List of Lessons
The Coagulation Mechanism
The classical theory of Morowitz proposed that four components interact to form a clot as follows:
From this concept, the modern theory was devised. The modern theory is based on four stages: (I) the formation of thromboplastin, (II) the conversion of prothrombin to thrombin, (III) formation of an insoluble fibrin clot through the interaction of fibrinogen and thrombin, and (IV) the lysis of the fibrin clot by fibrinolysin. These stages are illustrated in Figure 8-3.
Figure 8-3. Stages of coagulation.
STAGES OF COAGULATION
Stage I--The Generation of Plasma Thromboplastin. Stage I involves the information of intrinsic (plasma) thromboplastin. This stage is initiated by the platelets adhering and rupturing, releasing platelet factor 3. Platelet factor 3 reacts with factor XII, along with prekallikrein and high molecular weight kininogen (HMWK), PTA (factor XI), PTC (factor IX), AHF (factor VIII) and in the presence of calcium (factor IV), factor X, and factor V to form intrinsic thromboplastin. Tissue thromboplastin or extrinsic thromboplastin is released by the affected tissues.
Stage II--The Formation of Thrombin from Prothrombin. In the intrinsic system, prothrombin is converted to thrombin in the presence of plasma thromboplastin, calcium, and factors V and X, and platelets. The extrinsic system requires the presence of an additional factor, factor VII, for the conversion of prothrombin to thrombin.
Stage III--The Formation of Fibrin from Fibrinogen. After the thrombin is generated, it quickly reacts with fibrinogen to form a fine fibrin fiber. The fibrin fibers polymerize (form a mesh with other fibers with disulphide bonds) in conjunction with calcium ions and factor XIII, the fibrin-stabilizing factor, to form a stabilized clot. The stabilized clot is characterized by its insolubility in 5 M urea.
Stage IV--Clot Lysis. This stage involves the fibrinolytic dissolution of the clot. Circulating plasminogen can be converted to its active form plasmin, by both intrinsic and extrinsic factors. The intrinsic factors, which are present in circulation plasma include: factor XII, prekallikrein, HMWK, and pro-urokinase. The extrinsic factors, which are present in body tissues are: tissue plasminogen activator (t-PA), urokinase (UK), and streptokinase (SK). Plasmin, which is a serine protease, hydrolyzes arginine and lysine bonds that are present in fibrin, fibrinogen, and factors V and VIII. Thus, the clot in the presence of plasmin is dissolved, forming a series of fragments called fibrin or fibrinogen degredation products (FDP) or fibrin or fibrinogen split products (FSP). These fragments FDP-FSP will inhibit platelet aggregation and conversion of fibrinogen by thrombin.
In addition to the factors necessary for clot formation, inhibitors are present which control but do not prevent coagulation. Natural inhibitors have been described for virtually every clotting factor. Clotting activity is also inhibited by the administration of anticoagulants such as heparin and coumarin derivatives.