The physiologic coagulation cascade is felt to occur in vivo. This pathway is somewhat different from the traditional waterfall hypothesis. Factor XII is not included in this scheme because patients with isolated deficient Factor XII activity do not have bleeding problems. Therefore Factor XII probably does not play the role originally hypothesized in the classic waterfall hypothesis. In the physiologic cascade, the extrinsic pathway is the initiator of events. Normal non-vascular cells have a protein on their cell membranes called tissue factor. Endothelial cells, however, do not. Under normal circumstances, blood and its constituents are not exposed to tissue factor. When either blood vessel or tissue injury occurs, the plasma becomes exposed to tissue factor, allowing a complex between Factor VII and tissue factor to form. Factor VII is then activated to VIIa. The tissue factor-Factor VIIa complex subsequently catalyzes the initial activation of Factor IX (to IXa) and Factor X (to Factor Xa). When the concentration of tissue factor is high, preferential activation of Factor X occurs. However, when the concentration of tissue factor is low, it is felt that activation of Factor IX is predominant.. When formed, Factor IXa participates in further activation of X to Xa. Once Xa is formed, it in the presence of activated Factor V can catalyze the conversion of prothrombin to thrombin, which in turn catalyzes the conversion of fibrinogen to fibrin, the main constituent of a clot. This mechanism is felt to generate only limited amounts of thrombin. When small quantities of thrombin have been generated, thrombin may bind and activate a protein called Tissue Factor Pathway Inhibitor (TFPI). The thrombin-TFPI complex then inactivates the earlier formed Factor VII-tissue factor complexes, thus inhibiting further synthesis of Factor IXa and Xa through that mechanism, representing a negative feedback system thus controlling hemostasis.
How then is coagulation sustained? Well, the thrombin initially synthesized through the initial Factor VII-tissue factor complex pathway also has other functions that are procoagulant in nature. One of the main functions is to catalyze the activation of Factors XI, IX, VIII, and X. In this manner, the intrinsic pathway is activated, leading to generation of more thrombin, which can continue to catalyze the conversion of more fibrinogen to fibrin and hence sustaining the clotting mechanism. Therefore, it is felt that the extrinsic pathway is paramount in generation of enough thrombin to initiate coagulation and that this thrombin then activates the intrinsic pathway which in turn maintains coagulation.
|
|
|
|