Low molecular weight heparin inhibits plasma thrombin generation via direct targeting of factor IXa: contribution of the serpin-independent mechanism.
Low molecular weight heparin inhibits plasma thrombin generation via direct targeting of factor IXa: contribution of the serpin-independent mechanism.
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DOI：
10.1111/j.1538-7836.2012.04892.x
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Sheehan JP
中科院分区：
文献类型：
--
作者：
Buyue Y;Misenheimer TM;Sheehan JP
While heparin possesses multiple mechanisms of action, enhanced factor Xa inhibition by antithrombin is accepted as the predominant therapeutic mechanism. The contribution of factor IXa inhibition to heparin activity in human plasma remains incompletely defined. To determine the relevance of factor IXa as a therapeutic target for heparins, particularly serpin-independent inhibition of intrinsic tenase (factor IXa-factor VIIIa) activity. Thrombin generation was detected by fluorogenic substrate cleavage. Inhibitory potency (EC50) of low molecular weight heparin (LMWH), super-sulfated LMWH (ssLMWH), Fondaparinux, and unfractionated heparin (UFH) was determined by plotting concentration versus relative velocity index (ratio +/− heparin). Inhibition was compared under factor IX-dependent and independent conditions (0.2 or 4 pM TF, respectively) in normal plasma, and in mock- or antithrombin/factor IX-depleted plasma supplemented with recombinant factor IX. UFH and Fondaparinux demonstrated similar potency under factor IX-dependent and independent conditions, whereas LMWH (2.9-fold) and ssLMWH (5.1-fold) demonstrated increased potency with limiting TF. UFH (62-fold) and Fondaparinux (42-fold) demonstrated markedly increased EC50 values in antithrombin-depleted plasma, whereas LMWH (9.4-fold) and ssLMWH (2-fold) were less affected, with an EC50 within the therapeutic range for LMWH. The molecular target for LMWH/ssLMWH was confirmed by supplementing factor IX/antithrombin-depleted plasma with 90 nM recombinant factor IX possessing mutations in the heparin-binding exosite. Mutated factor IX demonstrated resistance to inhibition of thrombin generation by LMWH and ssLMWH that paralleled the effect of these mutations on intrinsic tenase inhibition. Therapeutic LMWH concentrations inhibit plasma thrombin generation via antithrombin-independent interaction with the factor IXa heparin-binding exosite.
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DOI：
10.1084/jem.190.1.91
发表时间：
1999-07-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Choudhri TF;Hoh BL;Prestigiacomo CJ;Huang J;Kim LJ;Schmidt AM;Kisiel W;Connolly ES Jr;Pinsky DJ
通讯作者：
Pinsky DJ
DOI：
10.1073/pnas.74.7.3028
发表时间：
1977-01-01
影响因子：
11.1
作者：
GITEL, SN;STEPHENSON, RC;WESSLER, S
通讯作者：
WESSLER, S
影响因子：
46.9
作者：
Guerrini, Marco;Beccati, Daniela;Sasisekharan, Ram
通讯作者：
Sasisekharan, Ram
影响因子：
--
作者：
Casu B;Vlodavsky I;Sanderson RD
通讯作者：
Sanderson RD
影响因子：
7.5
作者：
Kitazato, K;Kitazato, KT;Minamiguchi, K
通讯作者：
Minamiguchi, K