Clopidogrel affects leukocyte dependent platelet aggregation by P2Y12 expressing leukocytes
Clopidogrel affects leukocyte dependent platelet aggregation by P2Y12 expressing leukocytes
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DOI：
10.1007/s00395-009-0073-8
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发表时间：
2010-05-01
影响因子：
9.5
通讯作者：
Moser, Martin
中科院分区：
文献类型：
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作者：
Diehl, Philipp;Olivier, Christoph;Moser, Martin
在接受冠状动脉支架治疗的所有患者中，高达30%的患者对抗血小板治疗反应不充分。这种情况导致血栓性并发症的风险增加，如支架血栓形成和心肌梗死。本研究的目的是确定调节阿萨和氯吡格雷反应性的临床参数。患者被纳入三组：（A）接受100 mg/天阿萨治疗的近期未接受PCI的冠状动脉疾病患者（n = 67）。(B)接受冠状动脉支架植入术并服用100 mg/d阿萨和75 mg/d氯吡格雷的患者（n = 87）。(C)经血管造影排除CAD且未接受抗血小板药物治疗的患者作为对照组（n = 32）。使用Multiplate（A（R））床旁装置通过阻抗聚集测定法测定血小板聚集。通过用花生四烯酸（AA，阿萨反应性）或二磷酸腺苷（ADP，氯吡格雷反应性）刺激全血来区分药物反应。RT-PCR检测P2 Y（12）受体表达。ADP诱导的血小板聚集与白细胞计数呈显著正相关（r = 0.61，p < 0.001），提示血小板与白细胞在功能上相互作用。氯吡格雷治疗消除了白细胞对血小板的影响，并导致白细胞活化降低。我们检测到氯吡格雷靶点P2 Y（12）在白细胞上的表达，表明氯吡格雷可能直接作用于这些细胞，而不仅仅是血小板。与阿萨反应相反，氯吡格雷反应与体重指数相关（r = 0.34; p = 0.001）。结论：（1）白细胞影响ADP诱导的血小板聚集最可能是通过P2 Y（12）受体的表达。氯吡格雷可消除这种相互作用。因此，氯吡格雷可通过P2 Y（12）受体直接作用于白细胞。(2)氯吡格雷可能在肥胖患者中剂量不足。
Up to 30% of all patients who are treated with a coronary stent do not respond sufficiently to antiplatelet therapy. This condition results in an increased risk for thrombotic complications such as stent thrombosis and myocardial infarction. The aim of the study was to determine clinical parameters modulating ASA and clopidogrel responsiveness. Patients were enrolled into three groups: (A) Patients with coronary artery disease without recent PCI treated with 100 mg/day ASA (n = 67). (B) Patients who underwent coronary stent implantation taking 100 mg/day ASA and 75 mg/day clopidogrel (n = 87). (C) Patients in whom CAD was excluded by angiography and who were not treated with anti-platelet medication served as controls (n = 32). Platelet aggregation was determined by impedance aggregometry using the Multiplate(A (R)) point of care device. Drug response was differentiated by stimulation of whole blood with arachidonic acid (AA, ASA responsiveness) or adenosine diphosphate (ADP, clopidogrel responsiveness). P2Y(12) receptor expression was determined by RT-PCR. ADP induced platelet aggregation correlated with the leukocyte count (r = 0.61, p < 0.001) suggesting that platelets and leukocytes interact functionally. Clopidogrel treatment abolished the influence of leukocytes on platelets and caused decreased leukocyte activation. We detected the expression of the clopidogrel target P2Y(12) on leukocytes suggesting that clopidogrel may act directly on these cells and not only on platelets. In contrast to ASA responsiveness, clopidogrel response correlated with body mass index (r = 0.34; p = 0.001). In conclusion, (1) leukocytes influence ADP induced platelet aggregation most likely by expression of the P2Y(12) receptor. This interaction is abolished by clopidogrel. Therefore, clopidogrel may act directly on leukocytes via the P2Y(12) receptor. (2) Clopidogrel may be under dosed in obese patients.