Platelet GP IIIa PlA polymorphisms display different sensitivities to agonists
Platelet GP IIIa PlA polymorphisms display different sensitivities to agonists
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DOI：
10.1161/01.cir.101.9.1013
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发表时间：
2000-03-07
期刊：
影响因子：
37.8
通讯作者：
Bray, PF
中科院分区：
文献类型：
--
作者：
Michelson, AD;Furman, MI;Bray, PF
背景——遗传倾向和血小板高反应性都与缺血性冠状动脉事件有关，但通常缺乏支持不同受试者血小板之间遗传差异的机制。 GP IIIa 的血小板 PIA2 多态性与冠状动脉综合征之间的关联提出了这样的问题：这种遗传变异是否可能导致血小板高反应性。方法和结果-在这项研究中，我们对来自健康捐赠者的血小板中的功能参数进行了特征分析，这些血小板具有 Pl(A) (HPA-1) 多态性、Leu (Pl(A1)) 到 Pro (pl(A2)) 位置替换 血小板 GP IIb/IIIa 受体的 GP IIIa 亚基的 33（整合素 α(IIb)beta(3)）。我们研究了 56 名正常供体（20 名 PIA1,A1、20 名 P1(A1,A2) 和 16 名 P1(A2A2)）。与pl(A1,A1)血小板相比，Pl(A2)阳性血小板表现出显着的基因剂量效应，表面表达的P-选择素、GP IIb/IIIa结合的纤维蛋白原和响应低剂量ADP的激活的GP IIb/IIIa。 GP IIb/IIIa 的表面表达在所有 3 种基因型的静息血小板中相似，但在 ADP 刺激后在 Pl(A2,A2) 血小板上显着更高（与 Pl(A1,A1) 相比，P=0.003；与 pl(A1,A2) 相比，P=0.03)。 Pl(A1,A2)血小板对药理学相关浓度的阿司匹林和阿昔单抗的聚集抑制更敏感。结论-Pl(A2)阳性血小板表现出较低的激活阈值，Pl(A)等位基因杂合的血小板表现出对2种抗血小板药物的敏感性增加，这些体外血小板研究可能与体内相关 血栓情况。
Background-Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet PIA2 polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity.Methods and Results-In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 PIA1,A1, 20 Pl(A1,A2), and 16 Pl(A2A2)). Compared with pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly,greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab.Conclusions-Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs, These in vitro platelet studies may have relevance for in vivo thrombotic conditions.