Defective VWF cleavage by ADAMTS13 variant

Under normal physiological conditions, a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ADAMTS13) downregulates VWF procoagulant activity by cleaving the peptide bond between Tyr1605 and Met1606 within the A2 domain of VWF in a shear-dependent manner. Deficiencies in ADAMTS13 activity results in defective cleavage of ultra large VWF multimer in the plasma and are associated with excessive thrombi formation in the microvasculature in patients with thrombotic thrombocytopenic purpura (TTP) (Zheng XL 2015; Sukumar S et al. 2021). TTP is caused either by inherited mutations in the ADAMTS13 gene or by acquired inhibitory autoantibodies directed against the ADAMTS13 protein. This Reactome event describes defective cleavage of VWF by TTP-causing loss-of-function ADAMTS13 variants, A250V, P475S, Q449*, which showed normal or slightly reduced secretion (Kokame K et al., 2002; Uchida T et al., 2004; Markham-Lee Z et al., 2022).

在生理常态下，解聚素和金属蛋白酶具有血栓烷素结合域1型重复序列13（ADAMTS13）通过剪切依赖性方式切割VWF（凝血因子V）A2结构域内的酪氨酸1605与甲硫氨酸1606之间的肽键，从而下调VWF的促凝活性。ADAMTS13活性不足会导致血浆中超大VWF多聚体的切割缺陷，并与血栓性血小板减少性紫癜（TTP）患者微血管中血栓过度形成相关（Zheng XL 2015；Sukumar S 等，2021）。TTP可能由ADAMTS13基因的遗传突变或针对ADAMTS13蛋白的获得性抑制性自身抗体引起。本Reactome事件描述了由引起TTP的功能丧失型ADAMTS13变异体A250V、P475S、Q449*导致的VWF切割缺陷，这些变异体表现出正常的或轻度降低的分泌水平（Kokame K 等，2002；Uchida T 等，2004；Markham-Lee Z 等，2022）。