| First Author | Casari C | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 12 | Pages | 5071-81 |
| PubMed ID | 24270421 | Mgi Jnum | J:207833 |
| Mgi Id | MGI:5559797 | Doi | 10.1172/JCI69458 |
| Citation | Casari C, et al. (2013) von Willebrand factor mutation promotes thrombocytopathy by inhibiting integrin alphaIIbbeta3. J Clin Invest 123(12):5071-81 |
| abstractText | von Willebrand disease type 2B (vWD-type 2B) is characterized by gain-of-function mutations in von Willebrand factor (vWF) that enhance its binding to the glycoprotein Ib-IX-V complex on platelets. Patients with vWD-type 2B have a bleeding tendency that is linked to loss of vWF multimers and/or thrombocytopenia. In this study, we uncovered evidence that platelet dysfunction is a third possible mechanism for bleeding tendency. We found that platelet aggregation, secretion, and spreading were diminished due to inhibition of integrin alphaIIbbeta3 in platelets from mice expressing a vWD-type 2B-associated vWF (vWF/p.V1316M), platelets from a patient with the same mutation, and control platelets pretreated with recombinant vWF/p.V1316M. Impaired platelet function coincided with reduced thrombus growth. Further, alphaIIbbeta3 activation and activation of the small GTPase Rap1 were impaired by vWF/p.V1316M following exposure to platelet agonists (thrombin, ADP, or convulxin). Conversely, thrombin- or ADP-induced Ca2+ store release, which is required for alphaIIbbeta3 activation, was normal, indicating that vWF/p.V1316M acts downstream of Ca2+ release and upstream of Rap1. We found normal Syk phosphorylation and PLCgamma2 activation following collagen receptor signaling, further implying that vWF/p.V1316M acts directly on or downstream of Ca2+ release. These data indicate that the vWD-type 2B mutation p.V1316M is associated with severe thrombocytopathy, which likely contributes to the bleeding tendency in vWD-type 2B. |
