==== Front TH Open TH Open 10.1055/s-00033990 TH Open: Companion Journal to Thrombosis and Haemostasis 2567-3459 2512-9465 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany 10.1055/s-0040-1721501 200060 Letter to the Editor Successful Use of Argatroban to Treat a Critically Ill Patient with Coagulopathy and Nephropathy Secondary to COVID-19 http://orcid.org/0000-0001-5575-2531Frise Matthew C. 12 Gates Rebecca E.V. 1 Curry Nicola S. 3 Danbury Christopher M. 1 1 Royal Berkshire NHS Foundation Trust, Royal Berkshire Hospital, Reading, United Kingdom 2 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom 3 Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Headington, Oxford, United Kingdom Address for correspondence Matthew C. Frise, DPhil Intensive Care Unit, Royal Berkshire HospitalLondon Road, Reading, RG1 5ANUnited Kingdommatthew.frise@royalberkshire.nhs.uk 10 2020 15 12 2020 4 4 e400 e402 08 7 2020 28 10 2020 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ) 2020The Author(s).This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ==== Body Data from early case series of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) indicated that disordered thrombosis and hemostasis were frequent features of coronavirus disease 2019 (COVID-19) portending a worse outcome. 1 2 3 4 For example, in a case series of 191 patients from two Wuhan hospitals, an elevated admission D-dimer level was associated with almost a 20-fold increased risk of death. 5 A further single center study of 183 patients from another Wuhan hospital found that elevated fibrin degradation product levels, as well as a prolonged prothrombin time and activated partial thromboplastin time (APTT), were associated with a significantly higher mortality. 6 As the pandemic has progressed, it has become clear that while the coagulopathy of COVID-19 shares features with both disseminated intravascular coagulation (DIC) 7 and thrombotic microangiopathy (TMA), 8 several aspects make it distinct from each of these entities. 9 10 It has even been suggested that in an extreme form, the coagulopathy of COVID-19 resembles antiphospholipid syndrome, evidenced by multiple thrombotic events and positive serological tests in keeping with such a diagnosis. 11 12 One aspect of the challenges posed by this unusual coagulopathy that has received relatively little attention is the impact on instituting renal replacement therapy (RRT). Acute kidney injury necessitating RRT occurs in at least one in five COVID-19 patients requiring intensive care unit (ICU) admission. 13 14 Difficulties related to thrombosis of extracorporeal circuits have been described 15 16 ; strategies to overcome this problem are urgently required, not simply so that RRT can be instituted in a timely manner and delivered effectively, but also because prolonging circuit life is essential in the context of a pandemic when supplies of consumables risk becoming exhausted. 14 Here we describe a patient with multiple organ failure secondary to COVID-19 who exhibited significant derangement of laboratory coagulation indices, and in whom attempts to institute acute RRT were hampered by repeated thrombosis of the hemofiltration circuit and vascular access catheters. In late March 2020, the patient, a 62-year-old man with hypertension, obesity, and hypercholesterolemia, presented to the Emergency Department with profound hypoxemia refractory to supplemental oxygen therapy. Admission laboratory findings of note included a D-dimer of 1,868 µg FEU/L, fibrinogen 10.17 g/L, creatinine 150 µmol/L, urea 12.2 mmol/L, C-reactive protein 364 mg/L, and ferritin 2,428 ug/L. He required intubation, mechanical ventilation, and circulatory support with norepinephrine, and went on to become anuric within 24 hours. Ten hours after admission the decision was taken to institute continuous venovenous hemodiafiltration (CVVHDF). A 12 Fr 20-cm dual-lumen Arrow vascular access catheter (Teleflex Inc, Reading, Pennsylvania, United States) was inserted into the right femoral vein under real-time ultrasound guidance. CVVHDF was commenced using a Prismaflex platform and ST150 filter set (Baxter International Inc, Deerfield, Illinois, United States) at 25 mL/kg/h using a predilution strategy. Anticoagulation was provided by systemic infusion of unfractionated heparin (UFH) aiming for an APTT of 45 to 70 seconds. It was impossible to institute effective RRT, as evidenced by a relentlessly climbing serum creatinine despite multiple attempts and repeated insertion of new vascular access catheters at different sites. The hemofiltration circuits clotted very quickly, one of them within minutes of commencement of therapy. Tinzaparin 175 units/kg once daily was given on three occasions in addition to intravenous UFH, with no obvious benefit. Fig. 1 illustrates these events. Six days into his ICU stay all heparin was discontinued and an infusion of argatroban commenced at an initial rate of 0.5 µg/kg/min. The APTT was measured every 4 hours and the infusion rate increased by 0.1 µg/kg/min until the APTT ratio was consistently between 1.5 and 3. A rapid improvement in the life of the hemofiltration circuits and vascular access catheters followed, and a corresponding decrease in the serum creatinine was swiftly observed. After several days of argatroban therapy, a tunneled semi-permanent dialysis catheter was sited under fluoroscopic guidance. This continued to function throughout a subsequent tracheostomy wean. On the 18th day of his admission the D-dimer had risen to 6,309 µg FEU/L, ultimately peaking at 18,775 µg FEU/L on the 28th day. He was eventually successfully decannulated, became independent of RRT, and was discharged home after nearly 2 months in hospital. Many intensivists will be familiar with the utility of argatroban, a small molecule direct thrombin inhibitor, from its use in critically ill patients with heparin-induced thrombocytopenia. 17 That we overcame the difficulties encountered in this case using argatroban supports the view that heparin resistance plays a central role in the coagulopathy of COVID-19. It also accords with the observation that rates of venous thromboembolism (VTE) in critically ill patients with COVID-19 are extremely high when prophylactic anticoagulation with low molecular weight heparin is used, and that VTE can be detected in the majority of patients with severe COVID-19 even when therapeutic anticoagulation is employed empirically early in the course of the disease. 18 Heparin resistance in this setting has been attributed to the combination of high factor VIII and fibrinogen levels accompanied by low circulating antithrombin, 19 a picture that has been described as a prothrombotic variant of DIC. 20 Since our patient's discharge from hospital, a single-center study has suggested argatroban to be effective when utilized as an escalation therapy in patients with COVID-19 who have already developed thromboembolism and who require continuous RRT. 21 Additionally, argatroban use has been described in a small group of patients more profoundly critically ill with SARS-CoV-2 infection, most of whom required extracorporeal membrane oxygenation (ECMO). 22 Aside from RRT and ECMO, an extracorporeal approach to removing circulating SARS-CoV-2 from the bloodstream is also being explored 23 ; effective anticoagulation strategies will be essential if such extracorporeal therapies are to be successful. Further studies are urgently required to determine the molecular pathogenesis of, and optimum treatment for, the coagulopathy seen in COVID-19. 3 4 Although direct infection of renal tissue by SARS-CoV-2 appears to be of greater importance than TMA in the pathophysiology of the nephropathy seen in the condition, 24 the prothrombotic state may seriously compromise the supportive care of these patients when critically ill. We believe it is important to highlight our experience with argatroban in this patient, in whom it appeared to be life-saving. We believe that the efficacy of argatroban in this setting should be explored in a randomized controlled trial. Fig. 1 Anticoagulation therapy, vascular access catheter insertions, and periods of hemodiafiltration after ICU admission. The final line inserted was a tunneled semi-permanent dialysis catheter. ICU, intensive care unit. Conflict of Interest None declared. ==== Refs References 1 Lippi G Favaloro E J D-dimer is associated with severity of coronavirus disease 2019: a pooled analysis Thromb Haemost 2020 120 05 876 878 32246450 2 Terpos E Ntanasis-Stathopoulos I Elalamy I Hematological findings and complications of COVID-19 Am J Hematol 2020 95 07 834 847 32282949 3 Kollias A Kyriakoulis K G Dimakakos E Poulakou G Stergiou G S Syrigos K Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action Br J Haematol 2020 189 05 846 847 32304577 4 Levi M Thachil J Iba T Levy J H Coagulation abnormalities and thrombosis in patients with COVID-19 Lancet Haematol 2020 7 06 e438 e440 32407672 5 Zhou F Yu T Du R 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 32171076 6 Tang 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 04 844 847 32073213 7 Violi F Pastori D Cangemi R Pignatelli P Loffredo L Hypercoagulation and antithrombotic treatment in coronavirus 2019: a new challenge Thromb Haemost 2020 120 06 949 956 32349133 8 Global COVID-19 Thrombosis Collaborative Group Bikdeli B Madhavan M V Gupta A Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research Thromb Haemost 2020 120 07 1004 1024 32473596 9 Iba T Levy J H Levi M Connors J M Thachil J Coagulopathy of coronavirus disease 2019 Crit Care Med 2020 48 09 1358 1364 32467443 10 Spiezia L Boscolo A Poletto F COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure Thromb Haemost 2020 120 06 998 1000 32316063 11 Zhang Y Xiao M Zhang S Coagulopathy and antiphospholipid antibodies in patients with COVID-19 N Engl J Med 2020 382 17 e38 32268022 12 Harzallah I Debliquis A Drénou B Lupus anticoagulant is frequent in patients with COVID-19 J Thromb Haemost 2020 18 08 2064 2065 32324958 13 Ronco C Reis T Husain-Syed F Management of acute kidney injury in patients with COVID-19 Lancet Respir Med 2020 8 07 738 742 32416769 14 Goldfarb D S Benstein J A Zhdanova O Impending shortages of kidney replacement therapy for COVID-19 patients Clin J Am Soc Nephrol 2020 15 06 880 882 32345750 15 Sise M E Baggett M V Shepard J O Stevens J S Rhee E P Case 17-2020: A 68-year-old man with COVID-19 and acute kidney injury N Engl J Med 2020 382 22 2147 2156 32402156 16 Wilbers T J Koning M V Renal replacement therapy in critically ill patients with COVID-19: a retrospective study investigating mortality, renal recovery and filter lifetime J Crit Care 2020 60 103 105 32795841 17 Saugel B Phillip V Moessmer G Schmid R M Huber W Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study Crit Care 2010 14 03 R90 20487559 18 Llitjos J F Leclerc M Chochois C High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients J Thromb Haemost 2020 18 07 1743 1746 32320517 19 White D MacDonald S Bull T Heparin resistance in COVID-19 patients in the intensive care unit J Thromb Thrombolysis 2020 50 02 287 291 32445064 20 Wang J Hajizadeh N Moore E E Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series J Thromb Haemost 2020 18 07 1752 1755 32267998 21 Shankaranarayanan D Muthukumar T Barbar T Anticoagulation strategies and filter life in COVID-19 patients receiving continuous renal replacement therapy: a single-center experience Clin J Am Soc Nephrol 2020 (e-pub ahead of print)10.2215/CJN.08430520 22 Arachchillage D J Remmington C Rosenberg A Anticoagulation with argatroban in patients with acute antithrombin deficiency in severe COVID-19 Br J Haematol 2020 190 05 e286 e288 32516429 23 Seffer M T Cottam D Forni L G Kielstein J T Heparin 2.0: a new approach to the infection crisis Blood Purif 2020 (e-pub ahead of print)10.1159/000508647 24 Su H Yang M Wan C Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China Kidney Int 2020 98 01 219 227 32327202