Successful Use of Argatroban to Treat a Critically Ill Patient with Coagulopathy and Nephropathy Secondary to COVID-19

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.1–4 For example, in a case series of 191 patients from twoWuhan 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 associatedwith 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 RRToccurs in at least one infive COVID-19 patients requiring intensive care unit (ICU) admission.13,14 Difficulties related to thrombosis of extracorporeal circuits have been described15,16; 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 12.2mmol/L, C-reactive protein 364mg/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 25mL/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

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 RRToccurs 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 APTTwas 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 lifesaving. We believe that the efficacy of argatroban in this setting should be explored in a randomized controlled trial.

Conflict of Interest
None declared.