Tissue thromboplastin activates

Ref Robbins 9/e, p 118 Coagulation Cascade The coagulation cascade constitutes the third arm of the hemostatic system. The pathways are schematically pre- sented in Figure 3-8; only general principles are discussed here. The coagulation cascade is a successive series of ampli- fying enzymatic reactions. At each step in the process, a proenzyme is proteolyzed to become an active enzyme, which in turn proteolyzes the next proenzyme in the series, eventually leading to the activation of thrombin and the formation of fibrin. Thrombin has a key role, as it acts at numerous points in the cascade (highlighted in Fig. 3-8). Thrombin proteolyzes fibrinogen into fibrin monomers that polymerize into an insoluble gel; this gel encases platelets and other circulating cells in the definitive secondary hemostatic plug. Fibrin polymers are stabilized by the cross-linking activity of factor XIIIa, which also is activated by thrombin. Each reaction in the pathway depends on the assembly of a complex composed of an enzyme (an activated coagula- tion factor), a substrate (a proenzyme form of the next coag- ulation factor in the series), and a cofactor (a reaction accelerator). These components typically are assembled on a phospholipid surface (provided by endothelial cells or platelets) and are held together by interactions that depend on calcium ions (explaining why blood clotting is preventedby calcium chelators). Figure 3-8 The coagulation cascade. Factor IX can be activated by either factor XIa or factor VIIa: In laboratory tests, activation is predominantly dependent on factor XIa, whereas in vivo, factor VIIa appears to be the predominant activator of factor IX. Factors in red boxes represent inactive molecules; activated factors, indicated with a lowercase a, are in green boxes. Note that thrombin (factor IIa) (in light blue boxes) contributes to coagula- tion through multiple positive feedback loops. The red X's denote points at which tissue factor pathway inhibitor (TFPI) inhibits activation of factor X and factor IX by factor VIIa. HMWK, high-molecular-weight kininogen; PL, phospholipid.