Pathogenetic analysis of a bleeding disorder characterized by platelet unresponsiveness to thromboxane A_2

以血小板对血栓素 A_2 无反应为特征的出血性疾病的发病机制分析

• 批准号: 12670978
• 负责人: FUSE Ichiro
• 金额: $ 1.86万
• 依托单位: Niigata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670978/
• 关键词: platelet dysfunction; thromboxane A2; thromboxane receptor; signal transduction

We already clarified that the Arg^<60> to Leu mutation in the first cytoplasmic loop of the thromboxane _2j (TXA_2) receptor causes a bleeding disorder characterized by platelet unresponsiveness to TXA_2. However, we found other causes of this type of bleeding disorder. The patients had mild to moderate bleeding tendencies, and their platelet aggregation and secretion induced by ADP, collagen, arachidonic acid, stable tyhromboxane A2 and Ca ionophore A23187 was defective or much reduced. The analysis of second messenger formation showed that the inositol 1, 4, 5-triphosphate formation or Ca mobilization induced by thrombin, STA2 or A23187 was normal. Furhtermore, the phosphorylation of 47 K Da protein (pleckstrin) and 20 K Da protein (myosin light chain, MLC) in response to those agonists was normal.These findings suggest that the defective site in the patients' platelets lies in the process distal to or independent of protein kinase C activation, Ca mobilization and MLC phosphorylation.

我们已经阐明了血栓素A_2J(TXA_2)受体第一个胞浆环的Arg^&lt；60&gt；to Leu突变导致了一种以血小板对TXA_2无反应为特征的出血性疾病。然而，我们发现了导致这种出血性疾病的其他原因。患者有轻、中度出血倾向，ADP、胶原、花生四烯酸、稳定酪蛋白A2和钙离子载体A23187诱导的血小板聚集和分泌功能有缺陷或明显减少。第二信使形成分析表明，凝血酶、STA2或A23187诱导的肌醇1，4，5-三磷酸形成或钙动员是正常的。此外，47K Da蛋白(Pleckstrin)和20K Da蛋白(MLC)对这两种激动剂的磷酸化反应也是正常的。这些结果表明，患者血小板中的缺陷部位位于蛋白激酶C激活、钙动员和MLC磷酸化的远端或独立于该过程。

项目成果

Fuse I: "Patients with congenital abnormality of platelet aggregation induced by Ca2+ ionophores may have a defect of the platelet P2Yl2 receptor for ADP"British Journal of Haematology. 115. 483-487 (2001)

熔断 I：“由 Ca2 离子载体诱导的先天性血小板聚集异常的患者可能存在 ADP 血小板 P2Y12 受体缺陷”《英国血液学杂志》。

Fuse I.: "Pathogenetic analysis of three cases with a bleeding disorder characterized by defective platelet aggregation induced by Ca^<2+> ionophores"Br J Haematol. 112. 603-608 (2001)

Fuse I.：“以 Ca ^ 2 离子载体诱导的血小板聚集缺陷为特征的出血性疾病三例的病理遗传学分析”Br J Haematol。

Fuse I, et al: "Pathogenesis of a bleeding disorder characterized by platelet unresponsiveness to thromboxane A_2"Seminars in Thrombosis and Haemostasis. 26. 43-45 (2000)

Fuse I 等人：“以血小板对血栓素 A_2 无反应为特征的出血性疾病的发病机制”血栓形成和止血研讨会。

Fuse I: "Arg^<60> to Leu mutation in the first cytoplasmic loop of the platelet TXA_2 receptor (TXR) is not essential for mediating inhibitory coupling between the receptor and adenylyl cyclase"Acta Haemtologica. 104. 95-98 (2001)

融合物I：“血小板TXA_2受体(TXR)的第一胞质环中的Arg^<60>到Leu的突变对于介导受体和腺苷酸环化酶之间的抑制性偶联不是必需的”Acta Haemtologica。

Fuse I: "Pathogenesis of a bleeding disorder characterized by platelet unresponsiveness to thromboxane A_2"Seminars in Thrombosis and Haemostasis. 26. 43-45 (2000)

保险丝 I：“以血小板对血栓素 A_2 无反应为特征的出血性疾病的发病机制”血栓形成和止血研讨会。