期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 1, 期 9, 页码 2022-2030出版社
WILEY
DOI: 10.1046/j.1538-7836.2003.00349.x
关键词
glycoproteins; platelets; thrombosis; von Willebrand factor
资金
- NHLBI NIH HHS [HL-48728, HL-42846, HL-31950] Funding Source: Medline
Inhibitors of the platelet glycoprotein (GP)IIb-IIIa receptor (integrin alpha(IIb)beta(3)) reduce acute thrombotic events in patients with coronary artery disease. To characterize the mechanism of action of these drugs, we evaluated the effects of different GPIIb-IIIa antagonists on shear-induced platelet aggregation, activation, and the expression of procoagulant activity. Samples of platelet-rich plasma from 16 volunteers were exposed to the shear rate of 10 800 s(-1) for 6 min in an optically modified cone-plate viscometer. Abciximab, tirofiban and eptifibatide inhibited aggregation to a similar extent (mean +/- SD: 74.1 +/- 8.5%, 69.5 +/- 13.6%, 65.6 +/- 17.0%, respectively), but only abciximab inhibited significantly microparticle release associated with shear-induced platelet activation (64.4 +/- 13.6%, P = 2.2 x 10(-7); tirofiban =20.0 +/- 23.4%; eptifibatide =23.9 +/- 17.4%). P-selectin platelet surface translocation was also strongly inhibited by abciximab, weakly by eptifibatide, but not by tirofiban. The addition of anti-alpha(v)beta(3) to tirofiban enhanced the inhibiting effects on shear-induced P-selectin translocation and microparticle release. Shearing of platelet-rich plasma shortened the re-calcification clotting time after addition of kaolin from 106.9 +/- 14.3 to 94.2 +/- 10.7 s (mean +/- SD; P = 0.0013). This effect, which is mediated by the appearance of procoagulant phospholipids on the surface of sheared platelets and microparticles, was prevented by abciximab and by the combination of tirofiban and anti-alpha(v)beta(3), but not by tirofiban alone or eptifibatide. The ability to inhibit shear-induced platelet activation, as evidenced by microparticle release and P-selectin surface translocation as well as the expression of procoagulant activity, differentiates the effects of anti-GPIIb-IIIa agents, which may explain the distinct antithrombotic efficacy of the agents.
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