Perfluorooctane sulfonate (PFOS) causes dysfunction of erythrocytes by calcium dysregulation, and a diabetic...

Epidemiological studies have well documented the association between perfluorooctane sulfonate (PFOS) and cardiovascular disease, and a recent study has also suggested that PFOS may affect erythrocytes. However, the underlying mechanisms by which PFOS affects erythrocytes remain poorly understood. In this study, we demonstrated that PFOS increased prothrombotic activation of human erythrocytes and enhanced their susceptibility to PFOS-induced damage in diabetic conditions. PFOS exposure to human erythrocytes caused functional impairment, including increased hemolysis, morphological alterations, reduced deformability, and disrupted membrane integrity by increasing phosphatidylserine (PS) externalization and microvesicle (MV) generation. These changes were caused by intracellular Ca²⁺ dysregulation, evidenced by recovered PS externalization after EGTA co-treatment. The Ca^2 + dysregulation reduced ATP levels in erythrocytes via PANX1 activation and altered the activity of phospholipid translocases, such as flippase and scramblase, ultimately disrupting membrane integrity. Consequently, PFOS increased erythrocyte adhesion to endothelial cells and elevated thrombin generation. Consistent with these in vitro findings, a rat venous thrombosis model showed increased thrombus weight following PFOS exposure. Moreover, human erythrocytes were more sensitive to PFOS under diabetic conditions, showing greater PS externalization and MV production in the presence of high glucose or methylglyoxal than with PFOS alone. Diabetic rats (STZ-induced) also showed increased thrombus weight following PFOS administration, indicating enhanced susceptibility to PFOS-induced prothrombotic activation. Together, these findings suggest that erythrocyte-mediated mechanisms may contribute to PFOS-associated thrombosis risk, particularly in vulnerable populations such as individuals with diabetes.