Two Phases of Coagulation

It can be helpful to consider secondary hemostasis as a process that occurs in two distinct phases. The initiation phase, triggered by the release of tissue factor into the bloodstream, results in the production of a relatively small amount of thrombin through the extrinsic pathway. Once this first thrombin is produced, the propagation phase of coagulation begins. Thrombin drives the conversion of factors V and VIII to their activated forms. Activated factor VIII combines with activated factor IX to produce the very powerful tenase complex. This complex drives the accelerated production of thrombin in a cycle that feeds on itself in an explosive manner.

The second phase of coagulation rapidly becomes the predominant mechanism of fibrin generation. In many ways, the two-phase process of coagulation can be compared to the ignition and subsequent explosion of a stick of dynamite. The first phase can be thought of as the slow-burning fuse that ignites the explosion of the second phase. This mental construct can help one to understand a fundamental limitation of one of the most common tests of coagulation: the prothrombin time (PT). The minimal amount of thrombin generated through tissue factor activation of the extrinsic pathway is adequate to produce quickly a detectable clot in the PT assay. The amplified thrombin generation associated with the second phase of coagulation is not required to produce a normal PT. This explains the fact that deficiencies of intrinsic pathway factors VIII, IX, and XI that produce the severe bleeding of hemophilia A, B, and C, respectively, do not typically produce an extended PT.

Effective physiologic coagulation requires the second (explosive) phase of thrombin generation, but clot formation in PT does not. PT is only sensitive to variations of components of the extrinsic pathway: factors VII, X, V, II, and fibrinogen. A more complete review of the clinical relevance and analytic testing for individual coagulation pathway factors can be found under their individual test descriptions.

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