrees C on patients (n = 27) with venous ulcers. Measurements were made at ulcer edge and proximally on the same limb for control. Similar measurements were also made on healthy volunteers (n = 14) in the medial aspects of the distal third of the legs. TcPO2 at ulcer edge was significantly lower (P = 0.001) than control values which in turn were lower than that measured on healthy volunteers. TcPO2 reflects skin nutrition. While low TcPO2 at ulcer edges might be the result of pericapillary barriers to oxygen transport, the control values measured on apparently normal skin suggest the need for further studies.