Methylglyoxal Promotes RBC-Driven Procoagulant Activity and Venous Thrombosis under Diabetes-Relevant Conditions

Diabetes is a metabolic disease that leads to various cardiovascular complications, including thrombosis. Methylglyoxal (MG) is a representative metabolite known to be elevated in the red blood cells (RBCs) of diabetic patients. While MG contributes to eryptosis-like change of RBC, it is needed to explore the impacts to induce RBC's thrombotic activity linked to venous thrombosis.We investigated the procoagulant and thrombotic activity in RBCs exposed to MG.Freshly isolated human RBCs were incubated with MG to assess their procoagulant and thrombotic activities. In addition to the in vitro model, a rat venous thrombosis model was performed to evaluate thrombus formation induced by MG. To apply the pathological conditions of diabetes, MG-treated RBCs were exposed to high shear stress and glucose. MG promoted phosphatidylserine externalization and morphological changes through an imbalance of intracellular calcium levels in human RBCs. MG increased RBC adhesion to endothelial cells, enhanced thrombin generation, and decreased deformability. Consistent with the in vitro findings, we observed that thrombus weight increased after MG administration in an in vivo venous thrombosis model. In addition, MG-treated RBCs exhibited enhanced procoagulant activity under diabetes-relevant conditions, including high shear stress and glucose treatment.Our study suggests that MG-treated RBCs promote the procoagulant activity, leading to enhanced thrombotic activity and the development of venous thrombosis. These results support linking RBC eryptosis-like changes to a thrombosis phenotype under diabetic conditions. It highlights MG as a potential key contributor to diabetes-associated thrombotic complications.