Blood coagulation or clotting takes place in 3 essential phases. The first phase is the activation of a prothrombin activator complex. The second phase is the activation of prothrombin. The third stage is clot formation as a result of fibrinogen cleavage by activated thrombin. (See Fibrinolysis Pathway)The prothrombin activation complex is formed by two pathways each of which results in a different form of the prothrombin activator. The intrinsic mechanism of prothrombin activator formation begins with trauma to the blood or exposure of blood to collagen in a traumatized vessel wall. This usually also results in damage to fragile platelets. The formation of a clot by this mechanism usually takes 1 to 6 minutes. This cascade begins with the activation of factor XII and the release of platelet factor 3 (PF3) from damaged platelets. Activated factor XII cleaves and actives factor XI and prekallikrein (PK). Factor XII is also activated by activated prekallikrein (aPK) in an internal amplification loop. Calcium (Ca++) is required for the initial three steps. The prothrombin activator in the intrinsic pathway is very similar to the activator in the extrinsic pathway. Antithrombin III inhibits the activity of thrombin and also two of the steps in the formation of the activator. Protein C is activated by thrombin and with the Protein S cofactor provides a strong negative feedback in this phase of clot formation.When blood is collected, the intrinsic pathway is activated by contact with the collection devices causing damage to the platelets and activation of factor XII. Antithrombin III is a hundred to a thousand times more effective when bound by heparin. Use of “nonwettable” surface materials can increase the clot formation time to over an hour. Disease Significance:Most of the clotting factors are formed in the liver. Diseases of the liver or damage to the liver can depress the levels of these factors in the blood resulting in excessive bleeding. Vitamin K deficiency can also result in a similar condition since Vitamin K is essential for the formation of factor VII, IX, X and prothrombin. Vitamin K is synthesized in the intestinal tract by bacteria.
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