Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice.

ABSTRACT: Platelets are anuclear organelle-rich cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity. The major platelet organelles, ?-granules, release proteins that participate in thrombus formation and hemostasis. Proteins stored in ?-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 ?-granules. Here we show that Nbeal2-knockout mice display the characteristics of human GPS, with defective ?-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 ?-granule secretion. This study demonstrates that platelet ?-granule constituents are critically required not only for hemostasis but also thrombosis, acute thrombo-inflammatory disease states, and tissue reconstitution after injury.

SUBMITTER: Deppermann C 

PROVIDER: S-EPMC4011026 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature