Relevance of chloride binding to von Willebrand factor in type 2B von Willebrand disease patients

Type 2B von Willebrand disease (VWD2B) is due to a gain-of-function variant of von Willebrand factor (VWF) characterized by an enhanced interaction with the platelet glycoprotein (Gp)Ib-α [1]. This condition may result in the sequestration of VWF onto the platelet surface, responsible for variable thrombocytopenia [2]. The first report of an increased proteolysis of VWD2B was by Zimmerman et al. [3], who showed the increased intensity of the inner bands of VWF triplet structure in VWD2B patients' plasma. More recently, Nishio et al. [4] demonstrated that the interaction of the GpIb-α with the VWF A1 domain increased the susceptibility of the adjacent A2 domain to ADAMTS-13, justifying the increased proteolysis in VWD2B. However, only recently De Cristofaro et al. [5] described a specific binding of chloride ions (Cl−) to the VWF A1 domain that reduced the susceptibility of the adjacent A2 domain to ADAMTS-13 activity. Furthermore, the VWD2B variant p.R1306W was found to have a reduced affinity for Cl− and an increased susceptibility to ADAMTS-13 proteolysis [6]. In this study, we extended our investigation to another four VWD2B variants, confirming that all reported mutations reduced their binding to Cl−, and increased their susceptibility to ADAMTS-13 cleavage, although to different degrees. In addition, using the VWF:RCo/Ag ratios, that in VWD2B patients are indicative of the partial loss of high molecular weight multimers (HMWM), we tried to correlate the increased susceptibility to ADAMTS-13 cleavage of these five VWD2B variants with the multimeric pattern in the plasma of patients who carry the corresponding mutations [7].