Heterogeneity of Platelet Functional Alterations in Patients With Filamin A Mutations

Objective-We examined platelet functions in 4 unrelated patients with filaminopathy A caused by dominant mutations of the X-linked filamin A (FLNA) gene. Methods and Results-Patients P1, P2, and P4 exhibited periventricular nodular heterotopia, heterozygozity for truncating FLNA mutations, and thrombocytopenia (except P2). P3 exhibited isolated thrombocytopenia and heterozygozity for a p. Glu1803Lys FLNA mutation. Truncated FLNa was undetectable by Western blotting of P1, P2, and P4 platelets, but full-length FLNa was detected at 37%, 82%, and 57% of control, respectively. P3 FLNa (p. Glu1803Lys and full-length) was assessed at 79%. All patients exhibited a platelet subpopulation negative for FLNa. Platelet aggregation, secretion, glycoprotein VI signaling, and thrombus growth on collagen were decreased for P1, P3, and P4, but normal for P2. For the 2 patients analyzed (P1 and P4), spreading was enhanced and, more markedly, in FLNa-negative platelets, suggesting that FLNa negatively regulates cytoskeleton reorganization. Platelet adhesion to von Willebrand factor under flow correlated with platelet full-length FLNa content: markedly reduced for P1 and P4 and unchanged for P2. Interestingly, von Willebrand factor flow adhesion was increased for P3, consistent with a gain-of-function effect enhancing glycoprotein Ib-IX-V/von Willebrand factor interaction. These results are consistent with a positive role for FLNa in platelet adhesion under high shear. Conclusion-FLNA mutation heterogeneity correlates with different platelet functional impacts and points to opposite regulatory roles of FLNa in spreading and flow adhesion under shear. (Arterioscler Thromb Vasc Biol. 2013; 33: e11-e18.)