Department of Medicine, McMaster University, Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada.
J Thromb Haemost. 2022 Dec;20(12):2722-2732. doi: 10.1111/jth.15873. Epub 2022 Sep 22.
Recombinant ADAMTS13 is currently undergoing clinical trials as a treatment for hereditary thrombotic thrombocytopenic purpura, a lethal microvascular condition resulting from ADAMTS13 deficiency. Preclinical studies have also demonstrated its efficacy in treating arterial thrombosis and inflammation without causing bleeding, suggesting that recombinant ADAMTS13 may have broad applicability as an antithrombotic agent. Despite this progress, we currently do not understand the mechanisms that regulate ADAMTS13 activity in vivo. ADAMTS13 evades canonical means of protease regulation because it is secreted as an active enzyme and has a long half-life in circulation, suggesting that it is not inhibited by natural protease inhibitors. Although shear can spatially and temporally activate von Willebrand factor to capture circulating platelets, it is also required for cleavage by ADAMTS13. Therefore, spatial and temporal regulation of ADAMTS13 activity may be required to stabilize von Willebrand factor-platelet strings at sites of vascular injury. This review outlines potential mechanisms that regulate ADAMTS13 in vivo including shear-dependency, local inactivation, and biochemical and structural regulation of substrate binding. Recently published structural data of ADAMTS13 is discussed, which may help to generate novel hypotheses for future research.
重组 ADAMTS13 目前正在作为遗传性血栓性血小板减少性紫癜（一种由 ADAMTS13 缺乏引起的致命微血管疾病）的治疗方法进行临床试验。临床前研究还表明，它在治疗动脉血栓形成和炎症而不引起出血方面具有疗效，这表明重组 ADAMTS13 作为一种抗血栓药物可能具有广泛的适用性。尽管取得了这些进展，但我们目前并不了解体内调节 ADAMTS13 活性的机制。ADAMTS13 逃避了蛋白酶常规调节方式，因为它作为一种活性酶被分泌，并且在循环中具有较长的半衰期，这表明它不受天然蛋白酶抑制剂的抑制。尽管剪切可以在空间和时间上激活 von Willebrand 因子以捕获循环中的血小板，但它也是 ADAMTS13 切割所必需的。因此，可能需要 ADAMTS13 活性的时空调节来稳定血管损伤部位的 von Willebrand 因子-血小板串。本综述概述了体内调节 ADAMTS13 的潜在机制，包括剪切依赖性、局部失活以及底物结合的生化和结构调节。还讨论了最近发表的 ADAMTS13 的结构数据，这可能有助于为未来的研究提出新的假设。
