INCREASED INVIVO PRODUCTION OF THROMBOXANE IN PATIENTS WITH SICKLE-CELL DISEASE IS ACCOMPANIED BY AN IMPAIRMENT OF PLATELET FUNCTIONS TO THE THROMBOXANE A(2) AGONIST U46619
INCREASED INVIVO PRODUCTION OF THROMBOXANE IN PATIENTS WITH SICKLE-CELL DISEASE IS ACCOMPANIED BY AN IMPAIRMENT OF PLATELET FUNCTIONS TO THE THROMBOXANE A(2) AGONIST U46619
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DOI：
10.1161/01.atv.13.3.421
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发表时间：
1993-03-01
期刊：
影响因子：
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通讯作者：
MACLOUF, J
中科院分区：
文献类型：
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作者：
FOULON, I;BACHIR, D;MACLOUF, J
血栓形成是镰状细胞病患者死亡的一个重要原因，除了由遗传异常血红蛋白的原发性缺陷引起的并发症。为了研究血小板在这些并发症中的参与，我们评估了49例镰状细胞病患者和33例对照组样本中血栓素A2的生物合成。患者血小板来源的主要花生四烯酸代谢物（11-脱氢血栓烷B2）和血管内皮细胞（2，3-二去甲-6-酮前列腺素F1 α）的尿排泄量显著增加（p < 0.0002）。在一小组患者（n = 14）中，我们进一步研究了他们的血小板对U46619（一种稳定的血栓烷A2类似物）的体外反应。与对照组相比，我们观察到聚集和[C-14] 5-羟色胺释放减少（p < 0.05）;同样，我们发现p47蛋白磷酸化受损（p < 0.05）。相反，这些患者的血小板对凝血酶反应正常（0.1单位/mL）。这些患者体内血小板对血栓烷的脱敏可能构成一种调节形式，可防止这种强效诱导剂引起的聚集传播，正如体外研究中所假设的那样。我们的研究结果也可能为使用抗血小板药物预防镰状细胞患者的血栓并发症提供理论依据。
Thrombosis represents an important cause of mortality in patients with sickle cell disease, in addition to the complications caused by the primary defect of inherited abnormal hemoglobin. To study the involvement of platelets in these complications, we assessed the biosynthesis of thromboxane A2 in samples from 49 patients with sickle cell disease and in 33 control subjects. The urinary excretion of the major arachidonic acid metabolite of platelet origin (11-dehydrothromboxane B2) and of the vascular endothelial cell (2,3-dinor-6-ketoprostaglandin F1alpha) were very significantly increased (p < 0.0002) in the patients. In a small group of patients (n = 14), we further investigated the ex vivo response of their platelets to U46619, a stable analogue of thromboxane A2. We observed decreased aggregation and [C-14]serotonin release compared with control (p < 0.05); similarly, we found impaired p47 protein phosphorylation (p < 0.05). In contrast, platelets from these patients responded normally to thrombin (0.1 unit/mL). In vivo desensitization of platelets from these patients to thromboxane may constitute a form of regulation that may prevent the propagation of aggregation by this potent inducer, as has been hypothesized in in vitro studies. Our results may also provide a rationale for using antiplatelet drugs in the prophylaxis of thrombotic complications in sickle cell patients.