Deppermann C, Cherpokova D, Nurden P, Schulz JN, Thielmann I, Kraft P, Vögtle T, Kleinschnitz C, Dütting S, Krohne G, Eming SA, Nurden AT, Eckes B, Stoll G, Stegner D, Nieswandt B, et al.
The Journal of clinical investigation. Date of publication 2013 Jul 1;volume ():.
1. J Clin Invest. 2013 Jul 1. pii: 69210. doi: 10.1172/JCI69210. [Epub ahead of
print]
Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient
mice.
Deppermann C, Cherpokova D, Nurden P, Schulz JN, Thielmann I, Kraft P, Vögtle T,
Kleinschnitz C, Dütting S, Krohne G, Eming SA, Nurden AT, Eckes B, Stoll G,
Stegner D, Nieswandt B.
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.
DOI: 10.1172/JCI69210
PMCID: PMC4011026
PMID: 23863626
