Elevated Angiopoietin-2 inhibits thrombomodulin-mediated anticoagulation in critically ill COVID-19 patients

Hultstrom, M.; Fromell, K.; Larsson, A.; Quaggin, S. E.; Betsholtz, C.; Frithiof, R.; Lipcsey, M.; Jeansson, M.

Several studies suggest that hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19. Here, we hypothesized that the high levels of the inflammatory cytokine Angiopoietin-2 (ANGPT2) reported in hospitalized COVID-19 patients might promote hypercoagulation through ANGPT2 binding to thrombomodulin with resulting inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. We therefore investigated plasma samples taken at two timepoints from 20 critically ill COVID-19 patients in intensive care regarding ANGPT2 levels and coagulation markers in comparison with 20 healthy blood donors. We found that ANGPT2 levels were increased in the COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. To test causality, we administered ANGPT2 to wildtype mice and found that it shortened bleeding time in a tail injury model. In further support of a role for ANGPT2 in physiological coagulation, bleeding time was increased in endothelial-specific Angpt2 knockout mice. Using in vitro assays, we found that ANGPT2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data reveal a novel mechanism for ANGPT2 in hypercoagulation and suggest that Angiopoietin-2 inhibition may be tested in the treatment of hypercoagulation in severe COVID-19, as well as in certain other conditions, including sepsis.