Abstract 605: Activation of NLRP3 Inflammasome Complex Regulates the Onset of Hypoxia Induced Thrombosis

Abstract

Objective: Besides well known predisposing conditions such as cancer, diabetes, cardiovascular disease and surgery; hypoxia per se has been suggested to be an additional risk factor for venous thrombosis (VT). We have recently shown that hypoxia, either localized due to stasis, or systemic, due to environmental factors such as high altitude exposure, results in a prothrombotic milieu. The proteomic analysis implicated some novel plasma factors that could trigger thrombotic propensity; however, the exact mechanism involved still remains poorly understood. Methods & Results: Effect of hypoxia on coagulation system was analysed using inferior vena cava ligation and simulated hypobaric hypoxia rat models. Data demonstrated that hypoxia modulates both coagulation and fibrinolytic pathways and thrombus developed under hypoxic atmospheres is an aggravated form of thrombus progression under normoxic environments. Moreover, the whole transcriptome analysis using RNA sequencing approach implicated the novel role of NOD Like receptors3 (NLRP3) and inflammasome in thrombus formation suggesting the hypoxia induced thrombosis to be an episode of sterile inflammation. The cytokine array profiling and immunofloroscence data also supported the role of innate immune components. Both pharmacological inhibition and siRNA mediated knockdown of caspase-1 and NLRP-3 respectively reinforced that the activation of NLRP3-inflammasome complex critically regulates thrombogenesis in response to hypoxia. This complex is likely to be activated as an early response to hypoxia, which precedes the platelet aggregation and hence, onset of thrombosis. The translational implication of this novel finding was evident by activation of NLRP3 inflammasome components in human patients who developed VT under hypoxic environments. Conclusions: The current study reveals a novel role of NLRP3 inflammasome in thrombosis induced by localised as well as systemic hypoxic environments. Further, the production of IL-1β by NLRP3 inflammasome augments platelet aggregation, the key event for thrombogenesis.