The coagulation cascade leading clot formation upon tissue injury is initiated by two different routes, intrinsic or contact factor pathway and extrinsic or tissue factor pathway. The intrinsic pathway starts with activation of Factor XII, then Factor XI, and Factor IX. The extrinsic pathway starts with the interaction of Tissue Factor (TF, Factor III) with Factor VII in the presence of Ca2+ (Factor IV). Both the IXa-VIIIa complex from the intrinsic pathway and the TF-VIIa complex from the extrinsic pathway convert Factor X to Xa, which in the Xa-Va complex activates Thrombin (Factor II). Thrombin cleaves Fibrinogen (Factor I) into Fibrin, which is cross-linked by XIIIa/Transglutaminase to form the Fibrin clot.
There are many additional regulatory factors involved in the coagulation cascade. For example, Factor XI and plasma Kallikrein (KLKB1) circulate in blood as separate complexes with high molecular weight Kininogen (HK). Similarly, von Willebrand factor (vWF) is a carrier for Factor VIII. Binding of thrombin to one of its receptors, Thrombomodulin/THBD/CD141, activates protein C-protein S complex, which degrades Factors Va and VIIIa and reduces the amount of Thrombin generated. Coordinate reduction of V and VIII due to the defects in MCFD2/SDNSF results in an autosomal recessive bleeding disorder. Activated Factors II, VII, IX, X, XI and XII and Protein C are inhibited by serine protease inhibitors such as alpha 2-Macroglobulin, TFPI/LACI, and Serpins A1, A5, C1 and D1. After Thrombin activation, Carboxypeptidase B2/CPB2/TAFI inhibits Fibrinolysis and stabilizes the Fibrin clot.