Chronically elevated Interleukin-6 suppresses venous thrombus formation in mice via alpha2-macroglobulin mediated thrombin inhibition

Interleukin-6 (IL-6) is a master regulator of the inflammatory cascade. To better understand the role of IL-6 in hemostasis and thrombosis, we generated mice overexpressing IL-6 specifically in myeloid cells, which are one main physiological source of this cytokine. These mice, termed LysM-IL-6^OE mice, displayed a prolonged tail bleeding time combined with prolonged International Normalized Ratio (INR), lacked venous thrombus formation (induced by inferior vena cava (IVC) stenosis), and exhibited gut inflammation. Interestingly, these mice expressed markedly elevated levels of the protease inhibitor alpha2-macroglobulin (A2m) which accumulated together with IL-6 within erythrocyte aggregates in the blood. Patients with inflammatory bowel disease (IBD), who exhibited chronically elevated IL-6 serum levels, also presented an increased INR and prolonged whole blood thrombin time. Erythrocytes from these patients also formed aggregates that incorporated IL-6 and A2m, recapitulating the findings in LysM-IL-6^OE mice. In vivo knockdown of A2m expression in the liver of LysM-IL-6^OE mice attenuated the prolongation of the whole blood thrombin clotting time. Our findings uncovered an unexpected role of chronically elevated IL-6 levels in promoting the accumulation of A2m on the surface of erythrocytes, thereby limiting thrombin induced hemostatic responses in chronic IL-6 driven inflammatory diseases.