The pivotal role of thrombin in coagulation


Coagulation is triggered in DIC via the extrinsic pathway, when FVII binds extravascular or intravascular tissue factor (TF), forming an autocatalytic complex. This binds to and activates FX; the TF-FVIIa-FXa complex then converts small amounts of prothrombin to thrombin. Thrombin amplifies its own production via the intrinsic pathway through FXI, which in turn activates FIX. Thrombin also activates the cofactors, FVIII and FV. Factor IXa forms a potent enzymatic (“tenase”) complex with FVIIIa and calcium, which activates FX. Factor Xa, with FVa as a cofactor and calcium (“prothrombinase” complex) generates an explosive burst of thrombin. The initiation of coagulation and the thrombin burst occurs on negatively charged surfaces. These are usually negatively charged phosphatidylserine-expressing cell membranes and membrane-derived extracellular vesicles (EV) provided by activated platelets, as well as other cells, although negatively charged DNA and histones in extracellular traps can also provide the necessary scaffold for thrombin generation. The thrombin burst cleaves fibrinogen to fibrin and activates factor XIII (FXIII) (which cross-links fibrin) and platelets, while simultaneously inhibiting fibrinolysis via activation of thrombin-activatable fibrinolytic inhibitor (TAFI). Release of short chain polyphosphates from activated platelets contributes to inhibition of fibrinolysis and activation of factor V, thus boosting thrombin generation. Thrombin also limits its own production by binding to thrombomodulin on endothelial cell surfaces, which activates protein C in the presence of the endothelial protein C receptor (EPCR). Activated protein C with free protein S as a cofactor decelerates thrombin production by inhibiting the cofactors, FVa and FVIIIa. The TF-FVIIa-FXa complex is inhibited by tissue factor pathway inhibitor with free protein S and endothelial glycocalyx components (glycosaminoglycans) as cofactors. Antithrombin, with endothelial glycocalyx cofactors, inhibits many activated coagulation factors including thrombin and FXa.