Platelet HIF-2α promotes thrombogenicity through PAI-1 synthesis and extracellular vesicle release

Abstract

xygen-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)-2a 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-a 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-2a and PAI-1. Thus, targeting platelet hypoxia signaling could be an effective antithrombotic strategy.

Impaired fibrinolysis in critically ill COVID-19 patients

“…Therefore, it is not clear whether the differences found were due to the higher age or to the disease itself. Also, the healthy population could not be matched for other variables such as comorbidities and therefore (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) 14 (10)(11)(12)(13)(14)(15)(16)(17) 31 (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) -17 (-20 to -14) <0.01 0/0 A20 (mm) 17 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) 15 (12)(13)(14)(15)(16)(17)(18) 33 (27)…”

Pulmonary Artery Thrombosis: A Diagnosis That Strives for Its Independence

“…Endothelial activation can be induced by hypoxia, which provokes secretion of the ROS and production of hypoxia inducible factors (HIFs) 1 and 2 in the endothelial cells [ 59 , 60 ]. With a decrease in oxygen concentration, HIFs accumulate in the cell nucleus and bind to the hypoxia-responsive element (HRE) on the promoter or enhancer of targeted genes, which activates their transcription [ 61 , 62 ].…”

“…Hypoxia causes platelet hyperreactivity [ 100 ]. Platelets from acute COPD patients express higher levels of HIF2a than platelets from healthy people [ 60 ]. In the patients with blood PaO 2 below 60 mmHg, the levels of HIF2α and PAI-1 in platelets are augmented [ 60 ].…”

“…Platelets from acute COPD patients express higher levels of HIF2a than platelets from healthy people [ 60 ]. In the patients with blood PaO 2 below 60 mmHg, the levels of HIF2α and PAI-1 in platelets are augmented [ 60 ]. Hypoxia induces shedding of extracellular vesicles from platelets, which is accompanied by increased expression of both HIF2α and PAI-1.…”

“…Hypoxia induces shedding of extracellular vesicles from platelets, which is accompanied by increased expression of both HIF2α and PAI-1. Moreover, platelets from the patients are primed to produce HIF2a in response to either hypoxia or activation with thrombin [ 60 ].…”