Formation of Fibrin

Increased clotting may occur in the presence of thrombosis (enhanced formation of fibrin), stasis and phlebitis (diminished circulation), or embolism (dislocation and lodging of blood clots). Although heparin is an extremely effective anticoagulant, it has certain limitations that are not shared by the newer thrombin inhibitors. As a result, these novel inhibitors may have advantages over heparin for use in certain clinical settings. 

Thrombin activates platelets, converts fibrinogen to fibrin, activates factor XIII, which stabilizes fibrin, and activates factors V and Vni, which accelerate the generation of prothrombinase. Therefore, the inhibition of thrombin is essential in preventing and treating thromboembolic disorders. 

Platelets circulate in blood without adhering to other platelets or to the endothelium. However, when the endothelial cells are perturbed, the platelets adhere and undergo a change in shape, and aggregate. ADP is known to induce 

Hageman factor (XII), antihemophihc globuhn (VIII), Christmas factor (IX), plasma diromboplastin antecedent (XI), calcium (IV), and platelet phospholipids Tissue diromboplastin (III), Stuart factor (X), proconvertin (VII), and calcium (IV) 

Note In fibrinolysis, plasmin, an endopeptidase diat is converted from plasminogen by an activator, hydrolyzes fibrin, fibrinogen, factor V, and factor VIII to their inactive products. Hageman factor (factor XII) converts a proactivator to die active activator. Agents such thrombin, streptokinase, and urokinase therefore enhance the formation of plasmin and, hence, have fibrin lytic properties. Epsilon-aminocaproic acid inhibits the activator-mediated formation of plasmin and, hence, may be used as an antidote to streptokinase-urokinase or in a defibrination syndrome when bleeding from a mucous membrane occurs. 

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They release adenosine diphosphate [58-64-0 (ADP) and thromboxane [57576-52-0] which results in vascular contraction and, indirectiy, in the formation of fibrin clot. Platelet transfusions are indicated for patients with thrombocytopenia, ie, a shortage of healthy platelets or thrombocytopathy, ie, platelet malignancy associated with spontaneous hemorrhages. 

Primary hemostasis is the first phase of hemostasis consisting of platelet plug formation at the site of injury. It occurs within seconds and stops blood loss from capillaries, arterioles, and venules. Secondary hemostasis, in contrast, requires several minutes to be complete and involves the formation of fibrin through the coagulation cascade. 

Heparin inhibits the formation of fibrin clots, inhibits the conversion of fibrinogen to fibrin, and inactivates several of the factors necessary for the clotting of blood. Heparin cannot be taken orally because it is inactivated by gastric acid in the stomach therefore, it must be given by injection. Heparin has no effect on clots that have already formed and aids only in preventing the formation of new blood clots (thrombi). The LMWHs act to inhibit clotting reactions by binding to antithrombin HI, which inhibits the synthesis of factor Xa and the formation of thrombin. 

We shall first describe the coagulation pathway leading to the formation of fibrin. Then we shall briefly describe some aspects of the involvement of platelets and blood vessel walls in the overall process. This separation of clotting factors and platelets is artificial, since both play intimate and often mutually interdependent roles in hemostasis and thrombosis, but it facifitates description of the overall processes involved. 

Both Intrinsic Extrinsic Pathways Result in the Formation of Fibrin... 

By far the most widely measured marker of hemostatic activation is D-dimer, which is a product formed by the action of plasmin on cross-linked fibrin (95). D-dimer levels in plasma are generally elevated in DIC. The consumption of platelets and coagulation proteins as a result of thrombin generation leads to the deposition of fibrin thrombi at multiple organ sites. This triggers fibrinolysis with an increase in the formation of fibrin degradation products, which can cause bleeding at multiple sites. Because DIC can have a variety of causes and may coexist with systemic fibrinolysis, such as in pulmonary embolism or deep vein thrombosis, the d-Dimer test is not specific for DIC (95). 

Mecfianism of Action A systemic hemostatic that acts as an antifibrinolytic and an-tihemorrhagicby inhibitingthe activation of plasminogen activator substances. Therapeutic Effect Prevents formation of fibrin dots. 

Coagulation of blood comprises the formation of fibrin. There are thirteen factors (synthesized in liver) which are involved in the coagulation of blood. 

THROMBIN. A proteolytic enzyme that catalyzes the conversion of fibrinogen to fibrin and thus is essential in the clotting mechanism of blood. It is present in the blood in die form of prothrombin under normal conditions when bleeding begins, the prothrombin is converted to thrombin, which in turn activates the formation of fibrin. 

See color plate.) The coagulation cascade. The formation of fibrin strands is the result of a sequential activation of a number of enzymes. The hemostatic balance is maintained by endogenous inhibitors such as AT, HC-II, and TFPI. Abbreviations AT, antithrombin TFPI, tissue factor pathway inhibitor. 

Factor VII exhibits a weak procoagulant activity on its own, typically accounting for about I -2% of the total factor Vll/Vlla activity (17), Upon binding to tissue factor, a 10,000,000-fold increase in factor Vila enzymatic activity is observed (18). Both factor VII and factor Vila bind to tissue factor with equal affinity (19), How factor VII is initially activated is not known, though it is hypothesized that factor Xa can activate factor VII in a back-activation reaction. The factor VIla—tissue factor complex can then activate factor X leading to the generation of thrombin and ultimately to the formation of fibrin strands. 

Pharmacologic inhibitors of thrombin. Thrombin is a key enzyme in the hemostatic system in that it leads to the formation of fibrin strands and is a potent stimulus for platelet activation. Thrombin inhibitors, factor Xa inhibitors, and antiplatelet drugs act at different points in the hemostatic system to regulate the amount of thrombin that is generated. 

His other major contribution lies in the mechanism of the formation of fibrin from fibrinogen. He was quick to appreciate the power of the... 

Formation of fibrin (coagulation), which stabilises the platelet plug... 

Figure 4 Simplified schematic representation of the blood coagulation system leading to the formation of fibrin. Further details are given in the text for comprehensive reviews see references 29 and 30.

There is a fine line between hemorrhage and thrombosis. Clots must form rapidly yet remain confined to the area of injury. What are the mechanisms that normally limit clot formation to the site of injury The lability of clotting factors contributes significantly to the cont ol of clotting. Activated factors are short-lived because they are diluted by blood flow, removed by the liver, and degraded by proteases. For example, the stimulatory protein factors V , and VIIC are digested by protein C, a protease that is switched on by the action of thrombin. Thus, thrombin has a dual function it catalyzes the formation of fibrin and it initiates the deaclivation of the clotting cascade. 

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