期刊
THROMBOSIS AND HAEMOSTASIS
卷 96, 期 6, 页码 774-780出版社
GEORG THIEME VERLAG KG
DOI: 10.1160/TH06-07-0367
关键词
platelet microparticles; platelet glycoprotein lb; thrombin; high shear; antiplatelet agents
We studied the inhibition of platelet microparticle (MP) formation and thrombin generation under high shear forces. We hypothesized that an inhibitor of the GPlb alpha-von Willebrand factor (vWF) interaction would be more effective in suppressing MP formation and thrombin generation than GPIIb/IIIa inhibitors. Platelet-rich plasma (PRP) anticoagulated with PPACK (D-Phe-Pro-Arg chloromethyl ketone) was exposed in a cone-and-plate viscometer (shear: 5,000 s(-1) for 5 min) in the presence of antagonists to GPlb alpha (the monoclonal antibody [Mab] lb-23) or to GPIlb/Illa (abciximab, tirofiban, eptifibatide) at their IC90 determined in platelet aggregometry with ristocetin or ADP, respectively. We used double labeling (CD41-PE and annexin-V-FITC) for flow cytometric detection of MP and their aminophospholipid exposure. Thrombin generation was measured using PRP prepared from ACD anticoagulated blood. About 40% of the thrombin generation was found to be mediated by the MP fraction of the PRR Blockade of GPlb alpha with Mab lb-23 reduced MP formation and thrombin generation by 50%, and was more effective than any GPIlb/Illa antagonist. The combination of Mab lb-23 with one of the GPIlb/Illa inhibitors further reduced the MP formation to similar to 30%. The antibody also partially inhibited thrombin induced platelet aggregation. Epitope mapping suggested that Mab lb-23 binds between the amino acids 201 and 268 of GPlb alpha, explaining the interference with vWF and thrombin interaction. In contrast to the commonly used GPIlb/Illa antagonists, the blockade of GPlb alpha with Mab lb-23 effectively reduces the prothrombotic MP generation and thrombin formation at shear rates typically found in arterial stenoses.
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