Targeted inhibition of intrinsic coagulation limits cerebral injury in stroke without increasing intracerebral hemorrhage.
Targeted inhibition of intrinsic coagulation limits cerebral injury in stroke without increasing intracerebral hemorrhage.
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DOI：
10.1084/jem.190.1.91
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发表时间：
1999-07-05
期刊：
影响因子：
--
通讯作者：
Pinsky DJ
中科院分区：
文献类型：
--
作者：
Choudhri TF;Hoh BL;Prestigiacomo CJ;Huang J;Kim LJ;Schmidt AM;Kisiel W;Connolly ES Jr;Pinsky DJ
在卒中中恢复血管通畅的药物也会增加脑出血（ICH）的风险。由于因子IXa是内源性凝血途径中的关键中间体，因此靶向抑制因子IXa依赖性凝血可能会抑制卒中中的微血管血栓形成，而不会损害限制ICH的外源性止血机制。通过共价修饰因子IXa活性位点来制备用于组装成内在因子X活化复合物的天然因子IXa的竞争性抑制剂因子IXai。在改良的脑磷脂凝血时间测定中，因子IXai的体内施用引起凝块形成时间的剂量依赖性增加（与媒介物处理的对照动物相比，在300 μg/kg剂量下增加3.6倍，P < 0.05）。给予因子IXai并经历大脑中动脉闭塞和再灌注的小鼠通过免疫印迹和免疫染色证明了微血管纤维蛋白积聚减少，111 In标记的血小板沉积减少，（减少42%，P < 0.05），脑灌注增加（激光多普勒检测同侧血流量增加2.6倍，P < 0.05），脑梗死比溶剂处理对照组小（70%减少，P < 0.05）。在治疗有效剂量下，因子IXai与ICH增加无关，而组织纤溶酶原激活剂（tPA）或肝素则显著增加ICH。即使在中风发作后给予因子IXai也具有显著保护作用，表明即使在主要脑血管分支原发性闭塞后，微血管血栓形成仍在继续发展（并可能受到抑制）。
Agents that restore vascular patency in stroke also increase the risk of intracerebral hemorrhage (ICH). As Factor IXa is a key intermediary in the intrinsic pathway of coagulation, targeted inhibition of Factor IXa–dependent coagulation might inhibit microvascular thrombosis in stroke without impairing extrinsic hemostatic mechanisms that limit ICH. A competitive inhibitor of native Factor IXa for assembly into the intrinsic Factor X activation complex, Factor IXai, was prepared by covalent modification of the Factor IXa active site. In a modified cephalin clotting time assay, in vivo administration of Factor IXai caused a dose-dependent increase in time to clot formation (3.6-fold increase at the 300 μg/kg dose compared with vehicle-treated control animals, P < 0.05). Mice given Factor IXai and subjected to middle cerebral artery occlusion and reperfusion demonstrated reduced microvascular fibrin accumulation by immunoblotting and immunostaining, reduced 111In-labeled platelet deposition (42% decrease, P < 0.05), increased cerebral perfusion (2.6-fold increase in ipsilateral blood flow by laser doppler, P < 0.05), and smaller cerebral infarcts than vehicle-treated controls (70% reduction, P < 0.05) based on triphenyl tetrazolium chloride staining of serial cerebral sections. At therapeutically effective doses, Factor IXai was not associated with increased ICH, as opposed to tissue plasminogen activator (tPA) or heparin, both of which significantly increased ICH. Factor IXai was cerebroprotective even when given after the onset of stroke, indicating that microvascular thrombosis continues to evolve (and may be inhibited) even after primary occlusion of a major cerebrovascular tributary.
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影响因子：
8.3
作者：
Choudhri, TF;Hoh, BL;Pinsky, DJ
通讯作者：
Pinsky, DJ
影响因子：
15.9
作者：
SAPPINO, AP;MADANI, R;VASSALLI, JD
通讯作者：
VASSALLI, JD
影响因子：
120.7
作者：
HACKE, W;KASTE, M;HENNERICI, M
通讯作者：
HENNERICI, M
影响因子：
4.8
作者：
Connolly, ES;Winfree, CJ;Pinsky, DJ
通讯作者：
Pinsky, DJ
影响因子：
20.1
作者：
NAKA, Y;CHOWDHURY, NC;PINSKY, DJ
通讯作者：
PINSKY, DJ