Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels
Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels
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DOI：
10.1016/j.atherosclerosis.2004.02.008
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发表时间：
2004-07-01
期刊：
影响因子：
5.3
通讯作者：
Naseem, KM
中科院分区：
文献类型：
--
作者：
Riba, R;Nicolaou, AA;Naseem, KM
血浆中含硫氨基酸同型半胱氨酸（Hey）浓度升高与动脉粥样硬化和动脉血栓形成风险增加有关。Hey发挥这些作用的机制尚未完全阐明，尽管已经提出了多种可能的机制，包括内皮功能障碍或止血异常。然而，Hcy对血小板（动脉粥样硬化血栓形成过程的中心细胞）的影响从未在患者研究中得到直接解决。本文以间歇性跛行为证据，探讨轻度高同型半胱氨酸血症（hHcy）对外周动脉闭塞性疾病患者血小板功能的影响。患者（n = 39）根据血浆Hey浓度被分为两个亚组之一。hHcy患者的血浆Hcy浓度为18.9 +/- 1.0 muM (n = 24)，而正常同型半胱氨酸（nHcy）患者的血浆Hcy浓度为113 +/- 0.5 muM (n = 15)，年龄匹配对照组的血浆Hcy浓度为12.6 +/- 0.7 muM （n = 15）。对两组的体外血小板功能进行评估，并与年龄匹配的对照组进行比较。通过血小板纤维蛋白原结合和p -选择素表达来评估血小板活化和对一氧化氮介导抑制的敏感性。在低浓度的二磷酸腺苷（ADP: 0.1 mu）和凝血酶（0.02 U/ml）下，hHcy断口者的血小板比年龄匹配的对照组反应性更强，但nHcy断口者的血小板反应性不强。与其他各组相比，激动剂诱导的p -选择素在hHcy患者中的表达显著升高。有趣的是，在nHcy患者和年龄匹配的对照组之间没有观察到差异，这表明跛行本身并不影响血小板功能。由于体内血小板活性是由暴露于激动剂和拮抗剂决定的，因此我们随后使用相同的血小板标志物测试了血小板对一氧化氮（NO）抑制的敏感性。hHcy患者的血小板对GSNO （1-100 muM）介导的抑制的敏感性明显低于其他各组。CSNO （1 muM）分别对nHcy患者和年龄匹配对照组adp诱导的纤维蛋白原结合产生42.6 +/- 10和39 +/- 11.5%的抑制作用。然而，在hcy申请人中，只有16.4 +/- 9.7%。抑制作用显著低于其他各组（P < 0.01）。同样，在nHCy受试者和对照组之间没有观察到差异。这些结果表明，单独跛行并不影响血小板功能，但如果合并轻度高同型半胱氨酸血症，则对激动剂的敏感性增加，更重要的是，它们对抑制的敏感性大大降低。总的影响是增加血小板活化的倾向。即使是轻度升高的血浆Hey也会显著增加血栓形成的风险。2004爱思唯尔爱尔兰有限公司版权所有。
Elevated plasma concentrations of the sulphur-containing amino acid homocysteine (Hey) is associated with increased risk of atherosclerosis and arterial thrombosis. The mechanism by which Hey exerts these effects has yet to be fully elucidated, although a variety of possible mechanisms have been proposed, including endothelial dysfunction or haemostatic abnormalities. However, the influence of Hcy on platelets, cells central to the atherothrombotic process, has never been addressed directly in patient studies. Here, the influence of mild hyperhomocysteinaemia (hHcy) on platelet function was explored in patients with peripheral occlusive arterial disease as evidence by intermittent claudication. Claudicants (n = 39) were assigned to one of two subgroups depending on their plasma Hey concentrations. hHcy claudicants had plasma Hcy concentrations of 18.9 +/- 1.0 muM (n = 24), compared to 113 +/- 0.5 muM for normohomocysteinemic (nHcy) claudicants (n = 15) and 12.6 +/- 0.7 muM for age-matched controls (n = 15).Platelet function was evaluated ex vivo in both groups and compared to age-matched controls. Platelet activation and sensitivity to nitric oxide-mediated inhibition was assessed by platelet fibrinogen binding and P-selectin expression. At low concentrations of adenosine diphosphate (ADP: 0.1 muM and thrombin (0.02 U/ml), platelets from hHcy claudicants were more reactive than those from age-matched controls, but not nHcy claudicants. Agonist-induced P-selectin expression was significantly raised in hHcy claudicants compared to all other groups. lnterestingly no differences were observed between nHcy claudicants and age-matched controls, indicating that claudication per se did not affect platelet function. Since platelet activity in vivo is determined by the exposure to both agonists and antagonists, we subsequently tested the sensitivity of platelets to inhibition by nitric oxide (NO), using the same platelet markers. Platelets from hHcy claudicants were significantly less sensitive to GSNO (1-100 muM)-mediated inhibition than all other groups. CSNO (1 muM) induced 42.6 +/- 10 and 39 +/- 11.5% inhibition of ADP-induced fibrinogen binding for the nHcy claudicants and age-matched controls, respectively. However, in hHcy claudicants only 16.4 +/- 9.7%. inhibition was observed, significantly less than the other groups (P < 0.01). Again no differences between nHCy claudicants and controls were observed.These results suggest the presence of claudication alone does not influence platelet function but if complicated with mild hyperhomocysteinemia, the sensitivity to agonists is increased, and more importantly, their sensitivity to inhibition is greatly reduced. The overall effect would be an increased propensity for platelet activation. The presence of even mildly elevated plasma Hey could dramatically increase thrombotic risk. (C) 2004 Elsevier Ireland Ltd. All rights reserved.