Inhibition of tissue factor-activated platelets by low-molecular-weight heparins and glycoprotein IIb/IIIa receptor antagonist

被引:9
作者
Ahmad, S
Jeske, WP
Ma, Q
Walenga, JM
Fareed, J
机构
[1] Loyola Univ, Med Ctr, Hemostasis & Thrombosis Res Labs, Dept Thorac & Cardiovasc Surg,Stritch Sch Med, Maywood, IL 60153 USA
[2] Loyola Univ, Stritch Sch Med, Dept Pathol, Maywood, IL 60153 USA
[3] Loyola Univ, Stritch Sch Med, Dept Pharmacol, Maywood, IL 60153 USA
关键词
P-selectin expression; platelet activation; tissue factor; low-molecular-weight heparins; glycoprotein IIb/IIIa inhibitors; acute coronary syndrome;
D O I
10.1016/S0049-3848(01)00225-0
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Thrombotic disorders can lead to vascular distress and platelet activation eventually resulting in the rupture of the lesions where a sizable amount of tissue factor (TF) is generated during the pathogenesis of arterial diseases. Since low-molecular-weight heparins (LMWHs) and platelet glycoprotein (GP) IIb/III alpha inhibitors are clinically used for the management of acute coronary syndrome (ACS), studies were taken to determine the effects of these agents on TF-mediated activation of platelets. Freshly drawn native whole blood (WB) from normal healthy volunteers (n = 6) supplemented with a predetermined amount of TF was incubated with equivalent anti-Xa adjusted amounts of various LMWHs at 0.01-1.0 U/ml and tirofiban from 10 to 100 ng/ml. Platelet activation was assessed by measuring the expression of P-selectin (CD62) and the generation of platelet aggregates. At 0.01 U/ml, enoxaparin exhibited a stronger inhibition of TF-induced platelet activation compared to ardeparin and dalteparin. At 0.1 U/ml, these LMWHs produced a comparable inhibition of total P-selectin expression, and at 1.0 U/ml, a marked inhibition was noted. Since enoxaparin produced the best concentration-dependent inhibition of P-selectin expression (saline: 76 +/- 10% vs. 1.0 U/ml enoxaparin: 18 +/-7%; P < .02) and platelet aggregate formation (saline: 63 +/-7% vs. 1.0 U/ml enoxaparin: 35 +/-6%, P < .035), this agent was used for additional studies. Unlike enoxaparin, tirofiban produced a weak concentration-dependent inhibition of platelet activation. At 100 ng/ml, tirofiban produced a 40% inhibition of P-selectin expression and about 60% inhibition of platelet aggregate formation. To elucidate the potential interaction between tirofiban and enoxaparin, the effect of 10 and 100 ng/ml tirofiban was studied with enoxaparin-supplemented WE in a 0.01-1.0 U/ml range. Additive effects between these two agents were noted only at lower concentrations. Thus, at therapeutic concentrations (0.8-1.2 U/ml), enoxaparin itself was capable of inhibiting TF-mediated activation of platelets to > 70%; whereas tirofiban failed to produce such concentration-dependent inhibition. This suggests that the simultaneous administration of GPIIb/ IIIa receptor antagonist with LMWH may not have any added benefit in the clinical management of patients with ACS. (C) 2001 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:143 / 151
页数:9
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