GP1BA – Platelet-Type von Willebrand Disease

Platelet-type von Willebrand disease (PT-VWD) is an autosomal dominant bleeding disorder characterized by gain-of-function mutations in the platelet glycoprotein Ib alpha subunit (GP1BA), leading to enhanced binding of von Willebrand factor (VWF) and resulting thrombocytopenia due to removal of high-molecular-weight VWF multimers. Clinically, affected individuals present with mild to moderate mucocutaneous bleeding, variable thrombocytopenia, and increased ristocetin-induced platelet aggregation (RIPA) at low agonist concentrations (PMID:8486780).

Inheritance is autosomal dominant, with multiple unrelated families and registries reporting pathogenic GP1BA variants. At least 25 unrelated probands have been described across seven cohorts, including Gly233Val, Gly233Ser, Asp235Tyr, Met239Val, Trp246Leu, Gly249Val, Met255Ile, Leu194Phe, and Arg127Gln mutations, with one additional affected sibling segregating p.Gly233Ser in a Japanese pedigree (PMID:14521605).

The variant spectrum comprises solely missense substitutions within the VWF-binding domain of GPIbα, clustering in the Cys209–Cys248 disulfide loop and adjacent β-switch motif. Recurrent and founder alleles include p.Gly249Val (c.746G>T) and p.Met255Ile, detected in diverse ethnic groups and represented in gnomAD at low frequency, consistent with pathogenic gain-of-function (PMID:39975577).

Functional assays in recombinant systems and cell models have confirmed that PT-VWD mutations enhance VWF affinity. Expression of p.Gly249Val and p.Met239Val in CHO cells demonstrated increased ristocetin-induced VWF binding and slowed rolling under flow, recapitulating the bleeding phenotype (PMID:11535515). Kinetic analyses revealed that gain-of-function mutants decrease dissociation rates (2.2-fold for p.K237V) and alter association kinetics, consistent with stabilization of the receptor-ligand bond (PMID:14645097).

Structural and signaling studies elucidate the mechanism of pathogenicity. Hydrogen–deuterium exchange and crystal structures indicate that C-terminal loop mutations lock GPIbα in a high-affinity conformation, while variants in the leucine-rich repeats (p.Arg127Gln, p.Leu194Phe) act allosterically to induce loop activation. Constitutive VWF binding triggers Lyn-PECAM1 inhibitory signaling, contributing to platelet dysfunction beyond thrombocytopenia (PMID:34407603).

No studies have directly refuted the GP1BA–PT-VWD association; diagnostic misclassification with type 2B VWD underscores the need for genetic testing. Cryoprecipitate challenge and RIPA mixing assays aid differentiation, but identification of GP1BA mutations remains the gold standard (PMID:22102188).

In summary, AD gain-of-function missense mutations in GP1BA cause PT-VWD via increased VWF affinity and constitutive inhibitory signaling, manifesting as mucocutaneous bleeding and thrombocytopenia. Genetic confirmation of GP1BA variants informs appropriate management—platelet transfusion rather than VWF concentrates—and supports genetic counseling.

References

• The Journal of clinical investigation • 1993 • Expression of the phenotypic abnormality of platelet-type von Willebrand disease in a recombinant glycoprotein Ib alpha fragment. PMID:8486780
• Thrombosis and haemostasis • 2016 • A novel platelet-type von Willebrand disease mutation (GP1BA p.Met255Ile) associated with type 2B "Malmö/New York" von Willebrand disease PMID:27683759
• Journal of thrombosis and haemostasis : JTH • 2003 • Identification of a novel point mutation in platelet glycoprotein Ibalpha, Gly to Ser at residue 233, in a Japanese family with platelet-type von Willebrand disease. PMID:14521605
• Seminars in thrombosis and hemostasis • 2014 • Identification of p.W246L as a novel mutation in the GP1BA gene responsible for platelet-type von Willebrand disease. PMID:24474090
• British journal of haematology • 2023 • 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. PMID:37592722
• Thrombosis and haemostasis • 2012 • A novel Asp235Tyr mutation in the GP1BA gene enhances platelet interaction with von Willebrand factor in an Iranian family with platelet-type von Willebrand disease. PMID:23014764
• Thrombosis and haemostasis • 2011 • Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. PMID:21301777
• Blood • 2001 • Phenotype changes resulting in high-affinity binding of von Willebrand factor to recombinant glycoprotein Ib-IX: analysis of the platelet-type von Willebrand disease mutations. PMID:11535515
• Biophysical journal • 2003 • Kinetics of GPIbalpha-vWF-A1 tether bond under flow: effect of GPIbalpha mutations on the association and dissociation rates. PMID:14645097
• Platelets • 2021 • Regulation of platelet numbers and sizes by signaling pathways. PMID:33222582
• Haematologica • 2022 • Platelet dysfunction in platelet-type von Willebrand disease due to the constitutive triggering of the Lyn-PECAM1 inhibitory pathway. PMID:34407603

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