key: cord-0819572-c99oawkn authors: Doi, Shunichi; Akashi, Yoshihiro J; Takita, Mumon; Yoshida, Hideki; Morikawa, Daiki; Ishibashi, Yuki; Higuma, Takumi; Fujitani, Shigeki title: Preventing thrombosis in a COVID‐19 patient by combinatorial therapy with nafamostat and heparin during extracorporeal membrane oxygenation date: 2020-10-01 journal: Acute Med Surg DOI: 10.1002/ams2.585 sha: 2e301ca4d5ead6076f97f82936e3ef4878f3957f doc_id: 819572 cord_uid: c99oawkn BACKGROUND: Extracorporeal membrane oxygenation (ECMO) can be life‐saving in cases of coronavirus disease (COVID‐19); however, circuit thrombosis is a complication. This report describes a COVID‐19 patient treated with nafamostat and heparin to prevent circuit thrombosis during ECMO support. CASE PRESENTATION: A 63‐year‐old man was transferred to our hospital with respiratory failure due to COVID‐19 pneumonia. He was provided venous‐venous ECMO to maintain oxygenation. During ECMO support, occlusive circuit thrombosis developed despite systemic anticoagulation therapy with heparin. He was subsequently administered combination therapy with nafamostat and heparin. Although the combination therapy could prevent circuit thrombosis, it was converted to heparin monotherapy because of hyperkalemia and hemothorax. After tracheostomy and a gradual improvement in oxygenation, ECMO was discontinued. He was transferred to another hospital for further rehabilitation. CONCLUSION: Combination therapy with nafamostat and heparin can prevent circuit thrombosis during ECMO. However, bleeding can still develop with this combination therapy during ECMO. This article is protected by copyright. All rights reserved Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS- and may lead to coagulopathy 1 . More pronounced coagulation activation seems to be correlated with a severe disease course 2 . During hypoxic respiratory failure due to COVID-19 pneumonia, venous-venous extracorporeal membrane oxygenation (V-V ECMO) has been shown to be life-saving when performed with appropriate anticoagulation therapy to prevent circuit thrombosis 3 . Nafamostat, a serine protease inhibitor, is an anticoagulant that was recently shown to have antiviral properties against COVID-19 4 . Combination therapy with nafamostat and heparin has been hypothesized to be beneficial for patients with COVID-19 5 . However, clinical evidence for this is lacking; therefore, we present a case involving a patient with COVID-19 who was treated with nafamostat and heparin to prevent circuit thrombosis during ECMO support. A 63-year-old Japanese man with a history of hypertension was transferred to our hospital with acute respiratory failure due to COVID-19 pneumonia. On arrival, his blood pressure was 126/70 mmHg, pulse rate was 90 beats/minute, temperature was 37.7°C, and O 2 saturation was 91% on ventilation with the following settings: 15 During ECMO support, the dose of intravenous heparin was controlled by targeting an activated clotting time (ACT) value of 160-180 seconds. Although the activated partial thromboplastin time (APTT) was 88 seconds, circuit thrombosis appeared during ECMO therapy. Because V-V ECMO could not oxygenate his blood, This article is protected by copyright. All rights reserved replacement of the ECMO membrane was required 4 days after the initial V-V ECMO insertion (Figure 2 , first black triangle). Just after the new membrane insertion, circuit thrombosis rapidly developed. On day 11, nafamostat at 0.06 mg/kg/h was continuously infused into ECMO, in combination with intravenous heparin, to prevent circuit thrombosis. During this combination therapy, ACT was well controlled and remained between 180 and 220 seconds with appropriate adjustment of the heparin dose. During the combination therapy, circuit thrombosis was not produced. Blood tests showed that fibrinogen had decreased while D-dimer had not increased with the combination therapy ( Figure 2 ). On day 15, he developed hyperkalemia (potassium, 6.5 mEq/L) and hemothorax; thus, nafamostat infusion was stopped ( Figure 2 , black arrow). Rapid blood loss due to the hemothorax necessitated transfusion of 16 units of red blood cells and 12 units of fresh frozen plasma over a 48-hour period. Treatment with heparin was continued. However, ECMO membrane exchange was needed on days 17 and 28 ( Figure 2 ). On day 32, V-V ECMO was successfully discontinued because oxygenation was maintained without V-V ECMO support. Tracheostomy was performed when oxygenation substantially recovered. He was transferred to another hospital for rehabilitation on day 52. We presented a patient with COVID-19 who was treated with a combination of nafamostat and heparin during V-V ECMO. The results showed that combination therapy could prevent circuit thrombosis more effectively This article is protected by copyright. All rights reserved due to the high level of fibrinogen, resulting in high concentrations inside the dialyzer capillaries 7 . Nafamostat is reportedly associated with fewer bleeding complications during ECMO without increasing the incidence of thromboembolic episodes 8 . Another recent report showed that nafamostat not only had anticoagulant effects but also potential anti-inflammatory and antiviral effects against COVID-19 4 . In the present case, circuit thrombosis was suppressed with the combination therapy, probably because of these anticoagulant and anti-inflammatory effects. Bleeding can develop with combination therapy during V-V ECMO. Bleeding related to systemic heparinization during V-V ECMO was observed in up to 60% of patients and found to directly affect the prognosis in a previous study 9 . In this case, after combination therapy, increased bleeding due to hemothorax was observed, and the treatment was switched to heparin monotherapy. Figure 2 shows decreased fibrinogen and increased D-dimer levels during the combination therapy with heparin and nafamostat, indicating potential bleeding caused by the hemothorax. After the occurrence of this complication, the coagulation abnormality continued to worsen. The findings from this case suggest that combination therapy with nafamostat and heparin is more effective than heparin monotherapy in preventing circuit thrombosis during V-V ECMO support. Approval of the research protocol: N/A. COVID-19 and its implications for thrombosis and anticoagulation Analysis of coagulation parameters in patients with COVID-19 in Anticoagulation practices during venovenous Accepted Article This article is protected by copyright. All rights reserved extracorporeal membrane oxygenation for respiratory failure: A systematic review Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19 Potential of heparin and nafamostat combination therapy for COVID-19 High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Hemostasis and thrombosis in continuous renal replacement treatment Single-center experience of extracorporeal membrane oxygenation mainly anticoagulated with nafamostat mesilate Predictive factors of bleeding events in adults undergoing extracorporeal membrane oxygenation We are deeply grateful to all health care professionals of St. Marianna university hospital who have been fighting against COVID-19 pandemic. We would like to thank Editage (www.editage.co.kr) for English language editing.