A new case of platelet‐type von Willebrand disease supports the recent findings of gain‐of‐function GP1BA variants outside the C‐terminal disulphide loop enhances affinity for von Willebrand factor

Abstract

SummaryPlatelet‐type von Willebrand disease (PT‐VWD) is a rare autosomal dominant bleeding disorder characterized by an increased ristocetin‐induced platelet aggregation (RIPA) and enhanced affinity of platelet glycoprotein Ibα (GPIbα) to von Willebrand factor (VWF). To date, only seven variants have been described with this gain‐of‐function effect, most of them located in the C‐terminal disulphide loop of the VWF‐binding domain of GPIbα. We herein describe a patient with moderate bleeding symptoms, mild thrombocytopenia and increased RIPA. By direct sequencing of GP1BA, a novel leucine‐rich repeat heterozygous variant was identified (c.580C>T; predictably p.Leu194Phe), strongly suggestive as being the underlying cause for the PT‐VWD phenotype of our patient.

Wedging the door open on platelet‐type von Willebrand disease

“…1 By contrast, the newly discovered L194F variant, by Monteiro et al in this issue, occurs on the inside palm surface of GPIbα, within LRR7, proximal to the loop. 3 It introduces a phenylalanine with a large aromatic side chain that they hypothesize sterically interferes with other aromatic residues F217 in LRR8 and perhaps W246 in the flexible loop (Figure 1) forcing an open conformation that favours a higher affinity state of GPIbα. It is known that the classic PT-VWD variants within the loop predominantly act locally through sequence while indirectly affecting the conformational dynamics of distal LRRs.…”