Our data show that: (1) Zyx−/− mice display macrothrombocytopenia, (2) zyxin is essential for DMS formation and proplatelet production, (3) zyxin ablation results in GPIbα degradation leading to reduction of GPIb-IX surface expression and GPIb-IX-dependent platelet function, (4) deletion of zyxin alters actin cytoskeleton organization, and (5) the interaction of zyxin with VASP is required for proplatelet production and GPIb-IX surface expression. Here, GP1BA is linked to Macrothrombocytopenia.