Rasa3 deficiency minimally impacts thrombopoiesis but promotes severe thrombocytopenia due to integrin-dependent platelet clearance.

Fiche publication

Date publication

mars 2022

Journal

JCI insight

Auteurs

Membres identifiés du Cancéropôle Est :
Dr GACHET Christian

Tous les auteurs :
Lee RH, Ghalloussi D, Harousseau GL, Kenny JP, Kramer PA, Proamer F, Nieswandt B, Flick MJ, Gachet C, Casari C, Eckly A, Bergmeier W

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35290242

Résumé

Platelet homeostasis is dependent on a tight regulation of both platelet production and clearance. The small GTPase Rap1 mediates platelet adhesion and hemostatic plug formation. However, Rap1 signaling is also critical for platelet homeostasis as both Rap1 deficiency and uninhibited Rap1 signaling lead to marked thrombocytopenia in mice. Here we investigated the mechanism by which deficiency in Rasa3, a critical negative regulator of Rap1, causes macrothrombocytopenia in mice. Despite marked morphological and ultrastructural abnormalities, megakaryocytes in hypomorphic Rasa3hlb/hlb or Rasa3-/- mice demonstrated robust proplatelet formation in vivo, suggesting that defective thrombopoiesis is not the main cause of thrombocytopenia. Rather, we observed that Rasa3hlb/hlb platelets become trapped in the spleen marginal zone/red pulp interface, with evidence of platelet phagocytosis by macrophages. Clearance of mutant platelets was also observed in the liver, especially in splenectomized mice. Platelet count and platelet lifespan in Rasa3 mutant mice were restored by genetic or pharmacological approaches to inhibit the Rap1/Talin1/αIIbβ3 integrin axis. A similar pattern of splenic clearance was observed in mice injected with anti-αIIbβ3 but not anti-GPIbα platelet-depleting antibodies. In summary, we describe a novel, integrin-based mechanism of platelet clearance that could be critical for our understanding of select inherited and acquired thrombocytopenias.