Xenotropic and polytropic retrovirus receptor 1 (XPR1) is a major phosphate exporter in platelets.
Inhibiting XPR1 in platelets increases procoagulant polyphosphate levels and augments arterial and venous thrombosis in mice.
Polyphosphate is a procoagulant inorganic polymer of linear linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation, however the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. Here, we show that xenotropic and polytropic retrovirus receptor 1 (XPR1) regulates polyphosphate in platelets and is implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets. Xpr1 mRNA and protein expression inversely correlated with intracellular polyphosphate content and release. Pharmacological interference with XPR1 activity increased polyphosphate stores, led to enhanced platelet-driven coagulation and amplified thrombus formation under flow via the polyphosphate/factor XII pathway. Conditional gene deletion of Xpr1 in platelets resulted in polyphosphate accumulation, accelerated arterial thrombosis, and augmented activated platelet-driven pulmonary embolism without increasing bleeding in mice. These data identify platelet XPR1 as an integral regulator of platelet polyphosphate metabolism highlighting a fundamental role for phosphate homeostasis in thrombosis.