Haga Jason H, Slack Steven M, Jennings Lisa K
Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, California, USA.
J Cardiovasc Pharmacol. 2003 Mar;41(3):363-71. doi: 10.1097/00005344-200303000-00004.
The use of platelet glycoprotein IIb-IIIa (alphaIIbbeta3) antagonists is an accepted practice in the treatment of acute coronary syndromes. Recent studies have demonstrated that alpha beta receptor antagonists are effective in inhibiting the procoagulant activity of platelets under static conditions. No investigation, however, has compared the ability of these platelet antagonists to inhibit platelet procoagulant activity, defined as an increase in phosphatidylserine (PS) expression, under conditions of shear stress. Thus, the goal of this study was to quantify the amount of microparticle formation and PS expression of platelets exposed to physiologic and pathophysiologic levels of shear stress in the absence and presence of three clinically approved parenteral alpha beta antagonists (abciximab, eptifibatide, and tirofiban). Flow cytometric results demonstrated that although microparticle formation was significantly inhibited by all three antagonists, PS expression by sheared platelets was affected differently depending on the antagonist present. Specifically, abciximab suppressed PS expression compared with the saline control; both abciximab and eptifibatide significantly reduced PS expression compared with tirofiban; and tirofiban potentiated PS expression relative to the saline control at the highest shear stress. This is the first demonstration of differential regulation of platelet PS expression and, by inference, procoagulant activity in the presence of alpha receptor antagonists under shear stress. The current results may have future importance in improving the design of platelet antagonists as well as defining the general role of fluid shear stress in platelet thrombus formation.
血小板糖蛋白IIb-IIIa（αIIbβ3）拮抗剂的使用是治疗急性冠脉综合征的一种公认做法。最近的研究表明，αβ受体拮抗剂在静态条件下能有效抑制血小板的促凝活性。然而，尚无研究比较这些血小板拮抗剂在剪切应力条件下抑制血小板促凝活性（定义为磷脂酰丝氨酸（PS）表达增加）的能力。因此，本研究的目的是在不存在和存在三种临床批准的肠外αβ拮抗剂（阿昔单抗、依替巴肽和替罗非班）的情况下，量化暴露于生理和病理生理水平剪切应力的血小板的微粒形成量和PS表达。流式细胞术结果表明，虽然所有三种拮抗剂均显著抑制微粒形成，但剪切血小板的PS表达受不同拮抗剂的影响各异。具体而言，与生理盐水对照相比，阿昔单抗抑制PS表达；与替罗非班相比，阿昔单抗和依替巴肽均显著降低PS表达；在最高剪切应力下，替罗非班相对于生理盐水对照增强PS表达。这是首次证明在剪切应力下存在α受体拮抗剂时血小板PS表达的差异调节，由此推断还有促凝活性的差异调节。目前的结果可能对改进血小板拮抗剂的设计以及确定流体剪切应力在血小板血栓形成中的总体作用具有未来重要意义。
