Hypoxia and HIF activation as a possible link between sepsis and thrombosis

Abstract

Risk factors for thrombosis include hypoxia and sepsis, but the mechanisms that control sepsis-induced thrombus formation are incompletely understood. A recent article published in Thrombosis Journal: (i) reviews the role of endothelial cells in the pathogenesis of sepsis-associated microthrombosis; (ii) describes a novel ‘two-path unifying theory’ of hemostatic discorders; and (iii) refers to hypoxia as a consequence of microthrombus formation in sepsis patients. The current article adds to this review by describing how sepsis and thrombus formation could be linked through hypoxia and activation of hypoxia-inducible transcription factors (HIFs). In other words, hypoxia and HIF activation may be a cause as well as a consequence of thrombosis in sepsis patients. While microthrombosis reduces microvascular blood flow causing local hypoxia and tissue ischemia, sepsis-induced increases in HIF1 activation could conversely increase the expression of coagulant factors and integrins that promote thrombus formation, and stimulate the formation of pro-thrombotic neutrophil extracellular traps. A better understanding of the role of cell-specific HIFs in thrombus formation could lead to the development of novel prophylactic therapies for individuals at risk of thrombosis.

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“…Hypercoagulability has been recognized as a significant cause of the morbidity in this disease, resulting in pulmonary parenchymal thrombosis ( 9 ), venous thrombosis and emboli ( 5 , 4 ), and stroke ( 10 ). Multiple causative factors have been implicated including cytokine storm associated with SARS ( 11 ), endotheliitis ( 12 ), and hypoxia ( 13 ).…”

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“…It is caused by endothelial cell dysfunction, which is induced by local coagulation disorders followed by platelet dysfunction and fibrin formation, and septicemia followed by local hypoxemia and cytokine activation. 1 The main triggers of microthrombosis include the following.…”

Hypoxia response and acute lung and kidney injury: possible implications for therapy of COVID-19

“…However, caution is needed. Indeed, patients with SARS-CoV-2 infection develop a prothrombotic state causing micro or overt systemic thrombosis; during sepsis, HIF activation could increase the expression of coagulant factors and promote thrombus formation [ 58 ]. Adequate anticoagulation is now the standard of care for SARS-CoV-2 infection; this becomes of key importance in the case of a possible use of PHD inhibitors to treat patients with SARS-CoV-2 infection.…”