a | Traditional 'waterfall' model of the clotting cascade. Serine proteases (oval) and cofactors or other proteins (rectangles) of the intrinsic and extrinsic pathways converge at coagulation factor X (FX; coagulation factors are indicated using only the Roman numerals in the figure) in the common pathway and ultimately generate a stable fibrin clot. Amplification of the pathway occurs through the serial cleavage of clotting factors. The proteins that are absent in patients with haemophilia A or B, when activated, comprise the 'tenase' complex and are shown in pink. Selected non-factor therapies are shown in grey. b | Typical thrombin generation curve (thrombin concentration versus time) with the clotting phases indicated. Low levels of thrombin are generated during the initiation and amplification phases. The majority of the thrombin is generated in the propagation phase ('thrombin burst'). During the termination phase, negative regulators bring the thrombin concentration back to baseline. c | Cell-based model of coagulation. Initiation occurs when blood is exposed to a tissue factor (TF)-bearing cell owing to vascular damage. TF–activated FVII (FVIIa) generates traces of FXa, FIXa and thrombin (shown as II). This initiation is negatively regulated by TF pathway inhibitor (TFPI) inactivation of FVIIa and FXa. The initial amplification step occurs on the non-activated platelet surface, where thrombin activates components of the cascade, including FVa from FV, which is released from the platelet, as well as FVIIIa, which thrombin activates and releases from von Willebrand factor (VWF) and FXIa. Thrombin also activates platelets, thus generating a prothrombotic activated platelet surface, where most of the thrombin generation takes place in the propagation phase, further amplified by thrombin -mediated activation of upstream regulators (FXI, FVIII and FV), and leads to fibrin clot formation. Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). This activation leads to the termination phase, during which thrombin generation is downregulated through a combination of FVIIIa instability and inactivation of the activated factors by negative regulators such as antithrombin III (ATIII; which inhibits thrombin as well as FXa and FIXa) and APC (which cleaves FVIIIa and FVa). Ab, antibody; PS, protein S; siRNA, small interfering RNA.