Anti-glycoprotein VI treatment severely compromises hemostasis in mice with reduced α2β1 levels or concomitant aspirin therapy
Anti-glycoprotein VI treatment severely compromises hemostasis in mice with reduced α2β1 levels or concomitant aspirin therapy
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DOI：
10.1161/01.cir.0000146341.63677.3c
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发表时间：
2004-11-02
期刊：
影响因子：
37.8
通讯作者：
Nieswandt, B
中科院分区：
文献类型：
--
作者：
Grüner, S;Prostredna, M;Nieswandt, B
背景-血小板抑制是预防动脉血栓形成的主要策略，但它通常与原发性止血受损引起的出血增加有关。活化血小板胶原受体糖蛋白VI （GP VI）可能作为一个强大的抗血栓靶点，因为它的抑制或缺乏对动脉血栓形成有深刻的保护作用，但在小鼠中没有大出血。方法与结果-小鼠缺乏（-/-）或表达一半水平（+/-）的其他主要血小板胶原受体整合素α (2) β(1)注射抗gp VI抗体JAQ1，并在第5天进行分析。抗gp VI治疗导致α(2)（-/-）或α(2)（+/-）小鼠明显的止血缺陷，如显著延长尾出血时间所示。在高剪切条件下的离体全血灌注系统中研究了血小板与胶原的粘附。通过刺激血栓素A(2) （TxA(2)）受体激活弱整合素可恢复抗GP VI处理的野生型血小板对胶原的粘附缺陷，但不能恢复α(2)（-/-）或α(2)（+/-）血小板对胶原的粘附缺陷。这一过程需要同时激活G(q)和G（13）信号通路，正如使用各自的敲除菌株所证明的那样。相反，阿司匹林对TxA2产生的抑制严重损害了抗GP VI治疗或GP VI/Fc受体γ链缺陷小鼠的止血功能，但对照组没有。结论：抗GP - VI治疗可能导致α (2) β(1)水平降低或同时使用阿司匹林治疗的患者止血缺陷。这些观察结果可能对以抗GP - VI为基础的治疗方法在心血管疾病预防中的潜在应用具有重要意义。
Background - Platelet inhibition is a major strategy to prevent arterial thrombosis, but it is frequently associated with increased bleeding because of impaired primary hemostasis. The activating platelet collagen receptor, glycoprotein VI ( GP VI), may serve as a powerful antithrombotic target because its inhibition or absence results in profound protection against arterial thrombosis but no major bleeding in mice.Methods and Results - Mice lacking (-/-) or expressing half-levels (+/-) of the other major platelet collagen receptor, integrin alpha(2)beta(1), were injected with the anti -GP VI antibody JAQ1 and analyzed on day 5. Anti-GP VI treatment resulted in a marked hemostatic defect in alpha(2)(-/-) or alpha(2)(+/-) mice, as shown by dramatically prolonged tail bleeding times. Platelet adhesion to collagen was studied in an ex vivo whole-blood perfusion system under high shear conditions. Weak integrin activation by thromboxane A(2) (TxA(2)) receptor stimulation restored defective adhesion of anti - GP VI - treated wild-type but not alpha(2)(-/-) or alpha(2)(+/-) platelets to collagen. This process required the simultaneous activation of the G(q) and G(13) signaling pathways, as demonstrated by use of the respective knockout strains. Conversely, inhibition of TxA2 production by aspirin severely compromised hemostasis in anti - GP VI - treated or GP VI/Fc receptor gamma-chain - deficient but not control mice.Conclusions - Anti - GP VI therapy may result in defective hemostasis in patients with reduced alpha(2)beta(1) levels or concomitant aspirin therapy. These observations may have important implications for a potential use of anti - GP VI - based therapeutics in the prevention of cardiovascular disease.