Knock-in mice bearing constitutively active αIIb(R990W) mutation develop macrothrombocytopenia with severe platelet dysfunction.

Background: To date, several mutations that induce constitutive activation of integrin αIIbβ3 have been identified in congenital macrothrombocytopenia. Of these, αIIb(R995W) is the most prevalent mutation observed in Japanese patients with αIIbβ3-related congenital macrothrombocytopenia.

Objective And Methods: The present study aimed to explore the effects of constitutive activation of the αIIb(R995W) mutation on platelet production, morphology, and function. We generated αIIb(R990W) knock-in (KI) mice corresponding to human αIIb(R995W).

Results: Platelet counts of heterozygous (hetero) and homozygous (homo) KI mice were decreased by ~10% and ~25% relative to those of wild-type (WT) mice, respectively, with increase in platelet size. Decrease in absolute reticulated platelet numbers in steady state, delayed recovery from thrombocytopenia induced by anti-platelet antibody and impaired response to exogenous thrombopoietin administration suggested impaired platelet production in KI mice. WT and KI mice showed no significant differences in the number of megakaryocytes and ploidy of megakaryocytes, whereas proplatelet formation was significantly impaired in homo mice. We observed a slight but significant reduction in platelet lifespan in homo mice. The homo mice showed dramatic reduction in αIIbβ3 expression in platelets, which was accompanied by severe in vivo and in vitro platelet dysfunction.

Conclusion: The αIIb(R990W) KI mice developed macrothrombocytopenia, which was primarily attributed to impaired proplatelet formation. In addition, homo KI mice showed marked downregulation in αIIbβ3 expression in platelets with severe impaired platelet function, similar to Glanzmann thrombasthenia.