RT Journal Article SR Electronic T1 Platelet HIF-2α promotes thrombogenicity through PAI-1 synthesis and extracellular vesicle release JF Haematologica JO Haematologica FD Ferrata Storti Foundation SP 2482 OP 2492 DO 10.3324/haematol.2019.217463 VO 104 IS 12 A1 Chaurasia, Susheel N. A1 Kushwaha, Geeta A1 Kulkarni, Paresh P. A1 Mallick, Ram L. A1 Latheef, Nazmy A. A1 Mishra, Jai K. A1 Dash, Debabrata YR 2019 UL http://www.haematologica.org/content/104/12/2482.abstract AB Oxygen-compromised environments, such as high altitude, are associated with platelet hyperactivity. Platelets confined within the relatively impervious core of an aggregate/thrombus have restricted access to oxygen, yet they continue to perform energy-intensive procoagulant activities that sustain the thrombus. Studying platelet signaling under hypoxia is, therefore, critical to our understanding of the mechanistic basis of thrombus stability. We report here that hypoxia-inducible factor (HIF)-2α is translated from pre-existing mRNA and stabilized against proteolytic degradation in enucleate platelets exposed to hypoxia. Hypoxic stress, too, stimulates platelets to synthesize plasminogen-activator inhibitor-1 (PAI-1) and shed extracellular vesicles, both of which potentially contribute to the prothrombotic phenotype associated with hypoxia. Stabilization of HIF-α by administering hypoxia-mimetics to mice accelerates thrombus formation in mesenteric arterioles. In agreement, platelets from patients with chronic obstructive pulmonary disease and high altitude residents exhibiting thrombogenic attributes have abundant expression of HIF-2α and PAI- 1. Thus, targeting platelet hypoxia signaling could be an effective anti-thrombotic strategy.