Heparin chain-length dependence of factor Xa inhibition by antithrombin in plasma

Thrombosis Research
Alireza R Rezaie

Abstract

Heparin anticoagulants function by enhancing the inhibition of coagulation proteases by the serpin antithrombin (AT). A direct evaluation of the specific anti-factor Xa (fXa) activity of therapeutic heparins in the physiologically relevant plasma-based clotting assays has not been feasible since thrombin, the final protease of the cascade, is the primary target for inhibition by AT in the presence of heparin. To circumvent this problem, we developed an assay in which the native AT in plasma was replaced with an AT mutant which exhibits identical affinity for heparin and near normal reactivity for fXa, but does not react with thrombin and other coagulation proteases in either the absence or presence of heparin. This assay was used to distinguish the anti-fXa activity of different molecular weight heparins from their anti-thrombin activity in clotting assays which were initiated by the triggers of either the extrinsic or intrinsic coagulation pathway. The results suggest that the acceleration of fXa inhibition by AT exhibits a marked heparin chain-length dependence, with fondaparinux (a pentasaccharide) having the lowest and unfractionated heparin having the highest effect. Interestingly, comparative studies revealed that the fon...Continue Reading

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Citations

Mar 27, 2009·Journal of Thrombosis and Haemostasis : JTH·J-S Bae, A R Rezaie
Jan 24, 2019·The Journal of Biological Chemistry·Khue G NguyenDavid A Zaharoff
Apr 16, 2013·Journal of Thrombosis and Haemostasis : JTH·J WangA R Rezaie
Aug 16, 2016·Clinical Chemistry and Laboratory Medicine : CCLM·Luca SpieziaPaolo Simioni
Feb 7, 2009·Thrombosis Research·Martine M Fiore, Ian M Mackie

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