Abstract Number: PB1769
Meeting: ISTH 2020 Congress
Background: Pro-inflammatory cytokines like Interleukin-6 (IL-6) play an important role as activators of the hemostatic system and in the downregulation of physiological antithrombotic mechanisms. IL-6 has been described to influence platelet production and activation. It was associated with accelerated clotting and intravascular coagulation in tissue factor (TF)-driven murine thrombosis models.
Aims: Our goal was to analyze the precise role of myeloid cell-derived IL-6 on thrombosis formation.
Methods: We generated a new mouse model with Cre-recombinase driven constitutive overexpression of IL-6 in myeloid cells (LysM-IL-6OE/+, control mice: IL-6OE/+) and performed subtotal vena cava inferior ligation to analyze the development of deep vein thrombosis (DVT) via ultrasound analysis and histology. Thrombin generation, coagulation parameters and coagulation factors, as well as cytokine levels were measured.
Results: LysM-IL-6OE/+ mice displayed no DVT 3 days post inferior vena cava ligation compared to normal thrombus formation in controls. Platelets were more reactive in LysM-IL-6OE/+ mice compared to control mice. Platelet number was unaltered in LysM-IL-6OE/+ mice and there were no differences in D-Dimer levels. We found unstoppable post-operative bleedings in LysM-IL-6OE/+. They displayed a prolonged aPTT (LysM-IL-6OE/+: 104 s, IL-6ind/+: 29 s) and a significantly delayed INR (LysM-IL-6OE/+: 0.72, IL-6OE/+: 0.65) as well as moderately reduced levels of coagulation factors V and IX. An increase of von Willebrand factor in LysM-IL-6OE/+ mice as well as elevated levels of antithrombin. Besides, we detected increased levels of fibrinogen in LysM-IL-6OE/+ (LysM-IL-6OE/+: 536 mg/dl, IL-6ind/+: 211 mg/dl). Most importantly, hepatic levels of proteinase inhibitor α2 macroglobulin (α2M) mRNA and protein were highly increased in LysM-IL-6OE/+ mice. There was a significantly elevated erythrocyte sedimentation rate in line with agglutinating erythrocytes, which seemed to be at least partly mediated by IL-6 and α2M. Platelet-erythrocyte interaction seemed to be essential in this severe bleeding phenotype.
Conclusions: Chronic myeloid overexpression of IL-6 provokes a bleeding phenotype in mice.
To cite this abstract in AMA style:Knopp T, Lagrange J, Schüler R, Ridder F, Wild J, Rossmann H, Spronk HMH, Münzel T, Lämmle B, Ruf W, Wenzel P, Waisman A, Karbach S. Chronically Elevated Interleukin-6 Levels in Mice Lead to a Disturbance in the Coagulation System [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/chronically-elevated-interleukin-6-levels-in-mice-lead-to-a-disturbance-in-the-coagulation-system/. Accessed August 15, 2022.
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