Impaired exercise capacity in post-COVID-19 syndrome: the role of VWF-ADAMTS13 axis

Abstract

Post-COVID syndrome (PCS), or long COVID, is an increasingly recognized complication of acute SARS-CoV-2 infection, characterized by persistent fatigue, reduced exercise tolerance, chest pain, shortness of breath, and cognitive slowing. Acute COVID-19 is strongly linked with an increased risk of thrombosis, which is a prothrombotic state quantified by an elevated von Willebrand factor (VWF) antigen (Ag)/ADAMTS13 ratio that is associated with severity of acute COVID-19 infection. We investigated whether patients with PCS also had evidence of a prothrombotic state associated with symptom severity. In a large cohort of patients referred to a dedicated post-COVID-19 clinic, thrombotic risk, including VWF(Ag)/ADAMTS13 ratio, was investigated. An elevated VWF(Ag)/ADAMTS13 ratio (≥1.5) was present in nearly one-third of the cohort and was 4 times more likely to be present in patients with impaired exercise capacity, as evidenced by desaturation ≥3% and/or an increase in lactate level >1 from baseline on a 1-minute sit-to-stand test and/or a 6-minute walk test (P < .0001). Of 276 patients, 56 (20%) had impaired exercise capacity, of which 55% (31/56) had a VWF(Ag)/ADAMTS13 ratio ≥1.5 (P < .0001). Factor VIII and VWF(Ag) were elevated in 26% and 18%, respectively, and support a hypercoagulable state in some patients with PCS. These findings suggest possible ongoing microvascular/endothelial dysfunction in the pathogenesis of PCS and suggest a role for antithrombotic therapy in the treatment of these patients.

Graphical abstract

Figure 1.

Spread of VWF(Ag)/ADAMTS13 ratio across patients with PCS, and overview of exercise testing and associated VWF(Ag)/ADAMTS13 ratio. (A) Histogram showing distribution of the VWF(Ag)/ADAMTS13 ratio across the post-COVID patient cohort. (B) Flowchart showing performance in exercise testing and associated VWF(Ag)/ADAMTS13 ratio. (C) Median VWF(Ag)/ADAMTS13 ratio in patients with normal and abnormal exercise test results. Median VWF(Ag)/ADAMTS13 ratio was 1.5 in patients with an abnormal result, compared with a median ratio of 1.1 in patients with a normal result. P < . 0001.