Thrombin

Thrombin is a central serine protease in blood coagulation, generated from its zymogen prothrombin by the prothrombinase complex on phospholipid surfaces in the presence of calcium. Prothrombin is produced by the liver and requires vitamin K–dependent gamma-carboxylation for calcium binding and activity. Activation occurs in the common pathway when factor Xa, with factor Va, converts prothrombin to active thrombin.

Thrombin acts on multiple substrates to promote clot formation. It cleaves fibrinogen to form fibrin monomers and, with factor XIIIa, cross-links them to form a stable clot. It also activates platelets via protease-activated receptors (PAR-1 and PAR-4), amplifying aggregation and secretion. Thrombin further accelerates coagulation by activating cofactors V, VIII, and XI, thereby enhancing thrombin generation in a positive feedback loop. In addition, it activates thrombin-activatable fibrinolysis inhibitor (TAFI), which dampens fibrinolysis, helping to stabilize the clot.

Regulation of thrombin is tight and involves several checks. Antithrombin III neutralizes thrombin, with activity greatly enhanced by heparin. Endothelial thrombomodulin binds thrombin to form a complex that activates protein C; activated protein C, with protein S, inactivates factors Va and VIIIa, reducing further thrombin production. Tissue factor pathway inhibitor (TFPI) also modulates initiation of coagulation. Dysregulation of thrombin activity can lead to bleeding or thrombotic disorders, and therapeutic agents such as direct thrombin inhibitors are used as anticoagulants in clinical practice.