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Stunted Procoagulant Remodelling in Montreal Platelet Syndrome Kindred with p.V1316M mutation

ABSTRACT: The Montreal Platelet Syndrome Kindred (MPS) with p.V1316M mutation (2B-VWDMPS) has been associated with chronic macrothrombocytopenia, spontaneous platelet clumping, and mucocutaneous and other bleeding which can be largely prevented by von Willebrand factor concentrate infusion. However, supplemental platelet transfusion has been required on occasions, particularly for severe gastro-intestinal bleeds. This raises the question of whether a previously uncharacterized platelet dysfunction contributes to bleeding diathesis in 2B-VWDMPS patients. We studied the 2 members of the MPS kindred with the most severe bleeding phenotype and addressed this question by coupling quantitative platelet shotgun proteomics and validating biochemical assays, with the systematic analysis of platelet procoagulant membrane dynamics (PMD). Previously, we showed that membrane ballooning, a major procoagulant response of the human platelet after exposure to collagen, is driven by the influx of Na+ and Cl-, followed by the entry of osmotically obliged water. Here, we report in 2B-VWDMPS platelets, loss of the transmembrane chloride channel CLIC1, and reduced chloride ion influx after collagen stimulation. This was associated with diminished membrane ballooning and a distinct phenotypic composition of platelets over fibrillar collagen. Also, 2B-VWDMPS platelets showed marked loss of regulatory, cytoskeletal, and contractile proteins that may account for structure disorganization, giant platelet formation and further reduce the haemostatic response.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Platelet

SUBMITTER: Luiz Gustavo de Almeida

LAB HEAD: Antoine Dufour

PROVIDER: PXD035713 | Pride | 2023-08-22

REPOSITORIES: Pride

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