Platelets are anuclear organelle-rich cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity. The major platelet organelles, α-granules, release
proteins that participate in
thrombus formation and hemostasis.
Proteins stored in α-granules are also thought to play a role in
inflammation and wound healing, but their functional significance in vivo is unknown. Mutations in NBEAL2 have been linked to
gray platelet syndrome (GPS), a rare
bleeding disorder characterized by macrothrombocytopenia, with platelets lacking α-granules. Here we show that Nbeal2-knockout mice display the characteristics of human GPS, with defective α-granule biogenesis in MKs and their absence from platelets. Nbeal2 deficiency did not affect MK differentiation and proplatelet formation in vitro or platelet life span in vivo. Nbeal2-deficient platelets displayed impaired adhesion, aggregation, and
coagulant activity ex vivo that translated into defective arterial
thrombus formation and protection from thrombo-inflammatory
brain infarction following focal
cerebral ischemia. In a model of excisional skin
wound repair, Nbeal2-deficient mice exhibited impaired development of functional granulation tissue due to severely reduced differentiation of myofibroblasts in the absence of α-granule secretion. This study demonstrates that platelet α-granule constituents are critically required not only for hemostasis but also
thrombosis, acute thrombo-inflammatory disease states, and tissue reconstitution after injury.