Overcoming bleeding events related to extracorporeal membrane oxygenation in COVID-19
Authors: Hidesaku Asakura, Haruhiko Ogawa
Journal: The Lancet Respiratory Medicine (2020)

Matthieu Schmidt and colleagues1Schmidt M Hajage D Lebreton G et al.Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study.Lancet Respir Med. 2020; 8: 1121-1131Summary Full Text Full Text PDF PubMed Scopus (318) Google Scholar aimed to establish the clinical characteristics and outcomes of patients with COVID-19 and respiratory failure treated with extracorporeal membrane oxygenation (ECMO). Among 83 patients, 30 (36%) died, 35 (42%) had major bleeding events, and four (5%) had a haemorrhagic stroke. When discussing the effectiveness of ECMO, an essential aspect is assessing whether the associated bleeding events are adverse incidents, or events resulting from abnormal coagulation. Bleeding symptoms generally tend to be interpreted as adverse events related to heparin dissolved in the ECMO circuit. However, the amount of anticoagulant therapy used in their cases seemed to be appropriate and is unlikely to be the main cause of bleeding. Therefore, other mechanisms should be considered as reasons for bleeding under ECMO use in patients with COVID-19. Firstly, excessive fibrinolytic activation could occur. A report by Tang and colleagues2Tang N Li D Wang X Sun Z Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847Crossref PubMed Scopus (4024) Google Scholar showed that in the severe cases of COVID-19 leading to death, elevated fibrinogen dropped sharply to 1·0 g/L, and mildly elevated fibrin degradation products increased to 100 μg/mL in just 3 days (day 7 to 10 after admission). During this period, elevations in D-dimer were relatively gradual, leading to a large discrepancy between fibrin degradation product and D-dimer concentrations. These data suggest disseminated intravascular coagulation with enhanced fibrinolysis, indicating the development of coagulation disorders in COVID-19 that could cause major clinical bleeding.3Asakura H Classifying types of disseminated intravascular coagulation: clinical and animal models.J Intensive Care. 2014; 2: 20Crossref PubMed Scopus (198) Google Scholar Another plausible mechanism is vascular endotheliitis, given that severe COVID-19 reportedly causes severe vascular endothelial injury and vascular vulnerability.4Varga Z Flammer AJ Steiger P et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Summary Full Text Full Text PDF PubMed Scopus (4495) Google Scholar Acquired von Willebrand syndrome is also a possibility. During extracorporeal circulation, such as ECMO, high shear stress is known to destroy large multimers of von Willebrand factor.5Horiuchi H Doman T Kokame K Saiki Y Matsumoto M Acquired von Willebrand syndrome associated with cardiovascular diseases.J Atheroscler Thromb. 2019; 26: 303-314Crossref PubMed Scopus (59) Google Scholar In critical COVID-19 cases that require ECMO, it can be assumed that the phase of disseminated intravascular coagulation often changes from a suppressed-fibrinolytic type to an enhanced-fibrinolytic type. However, because of the rapid conversion, this change might be overlooked unless blood coagulation tests (table) are done regularly. In the report by Schmidt and colleagues,1Schmidt M Hajage D Lebreton G et al.Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study.Lancet Respir Med. 2020; 8: 1121-1131Summary Full Text Full Text PDF PubMed Scopus (318) Google Scholar although the concentration of fibrinogen was increased at 6·4 g/L, the data obtained at early stages of the disease are not representative of the actual coagulation state at the time of bleeding events.TableHaemostatic markers, their clinical significance, and treatmentImportance of testingSubsequent treatmentPlateletsDecreased due to various causes*Causes of platelet count reduction in COVID-19 include COVID-19 itself,6 DIC as a complication,2 immune thrombocytopenia, antiphospholipid syndrome, haemophagocytic syndrome, heparin-induced thrombocytopenia, pseudo-thrombocytopenia, and drug-induced myelosuppression; platelet count decrease is also associated with ECMO.7Treatment according to causeProthrombin time(1)Screening for vitamin K deficiency(2)Liver failure(1)Vitamin K supplementation(2)FFP replenishment, as neededActivated partial thromboplastin time(1)UFH monitoring(2)Screening for lupus anticoagulant(3)Screening for acquired haemophilia(1)Increase or decrease in UFH dose(2)Monitor for increased thrombotic tendency(3)Treatment of acquired haemophiliaFibrinogen(1)Diagnosis of DIC (particularly enhanced-fibrinolytic-type)†Rapid decrease in a few days.2(2)Screening for liver failure(1)Treatment of DIC‡Nafamostat, an antithrombin drug with strong antiplasmin action, is effective against DIC with enhanced fibrinolysis,3 and also has the effect of suppressing severe acute respiratory syndrome coronavirus 2 entry into host cells;8 during ECMO, heparin and nafamostat combination therapy is inevitable, because UFH is also administered.(2)Supplement with FFP or fibrinogen concentrate, as neededFDP or D-dimer(1)Diagnosis of DIC (particularly enhanced-fibrinolytic-type)§Rapid increase in a few days;2 in DIC with enhanced fibrinolysis, FDP concentrations increase significantly, but D-dimer is only mildly to moderately elevated, resulting in a discrepancy between FDP and D-dimer concentrations.2,3(2)Reflects lung injury(1)Treatment of DIC‡Nafamostat, an antithrombin drug with strong antiplasmin action, is effective against DIC with enhanced fibrinolysis,3 and also has the effect of suppressing severe acute respiratory syndrome coronavirus 2 entry into host cells;8 during ECMO, heparin and nafamostat combination therapy is inevitable, because UFH is also administered.(2)Treatment of COVID-19VWF (antigen and activity)Screening for acquired von Willebrand syndrome¶In acquired von Willebrand syndrome, VWF activity is lower than the amount of VWF antigen.Supplementation of VWF concentrate and FFP, as neededFFP=fresh frozen plasma. UFH=unfractionated heparin, DIC=disseminated intravascular coagulation. FDP=fibrin or fibrinogen degradation products. VWF=von Willebrand factor. ECMO=extracorporeal membrane oxygenation.* Causes of platelet count reduction in COVID-19 include COVID-19 itself,6Yang X Yang Q Wang Y et al.Thrombocytopenia and its association with mortality in patients with COVID-19.J Thromb Haemost. 2020; 18: 1469-1472Crossref PubMed Scopus (362) Google Scholar DIC as a complication,2Tang N Li D Wang X Sun Z Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847Crossref PubMed Scopus (4024) Google Scholar immune thrombocytopenia, antiphospholipid syndrome, haemophagocytic syndrome, heparin-induced thrombocytopenia, pseudo-thrombocytopenia, and drug-induced myelosuppression; platelet count decrease is also associated with ECMO.7Abrams D Baldwin MR Champion M et al.Thrombocytopenia and extracorporeal membrane oxygenation in adults with acute respiratory failure: a cohort study.Intensive Care Med. 2016; 42: 844-852Crossref PubMed Scopus (82) Google Scholar† Rapid decrease in a few days.2Tang N Li D Wang X Sun Z Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847Crossref PubMed Scopus (4024) Google Scholar‡ Nafamostat, an antithrombin drug with strong antiplasmin action, is effective against DIC with enhanced fibrinolysis,3Asakura H Classifying types of disseminated intravascular coagulation: clinical and animal models.J Intensive Care. 2014; 2: 20Crossref PubMed Scopus (198) Google Scholar and also has the effect of suppressing severe acute respiratory syndrome coronavirus 2 entry into host cells;8Hoffmann M Schroeder S Kleine-Weber H et al.Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19.Antimicrob Agents Chemother. 2020; 64: e00754-e00820Crossref PubMed Scopus (366) Google Scholar during ECMO, heparin and nafamostat combination therapy is inevitable, because UFH is also administered.§ Rapid increase in a few days;2Tang N Li D Wang X Sun Z Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847Crossref PubMed Scopus (4024) Google Scholar in DIC with enhanced fibrinolysis, FDP concentrations increase significantly, but D-dimer is only mildly to moderately elevated, resulting in a discrepancy between FDP and D-dimer concentrations.2Tang N Li D Wang X Sun Z Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847Crossref PubMed Scopus (4024) Google Scholar, 3Asakura H Classifying types of disseminated intravascular coagulation: clinical and animal models.J Intensive Care. 2014; 2: 20Crossref PubMed Scopus (198) Google Scholar¶ In acquired von Willebrand syndrome, VWF activity is lower than the amount of VWF antigen. Open table in a new tab FFP=fresh frozen plasma. UFH=unfractionated heparin, DIC=disseminated intravascular coagulation. FDP=fibrin or fibrinogen degradation products. VWF=von Willebrand factor. ECMO=extracorporeal membrane oxygenation. Follow-up data, such as fibrinogen and fibrinogen degradation product concentrations, or at least those at the time of major bleeding events, would be of interest to help elucidate the underlying mechanism of bleeding events. Such information might subsequently help to improve the survival of critically ill patients receiving ECMO. We declare no competing interests. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort studyThe estimated 60-day survival of ECMO-rescued patients with COVID-19 was similar to that of studies published in the past 2 years on ECMO for severe ARDS. If another COVID-19 outbreak occurs, ECMO should be considered for patients developing refractory respiratory failure despite optimised care. Full-Text PDF Overcoming bleeding events related to extracorporeal membrane oxygenation in COVID-19 – Authors' replyWe thank Hidesaku Asakura and Haruhiko Ogawa for their correspondence on our study on extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome related to COVID-19.1 They rightfully highlight that apart from heparin overdose, factors such as circuit-associated defibrination and thrombocytopenia, disseminated intravascular coagulation, acquired von Willebrand syndrome, and COVID-19-associated endotheliitis might cause bleeding in patients under ECMO support. Full-Text PDF