Molecular basis of hemostatic and thrombotic diseases

The coagulation system, composed of cells and soluble protein elements, leads to hemostasis (physiologic blood clotting) at the site of blood vessel injury. Thrombosis refers to the process of excessive clotting that results in adverse cardiovascular events, including myocardial infarction, thrombotic stroke, and venous thromboembolism. Hemostasis is normally regulated by antithrombotic mechanisms that serve to prevent excess clot formation. Disorders of hemostasis or thrombosis can occur when components of the coagulation system are missing or dysfunctional. Hemostatic defects may lead to bleeding via the following mechanisms: (1) deficient thrombin generation on the proper cellular surface due to deficiencies of factor VIII or IX (hemophilia A and B) required for the propagation phase of thrombin generation, deficiencies of factors in the final common pathway of thrombin generation (factors II, V, and X), deficiency of factor XI (required for "over-drive" of coagulation), defect in fibrin polymerization via either deficiencies or abnormalities of fibrinogen, or deficiency of Factor XIII (required for cross linking fibrin); (2) defect in primary hemostasis due to Von Willebrand disease or platelet dysfunction; or (3) abnormal fibrinolysis. Defects in the anticoagulant system lead to thrombosis via the following mechanisms: (1) unopposed or excess generation of thrombin via antithrombin deficiency or prothrombin G20210A mutation and (2) insufficient inactivation of procoagulant proteins via activated protein C resistance (including that due to the factor V Leiden mutation) and deficiencies of protein C or protein S.