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

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

Disclosures

Pharmacotherapy. 2003;23(6) 

In This Article

Natural Anticoagulant Mechanisms: The Heparin-Antithrombin System

Several endogenous anticoagulant mechanisms operate at the level of the coagulation cascade to control the generation of thrombin and resultant fibrin formation. These include the regulation of factors Va and VIIIa by the protein C system,[10,11] the inhibition of tissue factor-factor VIIa-mediated extrinsic pathway activation by tissue factor pathway inhibitor,[12] as well as other feedback interactions among components of the coagulation cascade that serve to harness or enhance activation at various points.

One of the most important physiologic mechanisms for the control of coagulation is based on antithrombin III and enhancement of its in vivo inhibitory activity by natural anticoagulant molecules -- heavily sulfated glycosaminoglycans that line the vascular endothelium and promote uninterrupted blood flow through the vasculature.[13] Heparin is the commercially isolated derivative of these natural anticoagulant molecules.

Antithrombin III is the most powerful endogenous inhibitor of thrombin and factor Xa activities and, to some extent, is involved in neutralizing factors IXa, XIa, and XIIa.[14] The role of heparin(s) in enhancing antithrombin III-mediated anticoagulation was elucidated through an understanding of the basic functional heterogeneity of isolated heparin preparations[15,16]; the relationship between the size of heparin molecules and their ability to neutralize thrombin, factor Xa, or both[17,18]; the identification of a critical pentasaccharide sequence within heparin that is required for its interaction with antithrombin III[19]; and the essential role of specific sulfate groups within the pentasaccharide sequence for high-affinity binding to antithrombin III.[20,21]

Binding of heparin to antithrombin III through the critical pentasaccharide sequence results in enhanced exposure of the serpin's reactive loop[22] and, depending on the length of the heparin chain, leads to marked acceleration in the rate of thrombin (1000 times) and/or factor Xa (300 times) inactivation.[23]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....