fibrin and Varicose-Ulcer

Topics: Blood Gas Monitoring, Transcutaneous; Edema; Evidence-Based Medicine; Fibrin; Fibrinolysis; Humans; Hypertension; Models, Cardiovascular; Oxygen; Oxygen Consumption; Pulmonary Diffusing Capacity; Risk Factors; Varicose Ulcer

Venous leg ulcers cause patients much distress. Treating them is expensive, with many hidden costs. As understanding of the causes and development of this condition improves, debate over the best treatments or treatment combinations is growing.

Topics: Bandages; Causality; Chronic Disease; Clinical Trials as Topic; Disease Progression; Fibrin; Humans; Leukocytes; Nitric Oxide; Skin Care; Treatment Outcome; Varicose Ulcer; Vascular Surgical Procedures; Wound Healing

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.

Topics: Capillaries; Fibrin; Fibrinogen; Humans; Leg; Leukocytes; Varicose Ulcer; Venous Pressure

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.

Topics: Arteriovenous Fistula; Capillary Permeability; Edema; Fibrin; Humans; Regional Blood Flow; Varicose Ulcer; Venous Insufficiency

Topics: Fibrin; Humans; Varicose Ulcer

We treated a small cohort of venous ulcers that were very unresponsive to standard and advanced therapies with autologous cultured bone marrow-derived mesenchymal stem cells (MSCs). This pilot clinical trial was randomized, controlled, and double-blinded. Subjects were treated with either normal saline (Group A), fibrin spray alone (Group B), or MSCs in fibrin (1 million cells/cm2 of wound bed surface) (Group C). The control and test materials were applied to the wound using a double-barreled syringe with thrombin and fibrinogen (with or without MSCs) in each barrel, or saline alone in both barrels. The MSCs were separated, cultured in vitro, and expanded in a dedicated Good Manufacturing Practice (GMP) facility from 30-50 ml of bone marrow aspirate obtained from the iliac crest in Group C subjects. To ensure that the study remained controlled and blinded, subjects who were randomized to one of the two control arms (saline or fibrin) underwent sham bone marrow aspiration performed by a hematologist who anesthetized the iliac crest area down to and pushing against the periosteum, but without penetrating the bone marrow. Therefore, both the clinician who evaluated wound progress and the study subjects had no knowledge of whether bone aspiration was actually performed and what treatment had been applied to the wound. The study was performed after full FDA investigational new drug (IND) approval. The primary endpoint was the rate of healing (wound closure as linear healing from the wound margins in cm/week), as measured by the Gilman equation. One-way ANOVA was used to calculate the statistical significance of differences between the mean healing rates of each of the 3 treatment groups every 4 weeks and over the 24 weeks of treatment. Overall, treatment with MSCs accelerated the healing rate by about 10-fold compared to those in the saline and fibrin control groups. Although the total number of patients in this pilot study was small (n=11), the statistical significance was surprisingly promising: p<0.01 and f-ratio of 15.9358. No serious adverse events were noted. This small but carefully performed prospective, controlled, randomized, and double-blinded pilot study in a rare population of totally unresponsive patients adds to previous reports showing the promise of MSCs in the treatment of chronic wounds and provides proof of principle for how to approach this type of very demanding clinical and translational research.

Topics: Bone Marrow; Fibrin; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pilot Projects; Prospective Studies; Varicose Ulcer

Objectives Compare the efficacy and safety of fibrin gel to 8% papain gel for wound dressing of venous ulcers. Method Patients with chronic venous ulcers were randomly assigned to one in three groups: Group 1-fibrin gel; Group 2-8% papain gel; Group 3-carbopol gel (control). Patients were seen every 15 days during 2 months, verifying reduction of the ulcer area, local infection, exudation, and epithelization. All serious or nonserious adverse events were recorded. Results Fifty-five patients (total of 63 ulcers) were randomly distributed in three groups (G1 = 21; G2 = 19; G3 = 23). No patient was excluded or discontinued treatment throughout the study. The areas of the ulcers were similarly reduced in all groups (14.3%, 21.1%, and 30.4% in groups 1, 2, and 3, respectively), and all had significant reduction in exudation and contamination. Conclusion The data demonstrate that neither fibrin gel nor papain gel were able to improve the process of ulcer-healing, as compared to control.

Topics: Adult; Aged; Aged, 80 and over; Bandages; Chronic Disease; Double-Blind Method; Elasticity; Female; Fibrin; Gels; Humans; Male; Middle Aged; Papain; Prospective Studies; Treatment Outcome; Varicose Ulcer; Wound Healing

The transplantation of keratinocytes suspended in fibrin carrier represents a candidate regimen for chronic ulcer treatment in an outpatient setting. We evaluated the integration and survival of autologous individualized keratinocytes applied within fibrin matrix onto chronic venous leg ulcers in vivo. Parallel in vitro culture was used to validate keratinocyte survival and apoptosis in fibrin compared to collagen matrix carrier.. Seven patients with chronic venous leg ulcers were transplanted with autologous keratinocytes suspended in fibrin sealant after isolation and expansion from full-skin biopsy. The fibrin carrier was removed in three patients after 7 days, whereas four patients served as control with fibrin remaining. In parallel in vitro cultures, primary keratinocyte movement in fibrin as well as viability in three-dimensional (3D) fibrin versus collagen lattices was examined.. Complete ulcer healing was observed in four of seven ulcers after a mean duration of 14.5 weeks. If the fibrin layer was removed, complete wound healing occurred in three of three patients, compared to one of four in the control group. In vitro, keratinocytes formed a monolayer underneath but remained isolated and nonmobile within the fibrin matrix, suggesting reepithelialization along the lower fibrin interphase. Keratinocyte culture in 3D fibrin at clinically used concentration (90 mg/mL) caused high levels of apoptosis, similar to 3D collagen, which was prevented by diluting fibrin concentration to 3 mg/mL.. Transplantation of autologous keratinocytes suspended in fibrin is efficient in the treatment of chronic venous leg ulcers. Due to an antimigratory and survival-compromising effect, the presently used fibrin carrier should be removed after a few days of transplantation.

Topics: Aged; Aged, 80 and over; Apoptosis; Cell Survival; Collagen; Female; Fibrin; Humans; Keratinocytes; Male; Middle Aged; Prospective Studies; Transplantation, Autologous; Varicose Ulcer; Wound Healing

Increasing evidence suggests that fibrin deposition is an important pathogenic component of venous ulceration and that fibrin removal could accelerate ulcer healing.. We sought to determine whether topical application of recombinant tissue plasminogen activator (tPA) compounded in 1% hyaluronate acid (HA) can be used safely in venous ulcers and whether it can accelerate healing.. Twelve patients were randomized in a double-blind fashion in three sequential groups of four subjects each, so as to receive daily topical application of either placebo (HA alone, one patient) or tPA/HA (three patients) at escalating doses of 0.25, 0.5, and 1.0 mg/ml of tPA for 4 weeks.. No safety problems occurred, and we found a close direct correlation between mean ulcer reepithelialization, fibrin removal, and the dose of topically applied tPA (r = 0.991).. In this first study to examine its usefulness, topically applied tPA appears to be a safe and promising agent for treating venous ulcers.

Topics: Administration, Cutaneous; Double-Blind Method; Epithelium; Feasibility Studies; Fibrin; Follow-Up Studies; Humans; Hyaluronic Acid; Pharmaceutical Vehicles; Pilot Projects; Placebos; Plasminogen Activators; Recombinant Proteins; Safety; Skin; Tissue Plasminogen Activator; Varicose Ulcer; Wound Healing

The pathogenesis of venous leg ulcers is based on the leakage of fibrinogen leading to a pericapillary fibrin cuff and plugging of capillaries by white blood cells. On the basis of a previous work, we had assumed that the key event in the pathogenesis of venous leg ulcers is related to inflammation generated by activated white blood cells that accumulate under unrelieved blood pressure, because in ulcer biopsies we had detected the presence of tumor necrosis factor-alpha (TNF-alpha) in intracapillary monocytes, elastase in the polymorphonuclear leukocytes near the vessels, and a pericapillary undegraded fibrin cuff causing a diffusion barrier to oxygen. This concept was developed because TNF-alpha synthesized by activated monocytes is responsible for many deleterious effects. It has a potent mitogenic effect on fibroblasts, leading to new collagen deposition and angiogenesis, it induces an increase in collagenase production, it acts through upregulation of an intracellular adhesion molecule (ICAM-1), leading to leukocyte sequestration and consequently a release of toxic metabolites by the polymorphonuclear cells, an early step in chronic inflammation, it activates the coagulation pathway via a marked increase in monocyte-associated tissue factor (TF) procoagulant activity, and it inhibits fibrinolysis by promoting the release of PAI-1, contributing to undegraded fibrin deposition. Therefore, we were interested in evaluating, in patients with venous leg ulcers, the effect of pentoxifylline administered at 1,200 mg daily (versus placebo) for 2-months, as this drug induces a decrease in TNF-alpha synthesis and also blocks its activity. This pilot assay was performed in blind. Evolution of several parameters in ulcer biopsies are analyzed: TNF-alpha, intact fibrin, fibrin degradation products, ICAM-1, TF, and elastase. Pentoxifylline administration induced a decrease of local elastase and of fibrin deposit. These results support the hypothesis that accumulation of activated leukocytes is the key event in venous leg ulcers.

Topics: Antibodies, Monoclonal; Fibrin; Humans; Pancreatic Elastase; Paraffin Embedding; Pentoxifylline; Pilot Projects; Varicose Ulcer; Vasodilator Agents

Venous ulcers are the most severe manifestation of post-thrombotic syndrome (PTS). We have previously demonstrated that formation of compact fibrin clots resistant to lysis is observed in patients following deep-vein thrombosis (DVT) who developed PTS. The current study investigated whether unfavourable fibrin clot properties can predict post-thrombotic venous ulcers. In a cohort study on 186 consecutive patients following DVT, we determined plasma fibrin clot characteristics, including clot permeability and lysability, inflammatory markers, thrombin generation, fibrinolysis proteins at 3 months since the index event. Occurrence of PTS and venous ulcers was recorded during follow-up (median, 53; range 24 to 76 months). Fifty-seven DVT patients (30.6%) developed PTS, including 12 subjects (6.45%) with a venous ulcer (4 individuals with recurrent ulcers). Patients who developed ulcers compared with the remainder had at enrolment 13.0% lower clot permeability (K

Topics: Adult; alpha-2-Antiplasmin; Body Mass Index; Cohort Studies; Female; Fibrin; Fibrin Clot Lysis Time; Humans; Male; Middle Aged; Postthrombotic Syndrome; Risk Factors; Varicose Ulcer; Venous Thrombosis

Chronic venous ulceration represents a very common event. Current standard treatment includes local wound care with the application of compression. We report the effects of platelet-rich plasma in patients with chronic venous ulcers, which is able to stimulate fibroblasts, macrophages and mesenchymal cells and growth factors in order to achieve re-epithelialisation and neovascularisation within the microenviroment of the wound. We also documented the efficacy of this method as the sole treatment without surgical procedures.

Topics: Aged; Aged, 80 and over; Antigens, CD34; Chronic Disease; Female; Fibrin; Humans; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Platelet-Rich Plasma; Treatment Outcome; Varicose Ulcer; Wound Healing

The initial element in the causation of venous ulceration is a disturbance of venous blood flow that leads to an increase in venous pressure. Eventually, however, it is the microcirculatory consequences of venous hypertension that lead to trophic skin changes and finally to ulceration. A reduction in blood viscosity results in an improvement at the microcirculatory level. The elimination of fibrinogen from plasma improves blood viscosity. This case report concerns a 75-year-old woman with venous ulcers of both legs (left lower leg: deep ulceration with a surface area of 3 x 5 cm; right lower leg: superficial, confluent ulceration with a total surface area of 5 x 10 cm). The patient underwent 20 sessions of fibrinogen adsorption, while simultaneously continuing with a regimen of conservative measures (activated charcoal cloth dressing with silver, calcium alginate dressings and short-stretch compression bandages). Following binding to a peptide (Gly-Pro-Arg-Pro-Lys), fibrinogen and fibrin were specifically removed from the patient's plasma: her fibrinogen concentration was lowered from an original mean level of 310 mg/dl (SD +/- 104 mg/dl) to 136 mg/dl (SD +/- 54 mg/dl), and there was no return to the baseline concentration by the time of the next fibrinogen adsorption session. In response to this treatment the patient's ulcers healed rapidly within 9 weeks. Dizziness and hematomas at the vascular access sites in both antecubital fossae were reported as adverse effects. A fall in hematocrit was also noted (before treatment 37% +/- 1%; after treatment 35% +/- 2%). This may have been caused by hemodilution due to the procedure and to cell losses during blood-plasma separation, a phenomenon that is known to occur during apheresis. This case report suggests that fibrinogen adsorption is low in adverse effects and is a useful addition to the range of treatments available for ulcers of venous etiology.

Topics: Adsorption; Aged; Blood Component Removal; Combined Modality Therapy; Female; Fibrin; Fibrinogen; Humans; Treatment Outcome; Varicose Ulcer

This study investigated the possibility that pericapillary fibrin deposition, found in the calf skin of patients with venous ulceration and lipodermatosclerosis, might already be present in the dermis of the gaiter area of apparently healthy limbs before any skin changes were visible. The apparently healthy limbs of 19 consecutive patients with a healed venous ulcer on one leg and no history of ulceration or clinical evidence of lipodermatosclerosis in the opposite calf, were studied. Bipedal ascending phlebography and foot volume plethysmography were performed, and systemic fibrinolytic activity and fibrinogen levels were calculated. Transcutaneous oxygen measurements were expressed as a ratio of levels from a fixed position in the gaiter skin over a control site on the arm. Biopsies of a standard site in the gaiter skin and the thigh were assessed for the presence of laminin, fibrinogen and fibronectin using immunofluorescent microscopy. The extent of pericapillary fluorescence was expressed as a ratio of the number of capillaries with deposits divided by the total number of capillaries staining with laminin (fibrin and fibronectin scores). Pericapillary fibrin deposits were observed in the dermis in 16 of the biopsies of the gaiter region (median score 0.20), and in eight of the biopsies from the thigh (median score 0.0). This difference was highly significant (P<0.01, Wilcoxon signed rank test). The transcutaneous oxygen ratio correlated negatively with the fibrin score (Spearman rank correlation coefficient -0.62, P<0.01), and there was a weak negative correlation between the half volume refilling time on foot volume plethysmography (an indicator of venous reflux) and the fibrin score (Speraman rank correlation coefficient -0.47, P<0.05). No such correlation could be shown between the fibrin score and the indicators of calf pump function, the euglobulin clot lysis time or the plasma fibrinogen. The presence of significant numbers of pericapillary fibrin deposits within the dermis of the gaiter skin has been demonstrated in 84% of this cohort of 'at risk' limbs before there is any evidence of clinical lipodermatosclerosis.

Topics: Adult; Aged; Aged, 80 and over; Blood Gas Monitoring, Transcutaneous; Capillaries; Dermis; Female; Fibrin; Fibrinolysis; Fibronectins; Humans; Leg; Male; Middle Aged; Scleroderma, Localized; Varicose Ulcer

To evaluate the influence of fibrin cuffs on the transcutaneous oxygen tension in patients with chronic venous insufficiency (CVI) we performed a prospective comparative study in an out-patient dermatological department of a district hospital in the Netherlands. 16 patients with CVI grade II or III, 6 patients with porphyria cutanea tarda (PCT) without any sign of CVI, 4 patients with clinical ecthyma type ulcers without CVI and 10 healthy volunteers were studied. Skin biopsies for fibrinogen staining, transcutaneous oxygen tension measurements (TcPO2) and light reflexion rheography (LRR) were performed. TcPO2 readings were significantly lower in patients with CVI compared to patients of the other groups. Fibrin cuffs were found in 8 out of 16 patients with CVI, all PCT patients and 3 out of 4 ecthyma-ulcer patients. On the basis of these results we conclude that the fibrin cuff alone does not act as a barrier for oxygen transport. Fibrin cuffs in CVI are not the cause of venous ulceration but only a part of the complicated mechanism of the altered microcirculation induced by reflux in the venous macrocirculation. Fibrin cuffs are not unique for CVI but an indication of a disturbed microcirculation.

Topics: Adult; Aged; Biopsy; Blood Gas Monitoring, Transcutaneous; Capillaries; Female; Fibrin; Fluorescent Antibody Technique; Humans; Male; Middle Aged; Porphyria Cutanea Tarda; Skin; Varicose Ulcer

The pathogenesis of venous ulceration is thought to involve formation of pericapillary fibrin cuffs as a result of venous hypertension, and a recent hypothesis suggests that extravasated plasma proteins may bind or trap growth factors. We have compared the tissue distribution of fibrin cuffs, plasma proteins, procollagen, and transforming growth factors (TGF-beta 1 and TGF-beta 2) within venous ulcers and normally healing graft donor sites. In venous ulcers, the papillary dermis and the ulcer bed contained convoluted capillaries with phosphotungstic acid haematoxylin-positive pericapillary fibrin cuffs. By immunohistochemical staining, the cuffs were positive for actin, and contained massively redundant lamellae of basement membrane material which stained positive for type IV collagen. Extravasated factor XIIIa and alpha 2-macroglobulin were present within the fibrin cuffs. Increased numbers of type I procollagen positive fibroblasts, and increased TGF-beta 1 immunoreactivity were present within the fibrin cuffs, but not in the provisional matrix in the ulcer bed around the cuffs. In contrast, in normally healing graft donor sites, tortuous capillaries and fibrin cuffs were absent, factor XIIIa and alpha 1-macroglobulin were restricted to the lumina of vessels, and procollagen and TGF-beta immunoreactivity were present within the granulation tissue and adjacent dermal matrix at the wound margin. These observations suggest that growth factors critical in wound healing, such as TGF-beta, are present within venous ulcers, but are abnormally distributed. Their distribution within fibrin cuffs and co-localization with extravasated plasma proteins, particularly alpha 2-macroglobulin, which is a recognized scavenger molecule for TGF-beta and other growth factors, provides evidence for a possible 'trapping' of growth factors in venous ulcers.

Topics: alpha-Macroglobulins; Blood Proteins; Capillaries; Collagen; Fibrin; Humans; Immunohistochemistry; Macromolecular Substances; Procollagen; Skin; Transforming Growth Factor beta; Transglutaminases; Varicose Ulcer

Nonoperative therapeutic approaches to chronic venous ulceration, although effective, often require prolonged dressing care and immobilization with leg elevation. Results of skin grafting, perforator ligation, and valve interpositions and reconstructions improve results of ulcer healing but have not uniformly prevented ulcer recurrence. Our hypothesis is that reconstruction of chronic venous ulcers by excision of the diseased tissue bed and replacement with a free flap containing multiple competent microvenous valves and a normal tissue microcirculation will result in long-term cure of these debilitated patients.. Six patients with chronic venous insufficiency and recurrent ulceration (class 3) underwent excision of ulcers and surrounding liposclerotic tissue beds and reconstruction with fasciocutaneous free flaps (two bilateral). Preoperative and postoperative photoplethysmography was used to assess venous refilling times. Duplex scanning was performed to assess deep venous reflux.. There were no flap failures. Photoplethysmographic venous refilling times measured on flaps demonstrated significant immediate and long-term increases from preoperative values (all results +3 by Society of Vascular Surgery outcome grading). Long-term maintenance of tissue integrity is shown by absence of recurrent ulceration and no evidence of recurrent tissue lipodermatosclerosis in all flaps at follow-up (8 months to 7.5 years; mean 24 months). No recurrent lipodermatosclerosis was seen on flap biopsy at 2 and 7 years. Separate cadaveric injection studies, including scanning electron microscopy, revealed numerous microvenous valves directed toward the draining pedicle in the flaps used for reconstruction.. This is the first comprehensive report providing combined laboratory and clinical evaluation, anatomic rationale, and long-term outcome of surgical rehabilitation of patients with chronic venous ulceration who have undergone microsurgical flap reconstruction.

Topics: Adult; Anastomosis, Surgical; Capillaries; Chronic Disease; Female; Fibrin; Humans; Hyperplasia; Male; Microcirculation; Microsurgery; Middle Aged; Photoplethysmography; Popliteal Vein; Scleroderma, Localized; Surgical Flaps; Tibia; Ultrasonography; Varicose Ulcer; Venous Insufficiency; Venules; Wound Healing

The pathogenesis of venous ulceration is unknown. We propose that macromolecules leaking into the dermis as a result of venous hypertension bind to or "trap" growth factors and matrix material, which then become unavailable for tissue repair and for the maintenance of tissue integrity.

Topics: alpha-Macroglobulins; Fibrin; Fibrinogen; Growth Substances; Humans; Macromolecular Substances; Models, Biological; Varicose Ulcer

Twenty-six patients with venous insufficiency and 15 normal controls were studied by local skin pathological and ultrastructure changes. Transcutaneous oxygen tension (Tcpo2) and tPA, PAI of venous blood were measured. Biopsies from the ulcerating and liposclerosis area showed pericapillary fibrins. The patients with severe venous disease resulting in liposclerosis or ulceration of the goiter area had Tcpo2 levels lower than the controls and patients with venous insufficiency but no skin changes. The more serious the skin changes in patients with venous insufficiency, the lower the fibrinolysis activity. We conclude that extravascular deposition of fibrins in patients with venous disease which block the diffusion and exchanges of oxygen between the blood and tissue is an important factor in the development of venous ulcerations. The decrease of fibrinolysis activity led to the decrease of removing pericapillary fibrins deposition, combined with extravascular fibrin caused venous ulceration.

Topics: Aged; Blood Gas Monitoring, Transcutaneous; Fibrin; Humans; Middle Aged; Plasminogen Inactivators; Skin; Tissue Plasminogen Activator; Varicose Ulcer; Venous Insufficiency

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.

Topics: Adult; Aged; Aged, 80 and over; Blood Gas Monitoring, Transcutaneous; Capillaries; Female; Fibrin; Fluorescent Antibody Technique; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Varicose Ulcer; Venous Insufficiency; Wound Healing

In and around ulcers complicating the chronic venous insufficiency syndrome and atrophie blanche a pericapillary cuff of fibrinoid material has been described. The aim of the present study was to find out whether pericapillary cuffs are present in atrophie blanche ulcerations, whether they consist of fibrinogen and/or fibrin in comparison to normal controls, and whether this cuff is composed of other components. Skin biopsies from ten patients adjacent to atrophie blanche ulcers, and from ten controls were taken. In all patients pericapillary cuffs consisting of fibrin were found. However, no fibrinogen was found in these cuffs. In the controls no cuffs were found. 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 several cases may indicate that breakdown of this fibrin cuff is impaired. The possible diffusion barrier caused by the pericapillary cuff together with the pattern of vascularization may be an important event in ulcer formation and impaired ulcer healing.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Biopsy; Collagen; Female; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Humans; Male; Middle Aged; Plasminogen Inactivators; Skin; Varicose Ulcer; Venous Insufficiency; von Willebrand Factor

Pericapillary fibrin cuffs are probably involved in the pathogenesis of venous leg ulcers. Factor XIII (Fibrin stabilizing factor) is of importance in wound healing. Its activity, which may affect ulceration, was found to be significantly reduced in the blood of venous leg ulcer patients and in post-phlebitic patients, compared with healthy controls.

Topics: Chronic Disease; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Leg Ulcer; Postphlebitic Syndrome; Varicose Ulcer; Wound Healing

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.

Topics: Aged; Collagen; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Granulation Tissue; Humans; Monocytes; Neutrophils; Pancreatic Elastase; Tumor Necrosis Factor-alpha; Varicose Ulcer

Clearance of subcutaneous 125I-labelled fibrin was prolonged from the legs but not from the arms of patients with uncomplicated varicose veins and patients with healed ulcers, compared with controls. The euglobulin clot lysis time (ECLT) of blood from the arms and legs of those with healed ulcers was prolonged; venous congestion significantly shortened the ECLT of blood from all limbs except legs with healed ulcers. The clearance of interstitial fibrin of both legs and arms correlated with the response of the ECLT to venous congestion (P less than 0.05). The clearance of interstitial 125I-labelled albumin in five patients with healed ulcers was faster from the legs than from the arms, whereas the clearance of interstitial 125I-labelled fibrin was faster from the arms in all cases. These results suggest that there is a defect in interstitial fibrinolytic activity as well as vein wall production of plasminogen activator in legs with chronic venous insufficiency.

Topics: Arm; Fibrin; Fibrinolysis; Humans; Leg; Serum Albumin; Varicose Ulcer; Varicose Veins; Venous Insufficiency

Topics: Diffusion; Fibrin; Humans; Oxygen Consumption; Skin; Varicose Ulcer

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.

Topics: Capillaries; Fibrin; Humans; Leg Ulcer; Skin; Thrombophlebitis; Varicose Ulcer

Topics: Blood Proteins; Capillaries; Capillary Permeability; Fibrin; Fibrinolysis; Humans; Hyperemia; Hypoxia; Leg; Rheology; Varicose Ulcer; Veins; Venous Insufficiency; Venous Pressure

Topics: Diffusion; Fibrin; Humans; Posture; Varicose Ulcer; Venous Pressure; Wound Healing

The effect of long and short-term venous hypertension upon lymph fibrinogen concentrations was studied in an attempt to explain the peri-capillary deposition of fibrin reported in patients with post-phlebitic syndromes. The clearance of radioactive fibrinogen/thrombin clots from the subcutaneous tissues of rats and human volunteers was also studied. Both long- and short-term venous hypertension were found to increase fibrinogen transport across the interstitial space by more than 600%. Not only was there evidence of fibrinolytic activity in the lymph but after long-term venous hypertension alpha 2 antiplasmin activity was also detectable. Skin biopsies from the venous hypertensive ankles showed deposition of interstitial fibrin. The clearance of radioactive fibrinogen/thrombin clots from the subcutaneous tissues of the rat was found to be delayed if the rats were given epsilon amino caproic acid but it could not be increased with stanozolol. In human subjects it was found that patients with lipodermatosclerosis had delayed clot clearance and retarded blood fibrinolytic activity when compared with normal volunteers and patients with uncomplicated varicose veins. The principle cause why tall men are more subject to ulcers than short men, Dr Young conceived to be then length of the column of blood in their veins; which by its pressure, renders the legs less able to recover when hurt by any violence.

Topics: Aminocaproic Acid; Animals; Dogs; Extracellular Space; Fibrin; Fibrinogen; Fibrinolysis; Humans; Hypertension; Lymph; Male; Rats; Rats, Inbred Strains; Skin; Varicose Ulcer

Forty-one biopsy specimens, taken from the ulcer-bearing skin of 41 legs of 21 patients attending the varicose vein clinic, were selectively stained for fibrin with phosphotungstic acid haemotoxylin before being blindly assessed,. Layers of fibrin were found surrounding the dermal capillaries in all 26 legs with lipodermatosclerosis. None of the specimens from the 15 legs with clinically normal skin contained fibrin. There was also an increased number of dermal capillaries cut in cross section per high powered field in 24 of the 26 legs with lipodermatosclerosis compared with two of the 15 legs with normal skin (p less than 0.001). The mean reduction in foot vein pressure during exercise was significantly less in the 26 limbs with pericapillary fibrin than in the other 15 limbs (p less than 10(-6). Lipodermatosclerosis is synonymous with pericapillary fibrin deposition and is associated with, and probably secondary to, both a persistently raised venous pressure and an increase in the size of the dermal capillary bed. This extravascular deposition of fibrin probably stimulates tissue fibrosis and blocks the diffusion of oxygen to the overlying epidermis, producing cellular death and venous ulceration.

Topics: Capillaries; Female; Fibrin; Humans; Leg Ulcer; Male; Scleroderma, Localized; Skin; Varicose Ulcer

Topics: Capillaries; Fibrin; Humans; Hypertension; Sclerosis; Skin; Varicose Ulcer; Venous Pressure