Bivalirudin resistance in a patient on veno-venous extracorporeal membrane oxygenation with a therapeutic response to argatroban

Abstract

A 48-year-old male patient requiring extracorporeal membrane oxygenation (ECMO) support for hypoxaemic respiratory failure failed to achieve therapeutic anticoagulation with bivalirudin after continuous dose escalations, and continued to have recurrent fibrin stranding in the circuit over a 6-day course of treatment. Suspecting bivalirudin resistance, the patient was transitioned to argatroban and achieved a therapeutic response in less than 24 hours. The case describes the challenges of anticoagulation in ECMO supported patients. The interplay between bivalirudin metabolism, renal replacement therapy, and immunological effects leading to a heparin-like-effect, inflammatory mediators, and thrombotic burdens may all impact the clinical effect during bivalirudin therapy. The structural biochemistry of thrombin and bivalirudin likely plays a role in the presented patient’s successful response to argatroban. Bivalirudin may fail at achieving therapeutic anticoagulation in patients with genetic thrombin mutations or structural defects that alter the binding pockets at the thrombin exosites.

Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support

“…In non-COVID patients, direct thrombin inhibitor resistance was speculated to be due to elevated factor VIII and fibrinogen, as well as large clot burden. 12,13 Hypercoagulability has been documented in COVID-19 patients, 14,15 but specific correlation with overall dosing of anticoagulants has not been explored. Patients with COVID-19 have been found to have markedly elevated fibrinogen and factor VIII levels.…”

HEROES V‐V—HEmorRhagic cOmplications in Veno‐Venous Extracorporeal life Support—Development and internal validation of multivariable prediction model in adult patients

“…Contact of blood components to circuit tubes and membrane surfaces cause hemolysis which in conjunction with anticoagulation agents, perturbs balance of hemostasis. 12,[23][24][25][26][27][28][29][30][31] Transfusions are also associated with additional risks, including acute hemolytic reactions, allergic reactions, and transfusionrelated lung injury. [32][33][34] It also has been shown that the utilization of red cell transfusion varies by a factor of three between V-V and V-A modalities.…”

“…The management of these complications is complex, involving transfusion support and interventions to control bleeding. Contact of blood components to circuit tubes and membrane surfaces cause hemolysis which in conjunction with anticoagulation agents, perturbs balance of hemostasis 12,23–31 . Transfusions are also associated with additional risks, including acute hemolytic reactions, allergic reactions, and transfusion‐related lung injury 32–34 .…”

The Emerging Role of Bivalirudin for Therapeutic Anticoagulation in Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation Support: Is It Time to Change the Routine Practice?

“…Several previous studies compared the use of unfractionated heparin and bivalirudin for anticoagulation during the use of ECMO, but they have variable designs and numbers of included patients. [12][13][14] Seelhammer et al [10] demonstrated a lower mortality rate in the adult group receiving bivalirudin than the use of heparin for anticoagulation in a large retrospective study including 424 patients requiring ECMO, 21% of them were pediatric. However, this difference was not reported among pediatric patients.…”

“…[12][13] Future research also needs to consider the concern on the reported resistance to bivalirudin in patients receiving ECMO. [14] The authors also reported double the cost of using bivalirudin in patients with COVID-19 in addition to the expected added costs of longer times on using ECMO and ICU stays than those with non-COVID-19 ARDS patients. [7] Ranucci et al demonstrated that compared with heparin use, there was a trend towards a lower cost of using Bivalirudin in adults and a statistically significantly lower cost in pediatric patients receiving post-cardiotomy ECMO.…”