We thank Al Shabeeb et al (1) for their interesting comments on our study (2). They report their local single-center experience of 69 patients with COVID-19–associated acute respiratory distress syndrome on extracorporeal membrane oxygenation (ECMO) support, in whom only two patients (3%) had intracranial hemorrhage (ICH). These two patients showed complete neurologic recovery, whereas the entire cohort had an excellent survival of 67%. In general, the cohort was rather young with a mean age of 43 years, whereas no information was provided regarding comorbidities, underlying frailty, or concomitant secondary organ failure. Nevertheless, Al Shabeeb et al (1) argue that the discrepancy between the ICH incidences cannot be clearly related to the underlying patient factors such as disease severity. They hypothesize that the nearly exclusive use of bivalirudin (a direct thrombin inhibitor) as their routine in-house ECMO anticoagulation strategy, as opposed to the primary use of unfractionated heparin (UFH) in our three centers in Bonn, Hannover, and Zürich, represents a key factor that might be responsible for the ICH differences.
First, we congratulate the authors on their low ICH rates and stellar overall-survival. Apart from the use of different anticoagulants, we believe that other factors may have contributed to the observed discrepancies and deserve further mentioning. The obvious age difference of 16 years arguably comes with significant fewer comorbidities such as diabetes mellitus, micro- and macroangiopathies, and chronic kidney disease, which were not mentioned but are all risk factors of bleeding events. The very young age suggests a highly selected cohort, analogous to a recent U.K. report that presented a commensurately low mortality rate in COVID-19 patients on ECMO support (3).
Second, our observation of higher than normal ICH rates in COVID-19 patients on ECMO stands not alone and has been reported by many groups around the globe, acknowledging both the critical combination of anticoagulation and a certain COVID-19–driven vascular susceptibility (4). Regarding choice of anticoagulation, UFH is used by the overwhelming majority of ECMO centers across the globe (5), whereas direct thrombin inhibitors are usually reserved for situations where UFH is contraindicated such as heparin-induced thrombocytopenia or plainly inefficient. Patients receiving bivalirudin as a first-line anticoagulant are, thus, certainly underrepresented in previous reports, begging the question whether its use might indeed favorably affect (intracranial) hemorrhage in COVID-19.
Direct thrombin inhibitors offer pharmacological advantages over heparin including their independence from antithrombin as a cofactor, the absence of plasma protein binding—improving predictability of their anticoagulant effect—and the ability to bind both soluble and fibrin-bound thrombin. In COVID-19, they may, therefore, attenuate the well-described endothelial activation (or endothelialitis), which is partly directly thrombin-mediated. Direct thrombin inhibitors may, thus, abate both thrombosis and bleeding events in COVID-19 by inhibiting endothelium-thrombin–mediated downstream effects of platelet activation and their subsequent interplay with neutrophils (termed immunothrombosis) as well as by suppressing fibrin degradation, preventing resultant microthrombi (6). Furthermore, it has been recently shown that target anticoagulation corridors are more reliably maintained with bivalirudin than UFH in COVID-19 patients (7).
With a growing body of evidence suggesting the safe applicability of bivalirudin in ECMO for indications other than COVID-19 (8) and single case reports even hinting toward improved survival in adults patients (6), we agree with Al Shabeeb et al (1) that prospective (multicentric) trials are warranted to investigate if the promising theoretical advantages translate into true patient benefit (NCT04445935).