Reply to Rappaport et al.: Anti-FXa Activity with Intermediate-Dose Thromboprophylaxis in COVID-19

From the Authors:

We read with interest the communication from Rappaport and colleagues describing their experience measuring anti–factor Xa (FXa) activity in critically unwell patients with coronavirus disease (COVID-19) infection, receiving intermediate-dose thromboprophylaxis with enoxaparin (0.5 mg/kg twice daily) as standard care. The authors conclude that their results suggest anti-FXa monitoring is not required for critically unwell patients receiving an escalated regime of thromboprophylaxis.

The authors measured anti-FXa activity in 40 critically unwell patients within 48 hours of admission and reported the need for dose adjustment thereafter to obtain a target anti-FXa activity of 0.2–0.5 U/ml. Seventy-five percent of patients achieved the target anti-FXa range with no further dose adjustment.

This contrasts with our own report (1), in which only 5% of intensive treatment unit patients (majority intubated) managed using a standard thromboprophylaxis regime (40 mg enoxaparin once daily) achieved target anti-FXa activity (0.2–0.4 U/ml). The authors did not define “critically unwell patients” as those requiring mechanical ventilation; however, these reports together provide support for more intensive thromboprophylaxis regimes for patients with severe COVID-19 infection admitted to the intensive treatment unit.

As highlighted in our research correspondence, we agree that uncertainty remains about the value of anti-FXa monitoring in patients receiving thromboprophylaxis with low molecular heparin (2). Nevertheless, in the absence of clinical trial data confirming an optimal anticoagulation strategy for a condition with a recognized spectrum of thrombosis and clinically relevant bleeding (3, 4), we suggest that the use of anti-FXa activity to inform dosing should not be completely dismissed.

Patients with COVID-19 demonstrate dynamic flux in their clinical progress accompanied by underlying changes in their inflammatory and coagulopathic state (5). Such fluctuations may influence heparin resistance and low–molecular weight heparin clearance. It is unclear whether Rappaport and colleagues measured anti-FXa serially during hospitalization to determine consistent activity within the target range and whether such fluctuations reflected changes in disease severity or outcomes. One of four patients, not an insignificant proportion, required dose adjustment and six of 11 patients experienced a bleeding or confirmed/suspected thrombotic event. The corresponding anti-FXa measured ahead or at the time of these events is not provided. Bleeding complications in patients with COVID-19 are reported in the literature and, in addition to thrombotic outcomes, represent important endpoints for ongoing randomized controlled clinical trials.

Since the start of the COVID-19 pandemic, despite an evolution in anticoagulation regimes for the prevention of thrombotic complications based mainly on retrospective data, we believe the relationship between patient-specific factors for thrombosis and hemorrhage and anti-FXa concentrations remain an important consideration. Until we understand further the discordance of the anti-FXa in COVID-19, its relevance, and the targets one should aim for to achieve safe and effective hemostasis, we would urge caution against disregarding anti-FXa activity as a potential tool in a patient group with a high risk of thrombosis and bleeding while receiving anticoagulation.