fibrin and von-Willebrand-Diseases

Activation and inhibition of the haemostatic system was reviewed including the interaction between the four biological systems involved in haemostasis: the vessel wall, the platelets, the coagulation system and the fibrinolytic system. The haemostatic mechanism is initiated at the site of injury through local activation of surfaces and release of tissue thromboplastin, resulting in formation and deposition of fibrin. The coagulation process is regulated by physiological anticoagulants. Activation of fibrinolysis is triggered by the presence of fibrin, and the role of tissue-type plasminogen activators (t-PA) at the site of fibrin formation in particular is emphasized. The process is regulated by physiological inhibitors, of which alpha 2-antiplasmin, histidine-rich glycoprotein and plasminogen activator inhibitor are reported to be of major physiological significance. The role of fibrinolysis in the regulation of the dynamic haemostatic balance is discussed, elucidated through examples of congenital deficiencies of the coagulation and the fibrinoytic system. Pharmacological inhibitors of fibrinolysis (i.e. epsilon-aminocaproic acid and tranexamic acid) and their possible effect on the haemostatic system are described. The systemic effects on the fibrinolytic system of surgery and oral surgery is reviewed, and it is concluded, that oral surgery has insignificant effects on blood fibrinolysis. In contrast, oral surgery induces changes of fibrinolysis in the oral environment; initially the fibrinolytic activity of saliva is reduced, due to the presence of inhibitors of fibrinolysis originating from the blood and the wound exudate. When bleeding and exudation cease, the fibrinolytic activity of the saliva will increase. Plasminogen and plasminogen activator, identified as t-PA are present in the oral environment under physiological conditions. Plasminogen is secreted in the saliva and the sources of t-PA include oral epithelial cells and gingival crevicular fluid. The presence of plasminogen and t-PA in the oral environment implies that when fibrin is present (i.e. after surgery), fibrinolysis is triggered. Haemorrhagic complications to oral surgery in patients without known defects of the coagulation system is reviewed. It is concluded that the investigations conducted to the present day do not permit final conclusions with respect to the pathophysiological role of defects in the coagulation and the fibrinolytic systems for the development of bleeding after

Topics: Anticoagulants; Blood Coagulation; Blood Platelets; Deamino Arginine Vasopressin; Fibrin; Fibrinolysis; Gingiva; Hemophilia A; Hemorrhage; Hemostasis; Hemostasis, Surgical; Humans; Mouth Mucosa; Saliva; Surgery, Oral; Tissue Plasminogen Activator; von Willebrand Diseases

The hemostatic mechanism has evolved to provide efficient protection from traumatic blood loss and yet maintain the blood in a fluid state in the circulation as a whole. Recent advances in biochemistry have provided both detailed understanding of hemostasis and clinically useful coagulation assays to exploit this understanding. Clinicians now have the means to delineate most of the hemostatic problems of clinical significance.

Topics: Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Factor VIII; Factor X; Factor Xa; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Hemophilia A; Humans; Prothrombin Time; Thrombin; Thrombin Time; Vitamin K Deficiency; von Willebrand Diseases

Disturbances of haemostasis caused immunologically and non-immunologically were observed after transfusion of blood and blood derivatives. Transfusion of heparin blood increased the bleeding susceptibility only in case of pre-existing high-degree defects of haemostasis or if they were performed as massive or exchange transfusions. Massive transfusions with blood stored for a long time will induce complex defects. Under intensive substitution therapy of haemophilia A the so-called paradoxical bleeding will occur in spite of a high factor VIII level. These bleedings are supposed to be disturbances of the thrombocyte function and are caused by fibrin(ogen) derivatives. Post-transfusional thrombocytopenias may be brought to remission by repeated plasmapheresis. Factor specific inhibitory bodies will appear after substitution in a small percentage of haemophilic patients. 5 to 7 days after the onset of therapy an anamnestic reaction can be observed as a titre increase by leaps. Usually, the inhibitory titre will decrease to a mostly low basal value in the course of three to five months. The therapy with cyclophosphamide simultaneously started with the substitution will more frequently prevent the anamnestic reaction or reduce it. Titres with more than 5 units cannot be overcome at the beginning even by higher concentrations of preparations. The substitution therapy should be preceded by exchange transfusions or plasmapheresis of up to 25 units. With still higher titres only procedures of inhibitor-bypassing are possible with factor VIII preparations of animal origin or better with activated prothrombin complex preparations, such as FEIBA. Recent reports give evidence that permanent substitution with factor VIII concentrates at a highest dosage can eliminate the production of inhibitors completely.

Topics: Blood Coagulation Disorders; Blood Transfusion; Cyclophosphamide; Factor IX; Factor IXa; Factor XIII; Fibrin; Fibrinogen; Hemophilia A; Hemostasis; Heparin; Humans; Platelet Aggregation; Thrombocytopenia; von Willebrand Diseases

Topics: Angioedema; Animals; Antithrombins; Blood Coagulation; Blood Coagulation Factors; Blood Platelets; Complement System Proteins; Enzyme Precursors; Factor VIII; Factor XII; Female; Fibrin; Fibrinogen; Fibrinolysis; Hemophilia A; Hemostasis; Humans; Kallikreins; Male; Platelet Adhesiveness; Thrombin; Thromboplastin; Thrombosis; von Willebrand Diseases

Topics: Blood Coagulation; Blood Coagulation Factors; Factor IX; Factor V; Factor VII; Factor VIII; Factor X; Factor XI; Factor XII; Factor XIII; Fibrin; Fibrinogen; Humans; Phosphatidylethanolamines; Prothrombin; Thromboplastin; von Willebrand Diseases

A microscopic method was developed to study the role of platelets in fibrin formation. Perfusion of adhered platelets with plasma under coagulating conditions at a low shear rate (250(-1)) resulted in the assembly of a star-like fibrin network at the platelet surface. The focal fibrin formation on platelets was preceded by rises in cytosolic Ca(2+), morphologic changes, and phosphatidylserine exposure. Fibrin formation was slightly affected by α(IIb)β(3) blockage, but it was greatly delayed and reduced by the following: inhibition of thrombin or platelet activation; interference in the binding of von Willebrand factor (VWF) to glycoprotein Ib/V/IX (GpIb-V-IX); plasma or blood from patients with type 1 von Willebrand disease; and plasma from mice deficient in VWF or the extracellular domain of GpIbα. In this process, the GpIb-binding A1 domain of VWF was similarly effective as full-length VWF. Prestimulation of platelets enhanced the formation of fibrin, which was abrogated by blockage of phosphatidylserine. Together, these results show that, in the presence of thrombin and low shear flow, VWF-induced activation of GpIb-V-IX triggers platelet procoagulant activity and anchorage of a star-like fibrin network. This process can be relevant in hemostasis and the manifestation of von Willebrand disease.

Topics: Animals; Blood Coagulation; Blood Platelets; Fibrin; Humans; Image Processing, Computer-Assisted; Mice; Mice, Transgenic; Microscopy, Confocal; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Shear Strength; von Willebrand Diseases; von Willebrand Factor

Topics: Factor VIII; Fibrin; Humans; Platelet Adhesiveness; Protein Binding; von Willebrand Diseases; von Willebrand Factor

Thrombin generation in platelet-rich plasma (PRP) involves complex interactions between platelets and coagulation proteins. We previously reported that the addition of fibrin to PRP enhances tissue-factor initiated thrombin generation by approximately 40%, and the current studies were designed to assess the mechanism(s) underlying thrombin generation in the absence and presence of fibrin. Blocking platelet GPIIb/IIIa + alphavbeta3 receptors with a monoclonal antibody (MoAb) inhibited basal thrombin generation, but did not affect the enhancement produced by fibrin. In contrast, blocking GPIb with any of three different MoAbs had no effect on basal thrombin generation, but essentially eliminated fibrin enhancement of thrombin generation. When thrombin generation was tested in PRP deficient in von Willebrand factor (vWF), both basal and fibrin-enhanced thrombin generation were markedly reduced, and the addition of factor VIII did not normalize thrombin generation. Botrocetin, which induces the binding of vWF to GPIb, enhanced thrombin generation. In all studies, the ability of PRP to support thrombin generation correlated with the production of platelet-derived microparticles and serum platelet-derived procoagulant activity. Thus, two separate mechanisms, both of which depend on vWF, appear to contribute to platelet-derived procoagulant activity: one is independent of fibrin and relies primarily on GPIIb/IIIa, but with a minor contribution from alphavbeta3; and the other is fibrin-dependent and relies on GPIb. These data may have implications for understanding the mechanisms of the abnormalities in serum prothrombin times reported in Bernard-Soulier syndrome, hemorrhage in von Willebrand disease (vWD), and the increased risk of thrombosis associated with elevated vWF levels.

Topics: Animals; Antibodies, Monoclonal; Blood Coagulation; Blood Platelets; Cattle; Crotalid Venoms; Factor VIII; Fibrin; Hemagglutinins; Humans; Kinetics; Mice; Phospholipids; Platelet Glycoprotein GPIb-IX Complex; Thrombasthenia; Thrombin; von Willebrand Diseases; von Willebrand Factor

After the formation of a platelet-plug, generation of fibrin is necessary for its stabilization. Both congenital and acquired deficiencies of clotting factors occur, leading to retarded formation of fibrin. In congenital disorders, preoperative correction is possible and necessary. In acquired deficiencies, the type and feasibility of correction depends on the cause of the deficiency.

Topics: Blood Coagulation Disorders; Fibrin; Hemophilia A; Hemophilia B; Hemostasis, Surgical; Humans; Vitamin K Deficiency; von Willebrand Diseases

Platelet adhesion to fibrin at high shear rates depends on both the glycoprotein (GP) IIb:IIIa complex and a secondary interaction between GPIb and von Willebrand factor (vWF). This alternative link between platelets and vWF in promoting platelet adhesion to fibrin has been examined in flowing whole blood with a rectangular perfusion chamber. Optimal adhesion required both platelets and vWF, as shown by the following observations. No binding of vWF could be detected when plasma was perfused over a fibrin surface or when coated fibrinogen was incubated with control plasma in an enzyme-linked immunosorbent assay. However, when platelets were present during perfusion, interactions between vWF and fibrin could be visualized with immunoelectron microscopy. Exposure of fibrin surfaces to normal plasma before perfusion with severe von Willebrand's disease blood did not compensate for the presence of plasma vWF necessary for adhesion. vWF mutants in which the GPIIb:IIIa binding site was mutated or the GPIb binding site was deleted showed that vWF only interacts with GPIb on platelets in supporting adhesion to fibrin and not with GPIIb:IIIa. Complementary results were obtained with specific monoclonal antibodies against vWF. Thus, vWF must first bind to platelets before it can interact with fibrin and promote platelet adhesion. Furthermore, only GPIb, but not GPIIb:IIIa is directly involved in this interaction of vWF with platelets.

Topics: Bernard-Soulier Syndrome; Binding Sites; Blood Flow Velocity; Blood Platelets; Fibrin; Humans; In Vitro Techniques; Microscopy, Immunoelectron; Mutation; Perfusion; Platelet Adhesiveness; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombasthenia; von Willebrand Diseases; von Willebrand Factor

To present current strategies for the treatment of hemophilia and von Willebrand's disease.. Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-D-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, porcine Factor VIII, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant. The induction of immune tolerance in patients in whom inhibitors develop should also be considered.. Morbidity and quality of life associated with bleeding and treatment.. Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of our reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and pertinent to a predetermined outline. The availability of treatment products in Canada was also considered.. Minimizing morbidity and maximizing functional status and quality of life were given a high value.. Proper prophylactic or early treatment with appropriate hemostatic agents minimizes morbidity and functional disability and improves quality of life. Economic gains are realized through the reduction of mortality and morbidity and their associated costs. The patient has a better opportunity to contribute to society through gainful employment and the fulfillment of social roles. Potential harms include HIV infection, hepatitis B, hepatitis C and the development of inhibitor antibodies to clotting-factor concentrates. The risk of viral transmission has been minimized through the development of procedures for the viral inactivation of plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents.. DDAVP is the drug of choice for patients with mild hemophilia or type 1 or 2 (except 2B) von Willebrand's disease whose response to DDAVP in previous testing has been found to be adequate. Therapeutic blood components of choice include recombinant products and virally inactivated plasma-derived products. In Canada the recommended products are recombinant Factor VIII for hemophilia A, high-purity plasma-derived Factor IX for hemophilia B and plasma-derived Factor VIII concentrates containing adequate von Willebrand factor (e.g., Haemate P) for von Willebrand's disease. Dosages vary according to specific indications. Adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant are useful for the treatment of oral or dental bleeds and localized bleeds in accessible sites. In patients with inhibitor antibodies, high-dose human or porcine Factor VIII is usually effective when the inhibitor titre is less than 5 Bethesda units/mL. In nonresponsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) are useful. Long-term management may include immune-tolerance induction.. These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. No similar consensus statements or practice guidelines are available for comparison.. These recommendations were developed at the request of the Canadian Blood Agency, which funds the provision of all coagulation-factor concentrates for people with congenital bleeding disorders, and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society.

Topics: Antifibrinolytic Agents; Canada; Deamino Arginine Vasopressin; Factor IX; Factor VIII; Fibrin; Health Care Costs; Hemophilia A; Humans; Recombinant Proteins; Thrombin; von Willebrand Diseases

We have found that glycoprotein IIb:IIIa (GPIIb:IIIa) expressed on nonstimulated platelets is the primary receptor for platelet adhesion to immobilized fibrinogen or fibrin. At low shear rates of the blood the interaction between GPIIb:IIIa and fibrin(ogen) is strong enough to resist the shear forces exerted on the platelet as was shown with experiments with antibodies against platelet membrane glycoproteins and perfusion studies with blood from patients lacking platelet membrane receptors. Impaired platelet adhesion to fibrin(ogen) was found with blood from a patient with Glanzmann's thrombasthenia (lacking GPIIb:IIIa), blood from patients with the Bernard-Soulier syndrome (lacking GPIb) and blood from patients with severe von Willebrand's disease. This indicates that at higher shear rates additional interactions via GPIb on the platelet and von Willebrand factor originating from plasma or platelets are necessary to increase the affinity of the platelet for fibrin(ogen).

Topics: Bernard-Soulier Syndrome; Fibrin; Fibrinogen; Humans; Platelet Adhesiveness; Platelet Membrane Glycoproteins; von Willebrand Diseases

Thrombus formation on collagen fibrils was quantified at venous (100/s) and arterial (650/s and 2,600/s) wall shear rates in blood from patients with various subtypes of von Willebrand disease (vWD) and with hemophilia A (HA). Nonanticoagulated blood was drawn directly from an antecubital vein over purified type III collagen fibrils exposed in parallel-plate perfusion chambers. Blood-collagen interactions were differentiated and quantified by morphometry as platelet adhesion, thrombus height, thrombus volume, and deposition of fibrin strands. Sixteen patients with vWD, including four type III, six type I, four type IIA, and two type IIB, were compared with 26 normal subjects and nine patients with HA, including six severe HA and three mild HA. Platelet adhesion and thrombus formation at 2,600/s were significantly decreased in blood from patients with vWD type III, IIA, and IIB, but not in blood from patients with type I and in HA. The abnormal thrombus formation was apparently not related to the decreased levels of factor VIII (F.VIII), because thrombus height and volume were normal in severe and mild HA. Thrombus formation at 650/s was also significantly decreased in patients with vWD type III, IIA, and IIB and slightly reduced in type I. Significant reduction in thrombus volume and height was also observed in blood from patients with severe HA, but not in mild HA. Thrombus dimensions were not affected at 100/s in the vWD subtypes. However, significantly decreased thrombus height and virtually absent fibrin deposition were observed in blood from patients with severe HA. Apparently, F.VIII supports thrombus formation at low and intermediate shear conditions, presumably through the generation of thrombin. In contrast, von Willebrand factor (vWF) mediates not only platelet adhesion, but also thrombus formation at intermediate and high shear rates. Thus, the relative contribution of coagulation (F.VIII) and platelet function (vWF) in thrombus formation appears to be shear rate dependent, but having optimal effects at different shear conditions.

Topics: Biomechanical Phenomena; Blood Coagulation; Collagen; Fibrin; Hemophilia A; Humans; Platelet Adhesiveness; von Willebrand Diseases

We have investigated the molecular basis of thrombus formation by measuring the extent of platelet deposition from flowing whole blood onto fibrin-coated glass coverslips under well-defined shear conditions in a rectangular perfusion chamber. Platelets readily and specifically adhered to fibrin-coated coverslips in 5 minute perfusion experiments done at either low (300 s-1) or high (1,300 s-1) wall shear rates. Scanning electron microscopic examination of fibrin-coated coverslips after perfusions showed surface coverage by a monolayer of adherent, partly spread platelets. Platelet adhesion to fibrin was effectively inhibited by a monoclonal antibody (MoAb) specific for glycoprotein (GP) IIb:IIIa. The dose-response curve for inhibition of adhesion by anti-GPIIb:IIIa at both shear rates paralleled that for inhibition of platelet aggregation. Platelet aggregation and adhesion to fibrin were also blocked by low concentrations of prostacyclin. In contrast, anti-GPIb reduced adhesion by 40% at 300 s-1 and by 70% at 1,300 s-1. A similar pattern of shear rate-dependent, incomplete inhibition resulted with a MoAb specific for the GPIb-recognition region of von Willebrand factor (vWF). Platelets from an individual with severe von Willebrand's disease, whose plasma and platelets contained essentially no vWF, exhibited defective adhesion to fibrin, especially at the higher shear rate. Addition of purified vWF restored adhesion to normal values. These results are consistent with a two-site model for platelet adhesion to fibrin, in which the GPIIb:IIIa complex is the primary receptor, with GPIb:vWF providing a secondary adhesion pathway that is especially important at high wall shear rates.

Topics: Antibodies, Monoclonal; Blood Platelets; Fibrin; Humans; Microscopy, Electron, Scanning; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Membrane Glycoproteins; von Willebrand Diseases; von Willebrand Factor

We studied the role of von Willebrand factor in coronary thrombosis in normal, heterozygous, and homozygous von Willebrand's disease pigs by producing coronary stenosis with a Goldblatt clamp positioned around the left anterior descending coronary artery. Flow velocity was assessed by a 20-MHz Doppler velocity probe distal to the Goldblatt clamp. Myocardial extracellular potassium levels were measured by potassium-sensitive electrodes in myocardium supplied by the left anterior descending artery. Whereas stenosis sufficient to block reactive hyperemia to a 20-second occlusion produced an elevation of myocardial extracellular potassium, it produced neither spontaneous cyclic flow reductions nor permanent cessation of coronary blood flow velocity. Injury of the coronary artery at the stenosis site with spring-loaded forceps produced cyclic flow reductions or permanent cessation of flow in eight of nine phenotypically normal pigs. On the other hand, flow variations occurred in none of the 10 von Willebrand's disease pigs, including four given purified von Willebrand factor at a dose that failed to correct the bleeding time (p less than 0.001, chi 2 test). Permanent cessation of flow was caused by an occlusive platelet-fibrin-red-blood-cell thrombus. Scanning electron micrographs from pigs with cyclic flow variations and from von Willebrand's disease pigs showed injured endothelium covered by adherent platelets, red and white blood cells, and fibrin. These data suggest an important role of native von Willebrand factor in sudden occlusive arterial thrombosis following stenosis and intimal injury.

Topics: Animals; Blood Flow Velocity; Constriction; Constriction, Pathologic; Coronary Circulation; Coronary Disease; Coronary Vessels; Fibrin; Microscopy, Electron, Scanning; Myocardium; Platelet Aggregation; Potassium; Swine; von Willebrand Diseases; von Willebrand Factor

Fibrin clot retraction (FCR) and collagen gel retraction (CGR) were studied in patients with inherited platelet defects, i.e. in Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly, giant platelet syndrome, as well as in patients with von Willebrand disease and factor XIII deficiency. FCR was abnormal only in thrombasthenia, while CGR was found to be reduced in 2 patients with Hermansky-Pudlak syndrome and in 4 out of 5 cases with von Willebrand disease. Both FCR and CGR were normal in May-Hegglin anomaly, giant platelet syndrome and severe factor XIII deficiency. In none of the examined bleeding disorders was a concomitant FCR and CGR reduction detected. Natural polyamines and anti-fibronectin antibodies did not affect platelet potency in FCR or CGR. Peroxidation of platelet membrane components by sodium periodate abolished the platelet-induced FCR and CGR. This effect was reversed by subsequent reduction by sodium borohydride.

Topics: Adolescent; Adult; Blood Platelet Disorders; Blood Platelets; Child; Clot Retraction; Collagen; Fibrin; Fibronectins; Humans; In Vitro Techniques; Middle Aged; Periodic Acid; Polyamines; von Willebrand Diseases

Systemic hemostatic agents are reviewed. Among the agents discussed are vitamin K preparations (phytonadione, menadione, menadione sodium bisulfite, menadiol sodium diphosphate); and blood products (whole blood, plasma, cryoprecipitate, factor VIII concentrates, factor IX concentrates and fibrinogen concentrates). Normal and abnormal hemostasis and fibrinolysis are discussed, as is the general management of systemic hemostatic defects. Specific disorders covered are clotting factor deficiencies, hemophilia A, factor VIII inhibitors, von Willebrand disease, hemophilia B (Christmas disease), other congenital coagulation disorders, acquired deficiency of factors II, VII, IX and X, and defibrination syndrome.

Topics: Antibodies; Blood Coagulation Disorders; Factor VIII; Fibrin; Fibrinolysis; Hemophilia A; Hemophilia B; Hemostasis; Hemostatics; Humans; Transfusion Reaction; von Willebrand Diseases

Topics: Adenine Nucleotides; Basement Membrane; Blood Platelet Disorders; Blood Platelets; Calcium; Catecholamines; Clot Retraction; Collagen; Diagnosis, Differential; Fibrin; Glass; Heparin; Humans; Platelet Adhesiveness; Platelet Aggregation; Purpura, Thrombocytopenic; Serotonin; von Willebrand Diseases

Topics: Adult; Arm; Biopsy; Blood Coagulation; Blood Platelets; Blood Transfusion; Blood Vessels; Collagen; Endothelium; Erythrocytes; Female; Fibrin; Granulation Tissue; Hemorrhage; Humans; Male; Microscopy, Electron; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Time Factors; von Willebrand Diseases; Wounds and Injuries

Topics: Fibrin; Hemophilia A; Humans; von Willebrand Diseases