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).
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).
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).
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.
