ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions
ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions
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DOI：
10.1182/blood-2002-05-1401
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发表时间：
2002-12-01
期刊：
影响因子：
20.3
通讯作者：
López, JA
中科院分区：
文献类型：
--
作者：
Dong, JF;Moake, JL;López, JA
血栓性血小板减少性紫癜（TTP）是一种由血小板和血管性血友病因子（VWF）组成的广泛微血管血栓引起的破坏性血栓性疾病。该疾病与VWF切割金属蛋白酶ADAMTS-13的缺乏有关，随后在血浆中积累超大（UL）VWF多聚体。与血浆形式的VWF不同，ULVWF多聚体自发粘附于血小板GP Ibalpha（GP Ib-IX-V复合物的一种成分）：我们已经发现，从刺激的内皮细胞（EC）分泌的ULVWF多聚体保持锚定在内皮表面，在那里血小板和表达GP Ib-IX-V复合物的中国仓鼠卵巢细胞附着形成长珠-on-a-，在静脉（2：5达因/cm（2））和动脉（20和50达因/cm 2）范围内的流体剪切应力存在下的弦结构。尽管体外测量ADAMTS-13 VWF切割金属蛋白酶的活性需要在非生理条件下将酶与VWF长时间孵育，但在正常血浆（含有约100%ADAMTS-13活性）存在下或在部分纯化的ADAMTS-13存在下，具有附着的血小板的EC衍生的ULVWF串在数秒至数分钟内被切割。相比之下，在含有0%至10%ADAMTS-13活性的TTP患者的血浆存在下，串持续整个灌注期（10分钟）。这些结果表明，ADAMTS-13对EC衍生的ULVWF多聚体的切割是发生在内皮细胞表面上的快速生理过程。(C)2002年，美国血液学会。
Thrombotic thrombocytopenic purpura (TTP) is a devastating thrombotic disorder caused by widespread microvascular thrombi composed of platelets and von Willebrand factor (VWF). The disorder is associated with a deficiency of the VWF-cleaving metalloprotease, ADAMTS-13, with consequent accumulation of ultra-large (UL) VWF multimers in the plasma. ULVWF multimers, unlike plasma forms of VWF, attach spontaneously to platelet GP Ibalpha, a component of the GP Ib-IX-V complex: We have found that ULVWF multimers secreted from stimulated endothelial cells (ECs) remained anchored to the endothelial surface where platelets and Chinese hamster ovary cells expressing the GP Ib-IX-V complex attached to form long beads-on-a-string structures in the presence of fluid shear stresses in both the venous (2:5 dyne/cm(2)) and arterial (20 and 50 dyne/cm2) ranges. Although measurement of the activity of the ADAMTS-13 VWF-cleaving metalioprotease in vitro requires prolonged incubation of the enzyme with VWF under non-physiologic conditions, EC-derived ULVWF strings with attached platelets were cleaved within seconds to minutes in the presence of normal plasma (containing approximately 100% ADAMTS-13 activity) or in the presence of partially purified ADAMTS-13. By contrast, the strings persisted for the entire period of perfusion (10 minutes) in the presence of plasma from patients with TTP containing 0% to 10% ADAMTS-13 activity. These results suggest that cleavage of EC-derived ULVWF multimers by ADAMTS-13 is a rapid physiologic process that occurs on endothelial cell surfaces. (C) 2002 by The American Society of Hematology.