Decreased thrombotic tendency in mouse models of the Bernard-Soulier syndrome
Decreased thrombotic tendency in mouse models of the Bernard-Soulier syndrome
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DOI：
10.1161/01.atv.0000251992.47053.75
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发表时间：
2007-01-01
影响因子：
8.7
通讯作者：
Lanza, F.
中科院分区：
文献类型：
--
作者：
Strassel, C.;Nonne, C.;Lanza, F.
目的 - 血小板糖蛋白 (GP) Ib-V-IX 复合物是 Bernard-Soulier 出血性疾病中正常止血缺陷所需的受体。为了评估 GPIb-V-IX 缺陷对血栓形成的影响，我们通过靶向 GPIb β 亚基生成了该疾病的小鼠模型。方法和结果 - 完全缺失 (GPIb β(-/-)) 或细胞内截短 (GPIb β Delta IC-/-) 再现了 Bernard-Soulier 的典型和变异形式，血小板表面复合物的缺失和部分 (20%) 表达。两种菌株均表现出血小板减少和血小板增大，微管结构异常，但颗粒成分正常。它们表现出延长的尾部出血时间，这在 GPIb beta Delta IC-/- 中不太明显。在高剪切力下将血液灌注到胶原涂层表面上后，观察到血栓形成减少。在 FeCl3 诱导的颈动脉损伤模型中观察到对血管闭塞的抵抗力和异常的血栓成分。在激光诱导的肠系膜小动脉损伤模型中，GPIb beta(-/-) 小鼠的血栓形成明显减少，而在 GPIb beta Delta IC-/- 动物中观察到的效果较温和。最后，这两种菌株在系统性血栓栓塞模型中得到了保护，免于死亡。 结论 - 这项研究提供了体内证据，证明伯纳德-苏利埃综合征小鼠模型中血栓形成倾向的降低与血小板 GPIb-V-IX 缺陷有关。
Objective - The platelet glycoprotein (GP) Ib-V-IX complex is a receptor required for normal hemostasis deficient in the Bernard-Soulier bleeding disorder. To evaluate the consequences of GPIb-V-IX deficiency in thrombosis we generated mouse models of the disease by targeting the GPIb beta subunit.Methods and Results - Complete deletion (GPIb beta(-/-)) or an intracellular truncation (GPIb beta Delta IC-/-) reproduced typical and variant forms of Bernard-Soulier, with absent and partial (20%) expression of the complex on the platelet surface. Both strains exhibited thrombocytopenia and enlarged platelets with abnormal microtubular structures but normal granule composition. They exhibited prolonged tail bleeding times, which were less pronounced in GPIb beta Delta IC-/-. Decreased thrombus formation was observed after blood perfusion over a collagen coated surface at high shear. Resistance to vascular occlusion and an abnormal thrombus composition were observed in a model of FeCl3- induced lesion of carotid arteries. In a model of laser-induced lesion of mesenteric arterioles, thrombosis was strongly reduced in GPIb beta(-/-) mice, while a more modest effect was observed in GPIb beta Delta IC-/- animals. Finally, the two strains were protected against death in a model of systemic thromboembolism.Conclusions - This study provides in vivo evidence of a decreased thrombotic tendency linked to defective platelet GPIb-V-IX in mouse models of Bernard-Soulier syndrome.