fibrin and Venous-Insufficiency

A condition called "chronic cerebrospinal venous insufficiency" (CCSVI) has been postulated to play a role in the pathogenesis of multiple sclerosis (MS). This hypothesis implies that a complex pattern of extracranial venous stenosis determines a venous reflux into the brain of MS patients, followed by increased intravenous pressure, blood-brain barrier breakdown and iron deposition into the brain parenchyma, thus triggering a local inflammatory response. In this review, we critically analyze the scientific basis of CCSVI, the current literature on the relationship between CCSVI and MS, as well as the ultrasound methodology that has been claimed to provide evidence of impaired cerebral venous drainage. We show that no piece of the CCSVI theory has a solid supportive scientific evidence. The CCSVI appears to be a rather alien condition and its existence should be definitely questioned. Finally, no proven (i.e., based on strict scientific methodology and on the rules of evidence-based medicine) therapeutic effect of the "liberation" procedure (unblocking the extracranial venous obstruction using angioplasty) has been shown up to date.

Topics: Animals; Brain; Disease Models, Animal; Dogs; Fibrin; Humans; Iron; Multiple Sclerosis; Venous Insufficiency

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.

Topics: Capillary Permeability; Cell Hypoxia; Chronic Disease; Fibrin; Fibrinogen; Humans; Hypertension; Leg Ulcer; Leukocytes; Microcirculation; Necrosis; Terminology as Topic; Thrombosis; Venous Insufficiency; 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

Venous ulceration remains a major cause of morbidity. Treatment has not improved significantly in recent years, possibly because our understanding of the pathophysiological mechanisms at work is still incomplete. We review the principal abnormalities found in the macro- and microcirculation in this condition and discuss the various theories put forward to explain the mechanism by which skin damage occurs.

Topics: Fibrin; Humans; Leukocytes; Microcirculation; Scleroderma, Localized; Skin; Skin Ulcer; Thrombosis; Venous Insufficiency; Venous Pressure

Reversible aggregation of red blood cells (RBC) plays an important role in determining blood flow properties, and it is this aggregation which increases blood viscosity at low shear rates. The structure and sites of venous thrombi, as well as the fact that stasis is a major predisposing factor in venous thrombosis, suggest a strong association between vein thrombosis, slow blood flow and increased blood viscosity. RBC aggregation and disaggregation were measured (SEFAM erythroaggregameter, France) in 54 patients with a history of unexplained leg vein thrombosis. Results were compared to those of controls classified according to age. Increased RBC aggregability was observed in 41% of the patients, and the mean values indicated a significant elevation of RBC aggregability in patients when compared with controls (P < 0.05). Subgroups were compared to study the influence of thrombus recurrence and thrombosis type (deep versus superficial vein thrombosis) on the aggregation parameters. No significant difference was found between these subgroups. The use of compression stockings and veinotropic drugs tended to reduce the abnormalities in RBC aggregability (P < 0.05). An increase in RBC aggregability and in the shear resistance of RBC aggregates, by predisposing to circulatory stasis, is likely to contribute to the evolution and complications of leg vein thrombosis.

Topics: Adult; Bandages; Blood Viscosity; Cardiovascular Agents; Chronic Disease; Erythrocyte Aggregation; Female; Fibrin; Hematocrit; Humans; Leg; Male; Middle Aged; Thrombophlebitis; Venous Insufficiency

The micromorphological alterations in chronic venous insufficiency are characterized by a patchlike distribution. At least in the initial stages, normal skin areas may alternate with regions containing severe alterations. The capillaries may be rarified, or elongated and dilated with formation of glomerulus-like clusters, or they may show proliferation within a granulomatous repair tissue. Pericapillary accumulation of fibrin may be observed only within necrotic tissue surrounding an ulcer. The pericapillary space which is enlarged and edematous in chronic venous insufficiency, cannot be anatomically defined. The interstitial tissue may contain a secondary chronic inflammation with repair function. Finally a hyaline scar tissue with so-called "avascular" fields and dystrophic calcification/ossification may result.

Topics: Capillaries; Collagen; Extracellular Space; Factor VIII; Fibrin; Humans; Immunoenzyme Techniques; Microscopy, Electron; Necrosis; Postphlebitic Syndrome; Skin; Venous Insufficiency

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

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

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

In 42 patients with a chronic venous insufficiency Stage I-III transcutaneous oxygen tension was measured above the medial ankle and the leg ulcer edges respectively at 44 degrees C. The measurement point was biopsied and evaluated immunfluorescencehistologically for pericapillary fibrin cuffs (PCF). Fibrin cuffs are associated with decreased tcpO2-tensions. All PCF-positive biopsies were from areas with a tcpO2 less than 35 mmHg. The difference of PCF-positive and PCF-negative biopsies concerning the mean tcpO2 was significant (Wilcoxon-U-Test; p less than 0.001). The evidence of pericapillary fibrin cuffs associated with tcpO2 tensions up to 33 mmHg proves that this phenomenon alone cannot be a diffusion barrier.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Capillaries; Capillary Permeability; Female; Fibrin; Fluorescent Antibody Technique; Humans; Male; Middle Aged; Oxygen; Skin; Venous Insufficiency

Based on a prospective study of 92 patients with DVT initiated in 1979, including a follow-up every year, the following investigations were performed: phlebography, Doppler-ultrasound, plethysmography (strain gauge and PPG) and foot-volumetry. In ulcer-patients skin blood flow was measured by Laser-Doppler and local oxygen supply by measurement of transcutaneous oxygen. Transcapillary protein-leakage was assessed by isotopic methods, local lymph-drainage by isotopic lymphography and indirect x-ray lymphography. From the results of these investigations the following course of events, which may be of importance for the development of venous ulceration, can be outlined: 1. Venous refluxes penetrating into the venules of the skin. 2. Chronic venous ambulatory hypertension (lack of pressure-fall during walking), waves of high pressure in the capillaries. 3. Protein-rich oedema. 4. Failure of fibrin clearance from the pericapillary space due to inadequate (exhausted?) fibrinolysis and deficient local lymph drainage. 5. Resulting changes in the ground substance, proliferation of fibres. 6. Local hypoxia due to a diffusion block by the impermeable pericapillary cuffs, partially due to a reduction of capillaries in the superficial layers.

Topics: Blood Proteins; Capillary Permeability; Fibrin; Follow-Up Studies; Humans; Leg; Leg Ulcer; Lymph; Oxygen; Phlebography; Plethysmography; Postphlebitic Syndrome; Prospective Studies; Skin; Ultrasonography; Venous Insufficiency; Venous Pressure

Topics: Arteriovenous Fistula; Capillary Permeability; Fibrin; Fibrinogen; Fibrinolysis; Humans; Leg Ulcer; Oxygen; Postphlebitic Syndrome; Venous Insufficiency; Venous Pressure

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

Topics: Antithrombin III; Chronic Disease; Fibrin; Fibrin Fibrinogen Degradation Products; Hemostasis; Humans; Solubility; Thrombophlebitis; Tinea; Venous Insufficiency