Abstract
Hypoxia exacerbates thromboembolism and sterile inflammation through the NLRP3 inflammasome, which is directly activated by HIF-1α, a factor that plays a pivotal role in potentiating deep vein thrombosis. One of the clinical manifestations of thromboinflammation is deep vein thrombosis, characterized by formation and propagation of a clot in the lower extremity of the body. The underlying inflammatory milieu promotes immune cell recruitment and platelet hyperactivation, further promoting a prothrombotic state. However, the intricate relationship between hypoxia, thromboembolism, and sterile inflammation is not fully understood. To address this knowledge gap, we integrated in vitro cell lines, ex vivo human peripheral blood mononuclear cells, in vivo animal models, and human patient-based studies to uncover the role of cellular interactions in driving hypoxia-induced thrombosis. We gained early mechanistic insights and subsequently tested the translational potential in humans who developed deep vein thrombosis at high altitudes (>11,000 feet). Our investigation revealed that hypoxia increased monocyte adhesion to endothelial surfaces, an effect mediated through CD11a/CD18 (β2 integrin) and F11R (junctional adhesion molecule-1; JAM-1). We determined the significance of the HIF-1α-NLRP3-Egr1-TF/ FVII axis in inflammation-induced coagulation under sterile conditions operating through NLRP3 elevating Egr-1, which subsequently augments tissue factor. This axis increases platelet hyperactivation and platelet association amplifying thromboinflammation. Human patients who developed high altitude thrombosis showed enhanced HIF-1α, NLRP3, Egr1, and TF/ FVII levels, confirming the clinical relevance of these factors. Finally, abrogating these molecules with either pharmacological inhibitors or siRNA demonstrated a potential to reverse these pathophysiological processes. These findings identify the HIF-1α-NLRP3-Egr1-TF/FVII axis as a potential therapeutic target for mitigating hypoxia-induced thromboinflammation.