Key result
The p.V1316M mutation in von Willebrand disease type 2B causes platelet hypofunction through preactivation and exhaustion of the protein kinase C signaling pathway.
PKC pathway defects in VWD type 2B platelets merit targeted investigation; leaves open any clinical translation to bleeding management.
mice. Using αIIbβ3 integrin activation as a read-out, we demonstrate that platelet dysfunction in VWD (p.V1316M) type 2B affects PKC-mediated, but not CDGI-mediated, activation of Rap1. Consistently, we observed decreased PKC substrate phosphorylation and impaired granule release in stimulated VWD type 2B platelets. Interestingly, the defect in PKC signaling was caused by a significant increase in baseline PKC substrate phosphorylation in circulating VWD (p.V1316M) type 2B platelets, suggesting that the VWF-GPIbα interaction leads to preactivation and exhaustion of the PKC pathway. Consistent with PKC preactivation, VWD (p.V1316M) type 2B mice also exhibited marked shedding of platelet GPIbα. In summary, our studies identify altered PKC signaling as the underlying cause of platelet hypofunction in p.V1316M-associated VWD type 2B.
No takes yet. Share an insight, caveat, or question.
Casari et al. (2018) studied von Willebrand disease (p.V1316M) type 2B. p.V1316M mutation was evaluated on PKC signaling and platelet function. The p.V1316M mutation in von Willebrand disease type 2B causes platelet hypofunction through preactivation and exhaustion of the protein kinase C signaling pathway.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: