V. PATHOPHYSIOLOGY

Thrombotic events occur when there is loss of balance between the blood coagulation and the fibrinolytic and regulatory anticoagulant systems. This loss of balance conjoined with environmental factors can lead to a prothrombotic state, reduced fibrinolytic state, or a lesser anticoagulant state. All these conditions have a cumulative effect of increasing thrombin formation, which in turn increases thrombotic risk. The figure below summarizes the important protein risk factors contributing to the thrombotic phenotype.

This figure juxtaposes the proteins involved in the coagulation, fibrinolytic, and anticoagulation systems. The proteins in green are involved in the coagulation system; the proteins in blue are involved in the fibrinolytic system; and the proteins in red are the major anticoagulant system. The blood coagulation system is initiated by factor VIIa-tissue factor formation (FVIIa-TF), leading to thrombin formation. Amplification of this thrombin generation pathway occurs when factor XI is activated by prior formed thrombin. Factor XI can also be activated by factor XII autoactivation on exposed collagen, RNA, platelet polyphates, or aggregated proteins. This latter pathway is not involved in hemostasis but may contribute to extent of clot formation in thrombosis. Those proteins inscribed in boxes are entities whose deficiency or defects are associated with venous thrombosis. Antithrombin (AT), protein C (APC) and protein S (Protein S) are considered high risk factors for thrombosis. Complement C4b binding protein (C4bBP) regulates the availability of protein S. This point is important because only “free” protein S, i.e., protein S not bound to C4bBP, is available to act as a cofactor for activated protein C (APC) to function as an anticoagulant. APC anticoagulant functions to inactivate FVIIIa and FVa serving as cofactors to generate more thrombin. The factor V Leiden (FVL) mutation makes FVa more resistant to inactivation by APC. The prothrombin 20210 polymorphism leads to higher plasma levels of prothrombin. Factor V Leiden (FVL), prothrombin 20210 (II G20210A), abnormal fibrinogens or abnormal plasminogens are entities that are considered lower risk for inciting VTE. Coagulation factors VII (VIIa-TF), IX, X, XI and XII are represented by their Roman numeral alone. An “a” after the Roman numeral represents an “activated” protein or enzyme.

Abbreviations: PK = prekallikrein, HK = high molecular weight kininogen,
TF = tissue factor, ScuPA = single chain urokinase plasminogen activator,
TcuPA = two chain urokinase plasminogen activator, tPA = tissue plasminogen activator