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.