Sustained prothrombotic changes in convalescent patients with COVID-19.

We read with great interest the Viewpoint by Leentjens and colleagues on COVID-19-associated coagulopathy and optimal anticoagulant treatment strategies. The authors provide a comprehensive overview of the available evidence (particularly from clinical trials) and knowledge gaps on anticoagulant treatment for patients with COVID-19 at different stages of disease. The collaborative efforts that were started in early stages of the pandemic and the rapidly initiated clinical trials have resulted in a rapidly growing body of research on the need for anticoagulant treatment for patients with COVID-19 who are admitted to hospital. However, as Leentjens and colleagues have stated, optimal dosing and duration of anticoagulant therapy are still debated, and while results from large clinical studies are awaited, data on anticoagulant treatment for out-patients and patients after hospital discharge are currently scarce. The authors described that coagulation markers in previously admitted patients with COVID-19 are restored after hospital discharge. However, recent studies2, 3 provide evidence for persistent haemostatic abnormalities even months after hospital discharge. One study showed elevated D-dimer concentrations in approximately 25% of patients 4 months after primary SARS-CoV-2 infection. Notably, almost a third of patients with persistent elevations in D-dimer were fully managed as out-patients (disease stage 1). Whether these results are compatible with ongoing systemic or local (intrapulmonary) activation of coagulation in a proportion of convalescent patients with COVID-19 requires further investigation. Additionally, we recently showed elevated thrombin-generating capacity and a hypofibrinolytic state in patients that predominantly had moderate disease (stage 2) 4 months after hospital discharge. Importantly, ex vivo hypercoagulability and hypofibrinolysis are associated with an increased risk of thrombotic events in the general population.4, 5 It is tempting to speculate that a persistent hypercoagulable state contributes to the post-acute sequelae of SARS-CoV-2 infection (PASC; also known as long COVID) by facilitating formation of microthrombi in the pulmonary vasculature, similar to the thrombotic events proposed in stage 1 disease. In this scenario, post-discharge thromboprophylaxis might benefit some convalescent patients with COVID-19, and larger controlled trials, such as the ACTIV-4 trial (NCT04498273), will provide important information on this matter. We feel that studies investigating underlying mechanisms and potential clinical consequences of sustained prothrombotic changes in convalescent patients with COVID-19 are needed, because they might have therapeutic implications.

We declare no competing interests.