The Clot Thickens in Atherosclerosis.

The clotting cascade plays an essential role in hemostasis but also contributes to many pathological processes, such as thrombosis. The cascade can be divided into 2 major phases: initiation and amplification (Figure). The initiation phase is triggered by the tissue factor/factor VIIa complex (known as the extrinsic pathway) and generates small amounts of thrombin that activates cofactors (FVIIIa and FVa) and proteases (FXIa). The tissue factor/factor VIIa complex is rapidly inactivated by tissue factor pathway inhibitor. The amplification phase is driven by components of the intrinsic pathway (FXIIa, FXIa, FIXa, and FVIIIa) and generates large amounts of thrombin. Importantly, individuals with deficiencies in either FVIII (hemophilia A) or FIX (hemophilia B) are prone to spontaneous hemorrhages. In contrast, individuals lacking FXI rarely exhibit any spontaneous hemorrhages. These observations suggest that FVIII and FIX form a primary amplification loop in thrombin generation, whereas FXI could be considered as a secondary amplification loop (Figure).