Subscribe to RSS
Mannose-Binding Lectin is Associated with Thrombosis and Coagulopathy in Critically Ill COVID-19 PatientsFunding The study was funded by grants from SciLifeLab/The Knut and Alice Wallenberg Foundation to M.H. (KAW2020.0182), the Swedish Research Council to R.F. (2014–02569 and 2014–07606), B.N. (2016–01060, 2020–05672), K.N.E. (2016–04519), and O.E. (2015–06429), the Swedish Heart-Lung Foundation to B.N. (HLF 2020–0398), and by faculty grants from Linnaeus University to K.N.E.
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.
All authors participated in conception and design of the study. O.E. performed MBL activity assay, analyzed data, and prepared the manuscript. Thereafter, all authors had access to the data and participated in data collection and interpretation. All authors contributed to manuscript revision and gave approval of the final version.
* Equal contribution as first authors.
** Equal contribution as last authors.
Received: 27 June 2020
Accepted: 21 July 2020
Article published online:
01 September 2020
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Al-Samkari H, Karp Leaf RS, Dzik WH. et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 2020; 136 (04) 489-500
- 2 Spiezia L, Boscolo A, Poletto F. et al. COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure. Thromb Haemost 2020; 120 (06) 998-1000
- 3 Zhou F, Yu T, Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-1062
- 4 Cugno M, Meroni PL, Gualtierotti R. et al. Complement activation in patients with COVID-19: a novel therapeutic target. J Allergy Clin Immunol 2020; 146 (01) 215-217
- 5 Ip WKE, Chan KH, Law HKW. et al. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis 2005; 191 (10) 1697-1704
- 6 Gao T, Hu M, Zhang X. et al. Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation. medRxiv 2020;2020.03.29.20041962
- 7 Palarasah Y, Skjoedt M-O, Vitved L, Andersen TE, Skjoedt K, Koch C. Sodium polyanethole sulfonate as an inhibitor of activation of complement function in blood culture systems. J Clin Microbiol 2010; 48 (03) 908-914
- 8 Klok FA, Kruip MJHA, van der Meer NJM. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020; 191: 148-150
- 9 Cattaneo M, Bertinato EM, Birocchi S. et al. Pulmonary embolism or pulmonary thrombosis in COVID-19? Is the recommendation to use high-dose heparin for thromboprophylaxis justified?. Thromb Haemost 2020; 120 (08) 1230-1232
- 10 Dean MM, Minchinton RM, Heatley S, Eisen DP. Mannose binding lectin acute phase activity in patients with severe infection. J Clin Immunol 2005; 25 (04) 346-352
- 11 Herpers BL, Endeman H, de Jong BA. et al. Acute-phase responsiveness of mannose-binding lectin in community-acquired pneumonia is highly dependent upon MBL2 genotypes. Clin Exp Immunol 2009; 156 (03) 488-494
- 12 Perez-Castellano M, Peñaranda M, Payeras A. et al. Mannose-binding lectin does not act as an acute-phase reactant in adults with community-acquired pneumococcal pneumonia. Clin Exp Immunol 2006; 145 (02) 228-234
- 13 Ekdahl KN, Persson B, Mohlin C, Sandholm K, Skattum L, Nilsson B. Interpretation of serological complement biomarkers in disease. Front Immunol 2018; 9: 2237
- 14 Eriksson O, Mohlin C, Nilsson B, Ekdahl KN. The human platelet as an innate immune cell: interactions between activated platelets and the complement system. Front Immunol 2019; 10: 1590
- 15 Garred P, Genster N, Pilely K. et al. A journey through the lectin pathway of complement-MBL and beyond. Immunol Rev 2016; 274 (01) 74-97
- 16 Kozarcanin H, Lood C, Munthe-Fog L. et al. The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation. J Thromb Haemost 2016; 14 (03) 531-545
- 17 Hess K, Ajjan R, Phoenix F, Dobó J, Gál P, Schroeder V. Effects of MASP-1 of the complement system on activation of coagulation factors and plasma clot formation. PLoS One 2012; 7 (04) e35690
- 18 Pavlov VI, Tan YS, McClure EE. et al. Human mannose-binding lectin inhibitor prevents myocardial injury and arterial thrombogenesis in a novel animal model. Am J Pathol 2015; 185 (02) 347-355
- 19 Orsini F, Villa P, Parrella S. et al. Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia. Circulation 2012; 126 (12) 1484-1494
- 20 Liang RA, Høiland II, Ueland T. et al. Plasma levels of mannose-binding lectin and future risk of venous thromboembolism. J Thromb Haemost 2019; 17 (10) 1661-1669
- 21 Mastellos DC, Ricklin D, Lambris JD. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 2019; 18 (09) 707-729