Merck Manual

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Major modulatory interactions of coagulation inhibitors and fibrinolysis with the coagulation cascade
Major modulatory interactions of coagulation inhibitors and fibrinolysis with the coagulation cascade

    The antithrombin anticoagulant pathway—The anticoagulant antithrombin (AT) is a serine protease inhibitor that physiologically inactivates thrombin (FIIa) and FXa and, to a lesser extent, FIXa, FXIa, and FXIIa.

    The protein C anticoagulant pathway—Protein C (PC) and protein S (PS) are vitamin K–dependent serine proteases. PC is the precursor to the protease referred to as activated protein C (PCa). PS is a nonenzymatic cofactor that enhances activity of PCa. PC exerts its antithrombotic effect when bound to a specific endothelial protein C receptor (EPCR); this binding enhances its activation to PCa and localizes its effect to endothelial surfaces. PCa proteolytically inactivates clotting factors FVa and FVIIIa on the platelet surface.

    Fibrinolysis—The major fibrinolytic enzyme is plasmin, formed from plasminogen by plasminogen activators such as tissue plasminogen activator (tPA). tPA is synthesized by endothelial cells in response to ischemia or hypoxia and thrombin. tPa is modulated by plasminogen activator inhibitor-1 (PAI-1), which is synthesized by hepatocytes, endothelial cells, adipocytes, and other cell types. alpha2-antiplasmin (alpha2-AP) is the major plasma inhibitor of plasmin in the circulation. Thrombin-activatable fibrinolysis inhibitor (TAFI) circulates as a proenzyme and is converted to a potent attenuator of the fibrinolytic system upon activation by thrombin, plasmin, or the thrombin-thrombomodulin complex. Functionally, TAFI downregulates fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin, thereby preventing the upregulation of plasminogen binding and activation. Clot breakdown products include D-dimer and FDPs (fibrinogen and fibrin degradation products, which are circulating fragments of fibrinogen and soluble fibrin).

Courtesy of Dr. Sharon Center,