VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP.
VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP.
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DOI：
10.1160/th14-09-0731
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发表时间：
2015-04
影响因子：
6.7
通讯作者：
Jilma B
中科院分区：
文献类型：
--
作者：
Schwameis M;Schörgenhofer C;Assinger A;Steiner MM;Jilma B
ADAMTS 13（一种具有血栓形成蛋白1型基序的去整合素和金属蛋白酶，成员13）活性缺失或严重降低，导致高度血栓形成的超大型血管性血友病因子（UL-VWF）多聚体在血管内持续存在和蓄积，是血栓性血小板减少性紫癜的病理生理机制。然而，VWF裂解蛋白酶水平的降低并不仅限于原发性血栓性微血管病（TMA），例如血栓性血小板减少性紫癜，而且也发生在其他危及生命的血小板减少性疾病中：在严重脓毒症、弥散性血管内凝血（DIC）和复杂的疟疾感染中观察到ADAMTS 13活性的严重降低。这些继发性血栓性微血管病的临床相关性日益得到认可，但其治疗意义尚未确定。在某些疾病中继发性TMA的存在可以定义可能受益于ADAMTS 13替代或VWF靶向治疗的患者群体。这篇简短的综述集中在UL-VWF多聚体在继发性TMA中的作用，并讨论了研究性治疗作为TTP治疗候选者的潜力。关于蛋白酶替代在体内的有效性的前瞻性临床试验似乎是合理的。仔细选择的继发性TMA患者可能受益于主要用于TTP患者的治疗。
Absent or severely diminished activity of ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) resulting in the intravascular persistence and accumulation of highly thrombogenic ultra large von Willebrand factor (UL-VWF) multimers is the pathophysiological mechanism underlying thrombotic thrombocytopenic purpura. Reduced VWF-cleaving protease levels, however, are not uniquely restricted to primary thrombotic microangiopathy (TMA), e.g. thrombotic thrombocytopenic purpura, but also occur in other life-threatening thrombocytopenic conditions: severely decreased ADAMTS13 activity is seen in severe sepsis, disseminated intravascular coagulation (DIC) and complicated malarial infection. The clinical relevance of these secondary thrombotic microangiopathies is increasingly recognized, but its therapeutic implications have not been determined yet. The presence of a secondary TMA in certain diseases may define patient groups which possibly could benefit from ADAMTS13 replacement or a VWF-targeting therapy. This short-review focuses on the role of UL-VWF multimers in secondary TMA and discusses the potential of investigational therapies as candidates for the treatment of TTP. Prospective clinical trials on the effectiveness of protease replacement in vivo seem reasonable. Carefully selected patients with secondary TMA may benefit from therapies primarily intended for the use in patients with TTP.