This Reactome event describes gain-of-function variants of glycoprotein Ib α GPIbα (encoded by GP1BA) that cause macrothrombocytopenia and mucocutaneous bleeding in patients with platelet-type von Willebrand disease (PT-VWD) due to enhanced affinity for von Willebrand factor (VWF) (Miller JL et al., 1991; Russell SD & Roth GJ 1993; Matsubara Y et al., 2003; Enayat S et al., 2012; Woods AI et al., 2014; Blenner MA et al., 2014; Bury L et al., 2022).
Circulating VWF binds to exposed vascular collagen at sites of vascular injury (Colace TV & Diamond SL 2013). Upon binding to collagen, VWF becomes anchored to the damaged surface. Shear forces then induce conformational changes to mechanosensitive VWF causing the bound VWF to stretch and unfold (Li F et al., 2004; Schneider SW et al., 2007; Fu H et al., 2017). VWF unfolding leads to exposure of the A1 domain to allow binding to GP1BA, a subunit of the platelet surface GP1B:IX:V complex (also known as GPIb complex) (Dumas JJ et al., 2004; Ju L et al., 2013). Genetic mutations in VWF or platelet glycoproteins such as GP1BA can compromise hemostatic processes such as platelet adhesion, activation and aggregation.
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.
