Mazharian, Alexandra; Maître, Blandine; Bornert, Alicia; Hennequin, Desline; Lourenco-Rodrigues, Marc; Geer, Mitchell Jon; Smith, Christopher W; ... Senis, Yotis A; + view all Mazharian, Alexandra; Maître, Blandine; Bornert, Alicia; Hennequin, Desline; Lourenco-Rodrigues, Marc; Geer, Mitchell Jon; Smith, Christopher W; Heising, Silke; Walter, Michaela; Montel, Florian; Walker, Lucy SK; de la Salle, Henri; Watson, Steve P; Gachet, Christian; Senis, Yotis A; - view fewer (2023) Treatment of congenital thrombocytopenia and decreased collagen reactivity in G6b-B-deficient mice. Blood Advances , 7 (1) pp. 46-59. 10.1182/bloodadvances.2022008873.

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Abstract

Mice lacking the immunoreceptor tyrosine-based inhibition motif-containing co-inhibitory receptor G6b-B (Mpig6b, G6b knockout, KO) are born with a complex megakaryocyte (MK)/platelet phenotype characterized by severe macrothrombocytopenia, expansion of the MK population and focal myelofibrosis in the bone marrow and spleen. Platelets are almost completely devoid of the GPVI-FcRγ-chain collagen receptor complex, have reduced collagen integrin α2β1, elevated Syk tyrosine kinase activity, and a subset have increased surface immunoglobulins. A strikingly similar phenotype was recently reported in patients with null and loss-of-function mutations in MPIG6B. To better understand the cause and treatment of this pathology, we used pharmacological- and genetic-based approaches to rescue platelet counts and function in G6b KO mice. Intravenous-immunoglobulin resulted in a transient partial recovery of platelet counts, whereas immune deficiency had no bearing on platelet count or receptor expression in G6b KO mice. Syk loss-of-function (R41A) rescued macrothrombocytopenia, GPVI and α2β1 expression in G6b KO mice, whereas treatement with the Syk kinase inhibitor BI1002494 partially rescued platelet counts, but had no effect on GPVI and α2β1 expression, or bleeding. Src family kinase inhibitor dasatinib had no benefit in G6b KO mice. In contrast, treatment with the thrombopoietin mimetic romiplostim rescued thrombocytopenia, GPVI expression, and platelet reactivity to collagen, suggesting this may be a promising therapeutic for patients lacking functional G6b-B. Intriguingly, GPVI and α2β1 expression are significantly downregulated in romiplostim-treated wild-type mice, whereas GPVI was upregulated in romiplostim-treated G6b KO mice, suggesting a cell intrinsic feedback mechanism that auto-regulates platelet reactivity, depending physiological needs.

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