López José A, Dong Jing-fei
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Semin Hematol. 2004 Jan;41(1):15-23. doi: 10.1053/j.seminhematol.2003.10.004.
When histamine-stimulated endothelial cells are perfused with platelets in buffer, the platelets form long beads-on-a-string structures on the surface of the cells. The strands connecting the platelets are composed of ultralarge multimers of von Willebrand factor (ULVWF) and can be rapidly cleaved when perfused with normal plasma or purified ADAMTS-13 metalloprotease, but not with plasma from patients with either congenital or acquired thrombotic thrombocytopenic purpura (TTP). These ULVWF strings anchor to the surface of the endothelial cell at least partly through P-selectin, as their formation is prevented by either soluble P-selectin or P-selectin antibodies. They are also able to support the attachment of beads coated with ADAMTS-13. The metalloprotease binds to both the A1 and A3 domains of VWF, the latter with higher affinity. This attachment docks the enzyme close to its substrate site within the A2 domain. We propose that attachment of newly released ULVWF to the endothelial cell surface facilitates its cleavage by ADAMTS-13 by allowing tensile force to be applied to the A2 domain, thereby exposing the ADAMTS-13 cleavage site.
当用缓冲液中的血小板灌注组胺刺激的内皮细胞时，血小板会在细胞表面形成长的“串珠”结构。连接血小板的链由超大分子量的血管性血友病因子多聚体（ULVWF）组成，当用正常血浆或纯化的ADAMTS-13金属蛋白酶灌注时，这些链可迅速裂解，但用先天性或获得性血栓性血小板减少性紫癜（TTP）患者的血浆灌注时则不会裂解。这些ULVWF链至少部分通过P-选择素锚定在内皮细胞表面，因为可溶性P-选择素或P-选择素抗体可阻止其形成。它们还能够支持包被有ADAMTS-13的珠子的附着。金属蛋白酶与VWF的A1和A3结构域结合，与后者的亲和力更高。这种附着将酶对接至A2结构域内靠近其底物位点的位置。我们提出，新释放的ULVWF附着在内皮细胞表面，通过允许对A2结构域施加拉力，从而暴露ADAMTS-13裂解位点，促进其被ADAMTS-13裂解。
