Emphasizing the Role of Endothelium-Related Hemostatic Factors in COVID-19 Sepsis

We read with great interest the recently published study by Wright and colleagues,¹ in which the authors have investigated the prognostic value of thromboelastography (TEG) measurements of coagulation in patients with COVID-19 admitted to the ICU. Despite the retrospective nature of the study and the low sample size, the authors have interestingly shown that fibrinolysis shutdown, as evidenced by elevated D-Dimer and complete failure of clot lysis at 30 minutes on TEG, predicted thromboembolic events and need for hemodialysis in these patients.

A recent prospective study confirms that SARS COVID-19 patients present a high number of clinically relevant thromboembolic events, and a significant percentage of these patients had pulmonary embolism,² indicating the clinical importance of constructing a predictive model for these events to target anticoagulation therapy. Routine ICU coagulation assessment includes platelets, activated partial thromboplastin time, prothrombin time, fibrinogen, and D-Dimers, but the diagnostic accuracy of these parameters for thromboembolic events remains suboptimal.

Recent findings have demonstrated significant abnormalities of von Willebrand factor (VWF) and disintegrin and metalloprotease with thrombospondin type motifs 13 (ADAMTS13) system in COVID-19 patients. These patients present low ADAMTS13 activity, while VWF levels, VWF/ADAMTS13 ratio and factor VIII levels were increased.^{3 , 4} These findings reveal an important coagulation disorder in SARS CoV-2 patients, probably indicating an important interaction between the injured endothelium and a dysregulated endothelium-related coagulation system. The above alterations might be related to the pronounced endothelial inflammation and neurohumoral activation observed in COVID-19 patients.⁵ However, further prospective studies are needed to provide prognostic information with regard to VWF/ADAMTS13 coagulation system in COVID-19 patients.

In addition to the above, we would also like to emphasize the clinical importance of another regulatory system, the thrombomodulin/protein C system, in preserving blood clotting homeostasis, and the functional integrity of microcirculation, which might be altered in sepsis. In a previous article published by our institute,⁶ we found important abnormalities of thrombomodulin/protein C and VWF/ADAMTS13 ratios in septic ICU patients who presented deterioration, while protein C (> or ≤17%) and ADAMTS13 (> or ≤22%) percentage differences during ICU stay were independent predictors of sepsis outcome.

Particularly in critically ill patients at high risk of thrombosis and thromboembolic events, such as COVID-19 septic patients, there might be a significant necessity to measure these endothelium-related hemostatic factors in order to set and optimize treatment. In their study, Wright and colleagues¹ show that TEG assessment is a promising tool to predict thromboembolic events in COVID-19 patients; however, we need prospective studies to demonstrate the prognostic validity of this global coagulation approach alone or in combination with other routine and/or specific coagulation parameters.

For these reasons, we strongly believe that a more sophisticated risk assessment model should be constructed and tested, including possibly the VWF/ADAMTS13 and thrombomodulin/protein C systems among other coagulation factors in relation to TEG in septic patients, particularly those at high risk of thromboembolic events, such as COVID-19 patients. This would allow us to better define which patients might benefit from full anticoagulation or alternative therapies targeting particularly specific disorders.