GPIb:IX:V binds to VWF multimer:collagen

The initial tethering of platelets at sites of vascular injury is mediated by the platelet receptor complex of glycoproteins Ibα, IX and V (GPIbα:IX:V, frequently referred to as the GPIb receptor). GPIbα, encoded by the GP1BA gene, binds to von Willebrand factor (VWF), which is complexed with collagen exposed in vascular epithelium following injury (Mody NA &King MR 2008). Shear-induced interaction between VWF and collagen leads to exposure of the A1 domain of VWF to allow binding to GPIbα (Dumas JJ et al., 2004; Ju L et al., 2013). Thus, the damaged vessel wall and platelets interactions are facilitated by VWF multimer, which under normal physiological flow conditions circulates in a folded, inactive form, which does not interact with platelets due to autoinhibitory regulation (Aponte-Santamaria C et al., 2015; Butera D et al., 2018; Arce NA et al., 2021; Zhao YC et al., 2022). However, under conditions of high shear stress, when a blood vessel is partially blocked, VWF can bind to GP1bα:V:IX in the absence of collagen causing thrombotic diseases like heart attack and stroke (reviewed by Mehta R et al., 2019; Kozlov S et al., 2022). <p>This Reactome event describes GPIbα:IX:V interaction with VWF:collagen that potentiates the binding of platelet-associated integrin αIIbβ3 to VWF and fibrinogen, triggering stable platelet adhesion to damaged vessels and platelet activation, which results in platelet aggregation (Dumas JJ et al., 2004; Ju L et al., 2013).<p>ADAMTS13 downregulates VWF procoagulant activity by cleaving the peptide bond between Tyr1605 and Met1606 within the A2 domain of VWF (Crawley JTB et al., 2011). <p>Caplacizumab (CABLIVI®, also known as ALX-0081), is a bivalent humanized antibody fragment consisting of a single variable domain that binds the A1 domain of VWF with high affinity (Lee HT et al., 2021). Caplacizumab inhibits binding between VWF and GPIbα.

血管损伤部位的血小板最初附着过程由糖蛋白Ibα、IX和V（GPIbα:IX:V，通常简称为GPIb受体复合物）的血小板受体介导。GPIbα由GP1BA基因编码，与血管内皮损伤后暴露的凝血因子VIII相关因子（VWF）结合，该因子与血管内皮中的胶原蛋白形成复合物（Mody NA & King MR 2008）。VWF与胶原蛋白之间的剪切力相互作用导致VWF的A1结构域暴露，从而允许其与GPIbα结合（Dumas JJ et al., 2004; Ju L et al., 2013）。因此，血管损伤壁与血小板的相互作用得以通过VWF多聚体促进，在正常的生理血流条件下，VWF以折叠、非活性形式循环，由于自身抑制调节，不与血小板相互作用（Aponte-Santamaria C et al., 2015; Butera D et al., 2018; Arce NA et al., 2021; Zhao YC et al., 2022）。然而，在高剪切应力条件下，当血管部分阻塞时，VWF可以在无胶原蛋白的情况下与GP1bα:V:IX结合，导致血栓性疾病，如心肌梗死和中风（Mehta R et al., 2019; Kozlov S et al., 2022）。本Reactome事件描述了GPIbα:IX:V与VWF:胶原蛋白的相互作用，该相互作用增强血小板相关整合素αIIbβ3与VWF和纤维蛋白原的结合，触发血小板与受损血管的稳定附着和血小板活化，从而导致血小板聚集（Dumas JJ et al., 2004; Ju L et al., 2013）。ADAMTS13通过切割VWF的A2结构域中Tyr1605和Met1606之间的肽键，下调VWF的促凝活性（Crawley JTB et al., 2011）。Caplacizumab（CABLIVI®，也称为ALX-0081），是一种双价人源化抗体片段，由单个可变结构域组成，该结构域以高亲和力结合VWF的A1结构域。Caplacizumab抑制VWF与GPIbα的结合。