title: 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, 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.
authors.forename: Carsten
authors.initials: C
authors.lastname: Deppermann
authors.forename: Deya
authors.initials: D
authors.lastname: Cherpokova
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Jan-Niklas
authors.initials: JN
authors.lastname: Schulz
authors.forename: Ina
authors.initials: I
authors.lastname: Thielmann
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Timo
authors.initials: T
authors.lastname: Vögtle
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dütting
authors.forename: Georg
authors.initials: G
authors.lastname: Krohne
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
authors.forename: Alan T
authors.initials: AT
authors.lastname: Nurden
authors.forename: Beate
authors.initials: B
authors.lastname: Eckes
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt