(A) Schematic representation of the procoagulant part of the coagulation cascade, indicating the proteins for which the prothrombin time (PT; red) and activated partial thromboplastin time (aPTT; gray) are sensitive. The proteins of the contact activation pathway are not depicted for clarity and because these proteins are not required for physiologic hemostasis. (B) Schematic representation of the coagulation system. Exposure of tissue factor (TF), a transmembrane protein present on numerous cell types in the extracellular matrix, initiates the coagulation system via activation of coagulation factors IX and X by the TF-VIIa complex. Thrombin is generated by the intrinsic and extrinsic tenase system (which consists of activated coagulation factors IXa and Xa complexed with their nonenzymatic cofactors VIIIa and Va, respectively). Thrombin-mediated activation of coagulation factor XI further amplifies thrombin generation. Thrombin is a central enzyme in the hemostatic system as it not only converts fibrinogen to fibrin, but it is also an activator of platelets and has multiple other substrates that regulate hemostasis. Thrombin formation is regulated by anticoagulant proteins (interrupted lines) that act in the initiation phase (tissue factor pathway inhibitor [TFPI]), inactivate the nonenzymatic cofactors VIIIa and Va (the protein C system), and directly inactivate thrombin (antithrombin [AT]). The protein C pathway is initiated by the thrombin–thrombomodulin (TM) complex. Once thrombin binds TM, which is a protein localized on endothelial cells, it loses the ability to convert fibrinogen to fibrin and becomes able to activate protein C. Activated protein C (APC) together with its nonenzymatic cofactor protein S (PS) enzymatically inactivates VIIIa and Va.