Selective Factor Xa Inhibition Improves Efficacy of Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Philip C. Comp, M.D., Ph.D.


Pharmacotherapy. 2003;23(6) 

In This Article

Coagulation Cascade

Hemostasis is achieved through a balance between the activity of the coagulation system, which generates thrombin and promotes fibrin formation, and natural anticoagulant mechanisms that serve to downregulate procoagulant activity.

Central to the coagulation system is the concept of a series of serine protease zymogens whose successive activation leads to amplified thrombin production[5,6] (Figure 1). The coagulation cascade consists of the serine proteases, factors XII, XI, IX, X, VII, and II (prothrombin) and the protein cofactors, factors V and VIII. Zymogen activation occurs on the vessel wall and on platelets, with an absolute requirement for phospholipid and calcium at most activation steps.[7] Thrombin generation occurs by two pathways, referred to as the extrinsic and intrinsic pathways of the coagulation cascade.[5,6,8] The extrinsic pathway is the major physiologic pathway for the initiation of fibrin formation.[9] It is triggered in response to vessel injury and exposure of the procoagulant, tissue factor. Subsequent interaction between tissue factor and factor VIIa to form the tissue factor-factor VIIa complex leads to direct activation of factors IX and X.[8] The intrinsic pathway is considered important for fibrin maintenance and propagation.[9] Although the physiologic stimulus responsible for triggering the intrinsic pathway remains poorly defined, factor XI activation is the critical first step for the subsequent successive activation of factors IX and X.[5]

Essential features of the coagulation cascade include the central position of factor X (Xa) at the start of the common pathway and the critical role of factor Xa in thrombin generation. (See text for details.)

Factor X plays a central role in thrombin generation based on its position at the start of the common pathway of the extrinsic and intrinsic coagulation systems. Once activated by either pathway, factor Xa becomes an essential component of the prothrombinase complex (together with factor Va, prothrombin, phospholipid, and calcium). Since assembly of the prothrombinase complex represents the penultimate step in thrombin generation,[7] interference with factor Xa activity directly affects the amount of active thrombin generated and, therefore, the amount of fibrin formed (Figure 1).


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