Mannose-Binding Lectin is Associated with Thrombosis and Coagulopathy in Critically Ill COVID-19 Patients

Abstract

The ongoing COVID-19 pandemic has caused significant morbidity and mortality worldwide, as well as profound effects on society. COVID-19 patients have an increased risk of thromboembolic (TE) complications, which develop despite pharmacological thromboprophylaxis. The mechanism behind COVID-19-associated coagulopathy remains unclear. Mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, has been suggested as a potential amplifier of blood coagulation during thromboinflammation. Here we describe data from a cohort of critically ill COVID-19 patients (n = 65) treated at a tertiary hospital center intensive care unit (ICU). A subset of patients had strongly elevated MBL plasma levels, and activity upon ICU admission, and patients who developed symptomatic TE (14%) had significantly higher MBL levels than patients without TE. MBL was strongly correlated to plasma D-dimer levels, a marker of COVID-19 coagulopathy, but showed no relationship to degree of inflammation or other organ dysfunction. In conclusion, we have identified complement activation through the MBL pathway as a novel amplification mechanism that contributes to pathological thrombosis in critically ill COVID-19 patients. Pharmacological targeting of the MBL pathway could be a novel treatment option for thrombosis in COVID-19. Laboratory testing of MBL levels could be of value for identifying COVID-19 patients at risk for TE events.

Complement Overactivation and Consumption Predicts In-Hospital Mortality in SARS-CoV-2 Infection

“…High levels of complement activation markers were associated with mortality and thromboembolic complications, however, prediction of mortality was not formally evaluated in survival models. Recently, the activation through the MBL pathway and pathological thrombosis in critically ill COVID-19 patients was described (30), highlighting the critical role of complement activation in important complications of SARS-CoV2 infection. In addition, Fang et al (19) reported low serum C3 levels in association with COVID-19 related mortality.…”

“…In a recent comprehensive review Perico and colleagues described multiple mechanisms of how endothelial cells, and complement system particularly, may contribute to severe thromboinflammation in COVID-19 (29). Finally, Eriksson et al have identified complement activation through the MBL pathway as a novel amplification mechanism that contributes to pathological thrombosis in critically ill COVID-19 patients (30).…”

Complement Factors in COVID-19 Therapeutics and Vaccines

“…concentration of sC5b-C9 was also associated with an increased odds of respiratory failure (odds ratio 31.9, confidence interval 1.3-746.6, P= 0.03) relative to those with lower concentrations [25]. In critically ill patients, the concentrations of MBL were correlated with markers of coagulopathy (D-dimer, Spearman's correlation coefficient 0.390, P = 0.002) [26]. One study evaluated the relationship between complement and mortality and found that increased C3 in serum was associated with a reduced odds of mortality (odds ratio 0.073, confidence interval 0.007-0.722, P = 0.025) relative to those with lower concentrations [27].…”

Course of D-Dimer and C-Reactive Protein Levels in Survivors and Nonsurvivors with COVID-19 Pneumonia: A Retrospective Analysis of 577 Patients

“…Potential mechanisms for the increase in D-dimer levels in patients with COVID-19 include pulmonary endothelial injury with inflammation-associated deposits of intra-alveolar fibrin, systemic endothelial injury with diffuse thrombosis of smaller vessels 10 or of larger veins, 11 and coagulopathy. [12][13][14] Therefore, the in-hospital course of D-dimer and other coagulation parameters may reflect disease activity in COVID-19 patients. Indeed, the velocity of D-dimer increase may predict VTE in patients with cancer, 15 whereas elevated D-dimer levels during anticoagulation for VTE or after discontinuation may predict recurrence.…”