Abstract Number: PB1672
Meeting: ISTH 2020 Congress
Background: (1) In VWD2B, spontaneous VWF binding via gain-of-function A1 domain variants to platelet GPIbα results in loss of high-molecular-weight VWF multimers, variable thrombocytopenia and a bleeding phenotype. Intrinsic platelet dysfunction has been reported in VWD2B; this can contribute to bleeding.
(2) The historic-MPS kindred was shown to have VWD2B with the V1316M variant (Jackson et al, Blood 2009).
Aims: To compare platelet function among VWD2B patients, with a focus on historic-MPS.
Methods: 9 patients, including 3 of the historic-MPS kindred, with genetically-confirmed VWD2B (6 V1316M; 2 R1341Q; 1 R1309C), with platelet counts ranging from 16-167×109/L and VWF:activity/VWF:antigen ratios, from 0.15-0.56, were studied. Informed consent was obtained from all subjects, and the study was approved by the institutional REBs. Platelets were studied by flow cytometry after activation in citrated-whole blood with: thrombin (T; 1U/mL); collagen (C; 20µg/mL); TRAP (50µM); or T+C or TRAP+C in the presence of GPRP and 2mM Ca2+. Platelets were identified using anti-CD41-FITC or anti-CD42a-PE. α-granule release was determined by anti-CD62P-PE binding, and GPIIb-IIIa activation, by PAC1-FITC binding. Procoagulant, phosphatidylserine (PS)-exposing platelets were identified by annexinA5-Alexa647 binding, and platelet-derived extracellular vesicles (EVs), as CD41-FITC positive events < 0.75µm.
Results: Historic-MPS patients’ platelets were larger than those of the other VWD2B patients, with platelet sizes (expressed as median forward scatter) of 30,900±5,200 (mean±SEM) vs 11,100±2,200 (P< 0.005). CD62P expression on activated historic-MPS platelets ranged from 40%-60% that on the other patients' platelets (P< 0.004-0.0001), while PS exposure was increased by 1.5-3-fold (P< 0.026-0.0001). Neither GPIIb-IIIa activation nor EV formation differed between the 2 groups.
Conclusions: This study uncovers an unexpected variability in platelet function among VWD2B patients: historic-MPS patients with the V1316M variant exhibit decreased α-granule secretion upon platelet activation and increased PS exposure compared with platelets from other patients with the same V1316M variant or the R1341Q or R1309C variants.
To cite this abstract in AMA style:Rand M, James P, Wang H, Bang KWA, Bowman M, Cloutier S, Jackson S, Poon M-. Variability in Platelet Function among Patients with von Willebrand Disease Type 2B (VWD2B): Focus on Patients Historically Diagnosed with Montreal Platelet Syndrome (Historic-MPS) [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/variability-in-platelet-function-among-patients-with-von-willebrand-disease-type-2b-vwd2b-focus-on-patients-historically-diagnosed-with-montreal-platelet-syndrome-historic-mps/. Accessed November 28, 2023.
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