Treatment of coagulopathy in patients with critical COVID-19

Abstract: Introduction: Thromboembolic complications affect a large proportion of patients with critical COVID-19, and it may be associated with an increased risk of death. It has been hypothesized that both the virus of SARS-CoV-2 itself and the inflammation caused by the infection puts patients in a pro-coagulative state. To reduce the risk of thromboembolism, lowmolecular weight heparins are recommended as thromboprophylaxis for all patients in intensive care, including patients with critical COVID-19. The overall aim of this thesis was to investigate treatment of coagulopathy in patients with critical COVID-19. Specifically, studies I and II aimed to investigate the association with outcomes by different dosing of lowmolecular- weight heparins, study III aimed to study the outcome depending on the dosage of glucocorticoids, and study IV explored outcomes associated with the monitored effect of lowmolecular- weight heparins by anti-Factor Xa measurements. The overall goal was to find ways to mitigate the risk of death and thromboembolism in patients with critical COVID-19 without increasing their risk of bleeding. Methods: Studies I, II, and IV were retrospective observational cohort studies, whereas study III was a post hoc analysis of an international, randomized, blinded trial. In all our studies, we included adult patients with critical COVID-19, defined as patients with polymerase chain reaction positive severe acute respiratory syndrome coronavirus 2, requiring intensive care due to respiratory failure. Patients were excluded if they already had the outcomes of thromboembolism or major bleeding at ICU admission. The four studies investigated patients during different time periods: studies I and II during the first wave, study III during the second wave, and study IV during both the first and second waves. The exposures in the first two studies were different doses of low-molecular-weight heparin: a low, intermediate, and high dose in study I, and an intermediate and high dose in study II. In study III, 12 versus 6 mg dexamethasone daily was investigated and in study IV, the activity of low-molecular-weight heparin by anti-Factor Xa was the exposure. Death, thromboembolism, and bleeding were the outcomes in all studies. To analyze the primary outcome, Cox regression was used in studies I, II and III, and logistic regression was used in studies III and IV. Multivariable models were used to adjust for pre-defined baseline variables with the potential to affect the outcome in studies I and II, for stratifying variables in study III, and for one potential confounder and interaction in study IV. Results: In study I, high dose low-molecular-weight heparin was associated with a significant reduction of death at 28 days compared to low dose: adjusted hazard ratio 0.33 (95% CI 0.13 to 0.87). There was also a lower incidence of thromboembolism for patients treated with high (2.7%) versus intermediate (18.8%) and low dose low-molecular-weight heparin (17.9%) (p = 0.04) but no difference in the risk of bleeding (p = 0.16). When focusing on intermediate vs high dose low-molecular-weight heparin in study II, we found no differences in the risk of death at 90 days, thromboembolism or bleeding at 28 days, with hazard ratios of 0.74 (95% CI 0.36 to 1.53), 0.93 (95% CI 0.37 to 2.29), and 0.84 (95% CI 0.28 to 2.54), respectively. In study III, the incidence of the composite outcome death and thromboembolism during the ICU stay did not differ for patients randomized to 12 or 6 mg dexamethasone, odds ratio 0.93 (95% CI 0.58 to 1.49), nor were there any significant differences for the secondary outcomes of thromboembolism, major bleeding, or any bleeding complications. In study IV, when analyzing anti-Factor Xa as a continuous variable in a spline model, associations were found between (1) lower peak anti-Factor Xa values and increased risk for thromboembolism and (2) higher trough anti-Factor Xa values and an increased risk of death and bleeding. When cut-off values of peak were investigated, patients with any value below 0.3 kIU/L had an associated odds ratio of thromboembolism of 5.1 (95% CI 1.8 to 14.4) compared to patients no values below 0.3 kIU/L. Trough values above 0.3 kIU/L were associated with an odds ratio of bleeding of 1.9 (95% CI 1.1 to 3.3), and trough values above 0.5 kIU/L were associated with an odds ratio of 2.4 (95% CI 1.0 to 5.6) of major bleeding, compared to patients with no values above these levels. Conclusion: In the early days of the pandemic, we found that a high dose of low-molecularweight heparin for thromboprophylaxis was associated with lower mortality compared to low dose. The results also suggested a benefit with high dose compared to intermediate dose, but no such association was found when including more patients and comparing only thromboprophylaxis with intermediate vs high dose low-molecular-weight heparin. A daily dose of 12 or 6 mg of dexamethasone did not result in a significant decrease in the composite outcome of death and thromboembolism, thromboembolism, or bleeding. Anti-Factor Xa values may be useful to guide thromboprophylaxis in patients with critical COVID-19