The clotting cascade involves the extrinsic and intrinsic pathways, both of which converge at FXa to form the common pathway. Protein factors (F) with trypsin-like specificity, including FII, FVII, FIX, and FX, form a fibrin meshwork. Calcium binds to the negatively charged γ-carboxyglutamate (Gla) residues in these clotting proteases, enabling them to bind to exposed phosphatidylserine at the injury site and on platelets. γ-Glutamyl carboxylase and vitamin K (in its hydroquinone form) are necessary for Gla residue formation. During this process, vitamin K is oxidized to its nonfunctional epoxide form. Warfarin, a synthetic analog of vitamin K, inhibits the enzyme vitamin K epoxide reductase, which restores the functional reduced form. The extrinsic pathway begins with the exposure of tissue factor (TF or FIII) in the subendothelium. TF binds to circulating FVII, triggering its activation. The TF-FVIIa complex then activates FX through proteolysis. FXa, from the extrinsic pathway, leads to thrombin production via the common pathway. Thrombin, in turn, activates components of the intrinsic pathway. The tissue factor pathway inhibitor rapidly inhibits the extrinsic pathway. The intrinsic pathway is initiated by FXIIa, which activates FXI, and FXIa then activates FIX. FIXa combines with FVIIIa, activating FX. Hemophilia A results from FVIII deficiency, while hemophilia B stems from FIX deficiency. FXa, along with FVa, forms prothrombinase, which cleaves prothrombin (FII) to form thrombin (FIIa). Thrombin cleaves fibrinogen (FI) to form fibrin (FIa). The soluble fibrin clot is formed by the association of fibrin monomers, which are cross-linked by FXIIIa, a transglutaminase, to form the insoluble fibrin clot. The liver and blood vessels synthesize proteins that balance coagulation and anticoagulation. Antithrombin III, a serine protease inhibitor, binds to and removes thrombin from the blood. Heparin increases its affinity for thrombin and is used therapeutically to limit clot formation. Protein C, a Gla-containing protein, is activated by the thrombin-thrombomodulin complex. Thrombomodulin reduces thrombin's affinity for fibrinogen, transforming it from a coagulation protein to an anticoagulation protein. The complex of protein C and protein S (another Gla-containing protein) forms the activated protein C (APC) complex, which cleaves the accessory proteins FVa and FVIIIa. FV Leiden is resistant to APC and is the most common inherited thrombophilic condition in the United States. Fibrinolysis, the cleavage of the fibrin clot, is carried out by the serine protease plasmin, generated from plasminogen by plasminogen activators like tissue plasminogen activator (TPA or t-PA). Clinically, recombinant TPA is used.
The formation of the fibrin meshwork by the clotting cascade involves the extrinsic and intrinsic pathways (and their associated protein factors [F]) that converge at FXa to form the common pathway. Many of the protein factors are serine proteases with trypsin-like specificity. Calcium binds the negatively charged γ-carboxyglutamate (Gla) residues present in certain of the clotting proteases (FII, FVII, FIX, and FX), facilitating the binding of these proteins to exposed negatively charged phosphatidylserine at the site of injury and on the surface of platelets. γ-Glutamyl carboxylase and its coenzyme, the hydroquinone form of vitamin K, are required for formation of Gla residues. In the reaction, vitamin K gets oxidized to the nonfunctional epoxide form. Warfarin, a synthetic analog of vitamin K used clinically to reduce clotting, inhibits the enzyme vitamin K epoxide reductase that regenerates the functional reduced form. The extrinsic pathway is initiated by exposure of FIII (tissue factor [TF]), an accessory protein, in vascular subendothelium. Exposed TF binds a circulating Glacontaining protein, FVII, activating it through conformational change. The TF–FVIIa complex then binds and activates FX by proteolysis. FXa from the extrinsic pathway allows thrombin production by the common pathway. Thrombin then activates components of the intrinsic pathway. The extrinsic pathway is rapidly inhibited by tissue factor pathway inhibitor. The intrinsic pathway is initiated by FXIIa. FXIIa activates FXI, and FXIa activates FIX. FIXa combines with FVIIIa (an accessory protein), and the complex activates FX. FVIII deficiency results in hemophilia A, whereas FIX deficiency results in the less common hemophilia B. FXa associates with FVa (an accessory protein), forming prothrombinase that cleaves prothrombin (FII) to thrombin (FIIa). Thrombin then cleaves fibrinogen to fibrin (FIa). Fibrin monomers associate, forming a soluble (soft) fibrin clot. The fibrin molecules get cross-linked by FXIIIa, a transglutaminase, forming an insoluble (hard) fibrin clot. Proteins synthesized by the liver and by blood vessels themselves balance coagulation with anticoagulation. Antithrombin III, a serine protease inhibitor, or serpin, binds to and removes thrombin from the blood. Its affinity for thrombin is increased by heparin, which is used therapeutically to limit clot formation. Protein C, a Gla-containing protein, is activated by the thrombin–thrombomodulin complex. Thrombomodulin decreases thrombin’s affinity for fibrinogen, converting it from a protein of coagulation to a protein of anticoagulation. Protein C in complex with protein S (a Gla-containing protein) forms the activated protein C (APC) complex that cleaves the accessory proteins FVa and FVIIIa. FV Leiden is resistant to APC. It is the most common inherited thrombophilic condition in the United States. The fibrin clot is cleaved (fibrinolysis) by the protein plasmin, a serine protease that is generated from plasminogen by plasminogen activators such as tissue plasminogen activator (TPA, t-PA).
Recombinant TPA is used clinically.