Depletion of all platelet integrins impacts hemostasis, thrombosis and tumor metastasis

Abstract

Platelet integrins, in addition to other platelet receptors, are known to control hemostasis, thrombosis but also metastatic progression. Yet, their exclusive but combined deficiency has never been tested in these processes. Taking advantage of PF4Cre-{beta}1-/-/{beta}3-/- mouse strain, we show that platelets are exclusively depleted for all integrins. While they displayed impaired binding to fibrinogen and annexin-V, P-selectin exposure was normal. Platelet adhesion was abrogated on immobilized fibrinogen and fibrillar fibronectin under shear flow. PF4Cre-{beta}1-/- /{beta}3-/- mice presented an increased bleeding time and a profound defect in experimental models of arterial thrombosis. Platelet adhesion to tumor cells was also reduced, with a profound impact on tumor growth and metastatic burden in a model of triple negative breast cancer. Overall, these results confirm the central role of platelet integrins in hemostasis and thrombosis, and define their role in tumor growth and metastasis formation. 40-word summary: Depletion of all platelet integrins in PF4Cre-{beta}1-/-/{beta}3-/- mice leads to increased bleeding time and inhibits in vivo arterial thrombosis. Integrin-null platelets reduce tumor growth and metastatic burden in orthotopic and experimental metastasis models. Platelet integrins control hemostasis, thrombosis and metastasis.