Evaluation of the protein C pathway in critically ill patients with severe COVID-19 as compared to bacterial sepsis

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Introduction Endothelial dysfunction has been shown to play a role in severe COVID-19, the pathophysiology of which may be attributed to a myriad of factors including unmitigated immune and inflammatory response, viral-induced injury to the endothelium, end-stage organ failure, and coagulopathy. In addition, severe COVID-19 is most often seen in patients with multiple comorbidities, which themselves are often associated with endothelial dysfunction (such as myocardial and renal failure, as well as thrombotic disorders). However, the literature is still emerging on this topic and there appears to be no consensus on the extent to which endothelial dysfunction plays a role in severe COVID-19. Method The aim of this study was to assess the functionality of the endothelial protein C pathway in hospitalized patients >18 years of age with severe COVID-19 as compared to those hospitalized with bacterial sepsis. COVID-19 (n=31) and sepsis (n=47) patients who were admitted to the ICU were assessed for rates of thrombin and activated protein C (APC) generation. Indirect markers of thrombin formation, including thrombin-antithrombin (TAT) complex, prothrombin fragment 1+2 (F1+2), as well as D-dimer, and protein C (PC) were measured additionally. Statistical analysis was performed via the Mann-Whitney test and a p value of <0.05 was considered statistically significant. Fig. 1 Thrombin and APC formation rates in patients with severe COVID-19 and bacterial sepsis. Results Plasma levels of free thrombin in COVID-19 and sepsis patients did not differ significantly, with (median, IQR) 0.59 (0.46-1.21) vs 0.57 (0.46-1.10) pmol/L, respectively. TAT was also increased at similar extent in both cohorts (192; 111-325 pmol/L in COVID-19 patients, 148; 73-213 pmol/L in sepsis patients), whereas F1+2 was higher in COVID-19 than in sepsis patients, with 850 (440-1940) vs 380 (130-620) pmol/L (p=1.3 x 10-5). Interestingly, rates of APC formation did not significantly differ between the two groups, with 7.47 (1.99-19.14) vs 9.87 (2.08-16.87) pmol/L ([ Fig. 1 ]). D-dimer and protein C were significantly higher in the COVID-19 patients than in those with sepsis (14.3 vs 8.1 mg/L, p=0.01, and 92.9% vs 58.5%, p=3x10-8, respectively). Conclusion We hypothesized that APC formation rates in response to thrombin formation would be significantly lower in patients with severe COVID-19 as compared to those with bacterial sepsis due to the well-known association between severe COVID-19 disease burden and endothelial dysfunction due to the downregulation of thrombomodulin expression. However, our results indicate that this may not be universally true in this patient population, as our observations suggest a largely intact functionality of the protein C pathway. Further studies are warranted to investigate the pathophysiology of severe COVID-19. Publication History Article published online: 20 February 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

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