Overview of hemostasis. There are two pathways to initiate coagulation: the primary extrinsic pathway (shown on the right) and the intrinsic (also called the contact pathway) (shown on the left). The components of these multistep processes are illustrated as follows: enzymes (pink circles), inhibitors (blue circles), zymogens (green boxes), or complexes (cream ovals). The intrinsic pathway has no known bleeding etiology associated with it; thus, this pathway is considered accessory to hemostasis. Upon an injury to the vessel wall, TF, a membrane-bound cofactor, is exposed to circulating factor VIIa, forming the extrinsic factor Xase, a complex enzyme. Factor IX and factor X are converted to the serine proteases factor IXa and factor Xa, which are the enzymatic components of the intrinsic factor Xase and the prothrombinase complexes, respectively. The combined action of all three complexes lead to an explosive burst of thrombin (FIIa). Once thrombin is generated, it cleaves fibrinogen (releasing fibrinopeptides A and B (FPA and FPB, resp.)) and activates factor XIII to form a cross-linked fibrin clot. Thrombin-thrombomodulin also activates thrombin-activatable fibrinolysis inhibitor (TAFI) that slows down fibrin degradation by plasmin. Thrombin has also been shown to activate factor XI. In addition to its multiple procoagulant roles, thrombin also acts as an anticoagulant when combined with the cofactor thrombomodulin in the protein Case complex. The product of the protein Case reaction, activated protein C (APC), inactivates the cofactors factors Va and VIIIa. The cleaved species, factors (FV) and VIIIai (FVIII), no longer support the respective procoagulant activities of the prothrombinase and the intrinsic factor Xase complexes. TF-triggered procoagulant response is also down-regulated by the stoichiometric inhibitors tissue factor pathway inhibitor (TFPI) and antithrombin (AT). TFPI serves to attenuate the activity of the extrinsic factor Xase, the trigger of coagulation. AT directly inhibits thrombin, factor IXa, and factor Xa. High molecular weight (HMW) kininogen is one of components of the intrinsic pathway. (An original version of this figure was published in Wintrobe’s Clinical Hematology) [8].
