Fibrin formation, mechanism

Activated factor XII leads to the activation of factor XI in turn, activated factor XI, along with Ca++ ions and factor IV, leads to activation of factor IX. Activated factor IX, along with Ca++ ions, factor VIII, and PF3, leads to the activation of factor X. From the point of factor X activation, the extrinsic and intrinsic mechanisms follow the same pathway to fibrin formation. 

Mechanism of action - Argatroban is a synthetic, direct thrombin inhibitor that reversibly binds to the thrombin active site. It inhibits thrombin-catalyzed or induced reactions, including fibrin formation activation of coagulation factors V, VIII, and XIII protein C and platelet aggregation. 

Summary - Many diverse novel compounds that inhibit different platelet functions show great promise, not only for potential anti-thrombotic agents, but also for more specific effects on prostaglandin and/or thromboxane A2 synthesis, and serotonin or calcium uptake and release. Many active compounds can be used as tools in the search toward a more complete understanding of the physiologic interactions of the hemostatic mechanisms. This better understanding would lead to the development and use of more potent and selective synthetic compounds in the inhibition of platelet aggregation and fibrin formation, and in the enhancement of fibrinolysis for the control of both arterial and venous thrombosis. It is hoped that some of these new compounds will be evaluated clinically in the near fu ture. 

Thrombosis and Its Clinical Implications As a normal hemostatic response to limit hemorrhage from microscopic or macroscopic vascular injury, the body undergoes a process termed local thrombosis. Specific proenzymes and proteins, platelets, and calcium participate in this process. The end result is the formation of insoluble fibrin, which mechanically blocks the flow of blood through ruptured vessels.55 Thrombosis is usually counterbalanced by physiological anticoagulation and thrombolysis. Under normal conditions, the thrombus is confined to the area of vessel injury and rarely obstructs flow to critical areas. However,... 

Therapy for the control or prevention of the acute events in death due to vascular disease can be approached in several ways. One general approach would be to control the interaction of blood components with the diseased blood vessel or with each other. In both these cases antithrombotic agents of diverse mechanism should be helpful. Whether control of fibrin formation, fibrinolysis or platelet function is desirable, each patient s problem would dictate the therapy best suited. Several reviews are available in which the different blood coagulation mechanisms that may be helpful in such therapy are discussed s " Reviews have also been published in which methodology is discussed for the testing of compounds and for the determination of abnormalities in platelet function. ... 

Blood coagulation resulting in the formation of a stable fibrin clot involves a cascade of proteolytic reactions involving the interaction of clotting factors, platelets, and tissue materials. Clotting factors (see table) exist in the blood in inactive form and must be converted to an enzymatic or activated form before the next step in the clotting mechanism can be stimulated. Each factor is stimulated in turn until an insoluble fibrin clot is formed. 

Mechanism of Action A blood modifier that interferes with blood coagulation by blocking conversion of prothrombin to thrombin and fibrinogen to fibrin Therapeutic Effect Prevents further extension of existing thrombi or new clot formation. Has no effect on existing clots. 

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. 

Fibrin polymers are responsible for the fibrin-dependent enhancement of Factor XIII activation (Greenberg et al, 2003). The mechanism for this effect involves the formation of a tight ternary complex between fibrin, Factor XIII, and thrombin, accompanied by a conformational change of Factor XIII that exposes the active site, after which Factor XHIa remains bound to fibrin. However, the B chains dissociate, which is necessary to expose the active site cysteine of plasma Factor XIII. Platelet Factor XIII without the B chains, is more rapidly activated by thrombin than plasma Factor XIII because of the time that it takes for the B chains to dissociate. 

SidelmannJJ, Gram J, Jespersen J, Kluft C. Fibrin clot formation and lysis basic mechanisms. Semin Thromb Hemost. 2000 26 605-618. 

Id vivo, the infusion of small amounts of thrombin (<200 NIH-U/kg/h) causes defibrinogenation. Because of the slow transformation of fibrinogen, the fibrin monomers formed are eliminated via reactive fibrinolysis and RES without precipitation of fibrin. Upon infusion of higher amounts of thrombin, these clearance mechanisms fail bo offset the thrombin action, which then leads to the formation of microthmmbi in the peripheral circulation. Correspondingly, the bolus injection of 1500 NIH-U thrombin/kg caused death of the experimental... 

---