The occurrence of pericapillary fibrin in venous hypertension and ischaemic leg ulcers: a histopathological study

The presence of pericapillary fibrin and complement C3c in the ulcers of 19 patients with venous hypertension and 14 patients with ischaemic leg ulcers was investigated using histochemical and immunohistochemical techniques. There was deposition of fibrin around the capillaries in the central part of the ischaemic ulcers, and the venous hypertension ulcers, and in the non-ulcerated skin around one of the venous hypertension ulcers and two of the ischaemic leg ulcers. The deposition of fibrin is a secondary phenomenon that occurs in the area of ulcerated skin and does not play a major causal role in the formation of chronic leg ulcers.     

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.     

Fibrin- and fibrinogen-related antigens in patients with venous disease and venous ulceration

Abnormalities in systemic fibrinolysis have been implicated in the pathogenesis of venous ulceration. Patients with venous disease have a prolonged euglobulin lysis time and elevated plasma fibrinogen levels, yet little is known about the metabolism of fibrinogen and fibrin in such patients. In this study, we have used a technique that involves electrophoresis and densitometric analysis of captured fibrin-related antigens to measure the concentration and proportions of the individual fibrin and fibrinogen degradation products in patients with venous disease of the lower extremity. As a group, patients with venous disease had markedly elevated levels of total fibrin-related antigen and D-dimer, the terminal degradation product of cross-linked fibrin. Levels of D-monomer, the breakdown product of fibrinogen and non-cross-linked fibrin monomer, and a measure of fibrinogenolysis were normal in all patients. In patients with ulcers, the levels of D-dimer were disproportionately higher than expected from fibrin monomer levels. On an individual basis, significant elevations of D-dimer were present in six (55%) of the 11 patients with venous disease with ulcers and in three (43%) of the seven patients with venous disease without ulcers. We conclude that patients with venous disease have uniform evidence for enhanced fibrin formation, as evidenced by elevated levels of total fibrin-related antigen and D-dimer. This is regardless of whether the venous disease is accompanied by ulceration.     

Chronic venous insufficiency and venous leg ulceration

Venous ulcers are the most common form of leg ulcers. Venous disease has a significant impact on quality of life and work productivity. In addition, the costs associated with the long-term care of these chronic wounds are substantial. Although the exact pathogenic steps leading from venous hypertension to venous ulceration remain unclear, several hypotheses have been developed to explain the development of venous ulceration. A better understanding of the current pathophysiology of venous ulceration has led to the development of new approaches in its management. New types of wound dressings, topical and systemic therapeutic agents, surgical modalities, bioengineered tissue, matrix materials, and growth factors are all novel therapeutic options that may be used in addition to the "gold standard," compression therapy, for venous ulcers. This review discusses current aspects of the epidemiology, pathophysiology, clinical presentation, diagnostic assessment, and current therapeutic options for chronic venous insufficiency and venous ulceration. (J Am Acad Dermatol 2001;44:401-21.) Learning objective: At the conclusion of this learning activity, participants should be familiar with the 3 main types of lower extremity ulcers and should improve their understanding of the epidemiology, pathogenesis, risk factors, clinical presentation, diagnostic assessment, and current therapies for chronic venous insufficiency and venous ulcers.     

Hyperaemic hypoxia in venous ulceration

Books reviewed in this article:
Allergic Contact Dermatitis to Ingredients used in Topically Applied Pharmaceutical Products and Cosmetics . A D ooms -G oossens .
The Year Book of Dermatology . Edited by A.J. S ober and T.B. F itzpatrick .
Cosmetic Dermatologic Surgery . S.J. S tegman and T.A. T romovitch .
Dermatologia Vascolare . V.P etruzzellis and A. S cardigno .
Current Issues in Dermatology , Volume 1. Edited by J.P. C allen , M.V. D ahl , L.E. G olitz , J.E. R asmussen and S.J. S tegman .
Hair Root Characteristics of the Human Scalp in Health and Disease . J.D.R. P eere B oom -W ynia .     

Lupus anticoagulant and venous leg ulceration

BACKGROUND: Most leg ulcers occur in patients with venous insufficiency. However, not all patients with venous insufficiency develop leg ulcers. Recent studies have found that factors causing clotting abnormalities, e.g. anticardiolipin antibody (ACA), are associated with leg ulcers. Although lupus anticoagulant, like ACA, belongs to the group of antiphospholipid antibodies, its presence in patients with venous leg ulceration has not been previously reported. OBJECTIVES: To determine the presence of lupus anticoagulant in patients with venous leg ulceration. METHODS: We investigated the presence of lupus anticoagulant in 27 patients with venous leg ulcers and compared these data with controls. Lupus anticoagulant was evaluated in all subjects by the Russell's viper venom test. RESULTS: Of 27 patients with venous leg ulceration, 16 (59%) were shown to have lupus anticoagulant, while only one of 32 controls (3%) was found to have lupus anticoagulant. Thus, lupus anticoagulant was significantly more frequent in patients with venous leg ulcers than in controls (P < 0.001). CONCLUSIONS: We suggest that lupus anticoagulant could be a hitherto unknown factor contributing to the development of venous leg ulcers.     

Matrix metalloproteinases and venous leg ulceration

Metalloproteinase-mediated proteolysis plays an important role during the phase of venous ulcer formation and wound repair. Venous ulcers manifest as a breakdown of the collagenous stromal tissue and are highly associated to chronic venous insufficiency. A major change in our understanding of the pathogenesis of venous ulcers occurred with the demonstration of extracellular matrix-degrading activity of matrix metalloproteinases to generate a dermal-epidermal skin defect. These proteases were intensely investigated in preceding stages and during wound repair of venous ulcerations. Different studies have revealed their significance in the process of proteolytic remodeling and recognized their potential importance in finding therapeutic rationales to manage late complications of chronic venous ulcers.     

Direct triggers for ulceration in patients with venous insufficiency

BACKGROUND: More than 80% of leg ulcers are caused by venous insufficiency. The actual causes of venous ulcers, beyond the presence of venous insufficiency, are rarely referred to in the literature. This study evaluates the direct triggers for ulceration in patients with venous insufficiency. METHODS: Sixty-four patients with 110 chronic venous ulcers, treated in the Chronic Wounds Clinic of Soroka University Medical Center from 1999 through 2002, were included in the study. In each patient, the actual trigger of ulceration was determined by history taking and reviewing of the medical chart. RESULTS: The actual triggers of ulceration, based on data for 64 patients with an overall total of 110 ulcers, were identified as follows: cellulitis (or erysipelas), 17 ulcers (15.4% of 110 ulcers); penetrating injury, 13 ulcers (11.8%); contact dermatitis, 12 ulcers (10.9%); rapidly aggravating leg edema, 12 ulcers (10.9%); burn wound, seven ulcers (6.3%); dry skin with subsequent scratching, six ulcers (5.4%); blunt trauma, five ulcers (4.5%); deliberately self-inflicted trauma, five ulcers (4.5%); insect bite, two ulcers (1.8%); bleeding from a supeficial varicose vein, two ulcers (1.8%). In 29 ulcers (26.3%) no specific trigger was identified. CONCLUSIONS: The development of a cutaneous ulcer is not necessarily "spontaneous" and should not be attributed solely to the presence of venous insufficiency. In many cases, it is possible to identify a specific trigger that causes the ulceration. Clinical implementation of the above findings in routine examination and treatment of patients with venous insufficiency may prevent the development of venous ulcers.     

Dermal mucinosis as a sign of venous insufficiency

Dermal mucinoses are a heterogeneous group of disorders characterized by abnormal deposition of dermal mucin, an amorphous substance composed of hyaluronic acid and sulfated glycosaminoglycans. We describe two cases of dermal mucinosis in the setting of chronic venous insufficiency. Both patients presented with painful, edematous lower extremity plaques. Biopsies of all lesions showed striking dermal mucin deposition, a slight increase in small blood vessel density, slightly thickened vessel walls and no inflammation. Neither patient showed laboratory or clinical findings consistent with a secondary mucinosis such as thyroid dysfunction, lupus erythematosus, dermatomyositis, scleroderma, granuloma annulare, graft‐vs.‐host disease or mucin deposition post‐ultraviolet or photochemotherapy treatment. Both patients were diagnosed with localized cutaneous mucinosis secondary to venous insufficiency. The clinicopathological features of this entity are described, and a pathogenic mechanism is proposed. Pugashetti R, Zedek DC, Seiverling EV, Rajendran P. Berger T. Dermal mucinosis as a sign of venous insufficiency.     

Age-related rather than ulcer-related impairment of venous function tests in patients with venous ulceration

Various noninvasive tests of venous function and skin oxygenation were studied in 12 patients with unilateral venous ulcer and in 24 control subjects. In the ulcer patients, there was no difference between the leg with and the leg without ulcer regarding all the tests studied. Except for the maximal venous outflow, the patients and their age- and sex-matched controls did not differ with regard to all parameters studied. In contrast to these findings, ageing was associated with a reduction in maximum venous outflow, a shortening in venous filling time, an increase in venous pressure in the posterior tibial vein and a diminution of transcutaneous partial oxygen pressure.     

Dermal oedema assessed by high frequency ultrasound in venous leg ulcers

Oedema is considered a key pathogenic factor in the development of venous leg ulcers. The purpose of this study was to determine the localization of oedema in legs with ulcers. Twelve patients with 13 venous leg ulcers (one bilateral), with a duration of 7–18 months, were examined by high-frequency B-mode ultrasound scanner. This was performed at three sites in the leg (low, middle and upper sites of the lower leg). In the same group of patients, the legs without ulcers were used as controls. The echogenicity and the thickness of the whole dermis were quantified by digital image analysis; the echogenicities of the upper (papillary) and lower portions of the dermis were measured. In the upper site no significant difference was found between the legs with ulcers and controls. In the middle and low sites of legs with ulcers, the dermal echogenicities were 34% and 64% ( P  < 0.01) less than those in controls, and the dermal thicknesses were 0.4 mm and 0.8 mm ( P  < 0.01) thicker than those in controls, respectively. This indicated intradermal oedema existing in the lower part (gaiter area) of the legs with ulcers. The ratios of low echogenic pixels in the upper and lower portions of the dermis, in the middle and low sites of legs with ulcers, were 0.5 and 0.9 ( P  < 0.05 and P  < 0.01), respectively, higher than those in controls, suggesting the papillary dermis as a preferential site of oedema formation. The present study demonstrates that in the low sites of legs with ulcers, a marked increase in oedema was seen in the papillary dermis. This may add to the understanding of the origin of leg ulcers in the gaiter area of the leg.     

Extensive calcification of the lower leg complicating venous ulceration

A case is presented of a severe variant of subcutaneous calcification complicating chronic venous ulceration of the lower leg.     

Protein C and protein S plasma levels in patients with lipodermatosclerosis and venous ulceration

Lipodermatosclerosis of the lower extremity, with or without ulceration, is a common manifestation of severe venous disease and the result of sustained venous hypertension. The latter is generally a sequela of deep vein thrombosis. Factors that enhance clot formation or impair fibrinolysis contribute to the pathogenesis of venous disease. It is already established that faulty fibrinolysis may play a pathogenic role in patients with venous disease. We examined the possibility that patients with venous disease have abnormally low plasma levels of proteins C and S, two proteins whose deficiencies have been reported to cause an increased frequency of thromboembolic disease. Using immunologic and functional assays for plasma proteins C and S, we found that 4 (21%) of 19 patients with lipodermatosclerosis and leg ulcers had abnormally low levels of protein C or protein S. One of 7 patients with lipodermatosclerosis without ulceration had a profoundly depressed level of protein C and a history of cerebral stroke at a young age. Plasma levels of protein C were normal in five patients with arterial insufficiency severe enough to cause leg ulceration. We conclude that abnormally low plasma levels of proteins C and S may be found in patients with lipodermatosclerosis and venous ulceration. As with the abnormally low fibrinolytic activity in these patients, our findings indicate a possible propensity for increased thrombotic disease.     

Detection of undegraded fibrin and tumor necrosis factor-alpha 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.