Researchers have identified a mechanism they believe explains why so many critically ill patients with coronavirus disease 2019 (COVID-19) have an increased risk of thromboembolic complications despite pharmacological thromboprophylaxis.
In a cohort of 65 patients with severe COVID-19 in intensive care, Oskar Eriksson, MD, University Hospital, and Uppsala University, Uppsala, Sweden, and colleagues observed a subset of patients that had strongly elevated mannose-binding lectin (MBL) plasma levels when they were admitted to the intensive care unit (ICU).
The 9 (14%) patients who developed symptomatic thromboembolism despite receiving thromboprophylaxis had significantly higher MBL levels than patients who did not experience a thromboembolic event (median 1,233 kU/L vs 470 kU/L; P = .0054).
In addition, MBL was strongly correlated to plasma D-dimer levels, a well-known marker of COVID-19 coagulopathy. No relationship was found between MBL and markers of cardiac (N-terminal fragment of probrain natriuretic peptide) or respiratory function (PO2/FiO2 ratio), nor with markers of inflammation (C-reactive protein, interleukin-6, or ferritin).
“MBL circulates in complex with the serine proteases mannose-associated serine protease (MASP)-1 and MASP-2, which activate the complement cascade upon MBL target binding.The MASPs intriguingly display coagulation factor-like substrate specificities and are activated during blood clotting. MASP-1 promotes clot formation by multiple mechanisms, including direct activation of factor XIII (FXIII) that cross-links fibrin,” the authors explained.
“The standard choice for thromboprophylaxis in COVID-19 patients is low-molecular-weight heparin (LMWH), which preferentially targets FXa. Here, MBL-associated MASPs could act as a LMWH bypass mechanism to directly promote fibrin formation, and indeed, all the TE events in our study occurred despite thromboprophylaxis,” the authors added.
The study, published in Thrombosis and Haemostasis, did not find a relationship between plasma MBL levels and survival, need for mechanical ventilation, or acute kidney injury.
All patients in the study received thromboprophylaxis with either dalteparin sodium (n = 64) or apixaban (n = 1). Of the 9 patients in the study who developed a symptomatic thromboembolic event during their time at the ICU, 2 were arterial thrombosis (stroke or myocardial infarction) and 7 were pulmonary embolisms (PEs). Interestingly, patients who developed PE all had MBL levels above the 95th percentile compared with control patients.
“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,” the authors concluded. “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 thromboembolic events.”