Hyperreactive platelet phenotypes: relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation.
Hyperreactive platelet phenotypes: relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation.
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DOI：
10.1160/th12-03-0202
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发表时间：
2013-01
影响因子：
6.7
通讯作者：
Williams R
中科院分区：
文献类型：
--
作者：
Berger JS;Becker RC;Kuhn C;Helms MJ;Ortel TL;Williams R
高反应性血小板表型的机制尚不清楚。由于5-羟色胺已被证明影响血小板生物学和动脉粥样硬化血栓形成，我们试图研究血小板5-羟色胺转运体数量、结合亲和力和摄取动力学与血小板聚集的关系。对542名健康志愿者进行了透光性血小板聚集测定法，测量了不同浓度的肾上腺素、5-羟色胺、肾上腺素加5-羟色胺、ADP和胶原蛋白的反应。测定转运体依赖的5-羟色胺摄取率(Vmax)、5-羟色胺转运体数目(Bmax)和结合亲和力(Kd)。用次最大浓度(2μM)肾上腺素刺激，可在该人群中引起明显的双峰模式的血小板聚集。相比之下，受试者仅对5-羟色胺的反应表现出最小的聚集。亚极量肾上腺素和5-羟色胺的联合刺激诱导血小板聚集到超过单独使用任何一种激动剂的水平，并保持双峰反应分布。受试者对肾上腺素和肾上腺素加5-羟色胺的血小板聚集率均增加(60%)，表现出更多的血小板5-羟色胺摄取、转运体数量和亲和力。在一组健康受试者中，肾上腺素和5-羟色胺的次最大浓度的共同刺激识别出一组具有与血小板5-羟色胺功能变化相关的高反应性血小板聚集谱的个体。
The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics to platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modeling. Stimulation with submaximal (2 μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.