Post-acute sequelae of SARS-CoV-2 in non-hospitalised patients: hypercoagulability and the effect of novel anticoagulants

Introduction Post-acute sequelae of SARS-CoV-2 are associated with thrombotic disorders regardless of acute severity. While thromboprophylaxis may benefit hospitalised patients, clinical trials do not support such therapy in non-hospitalised patients due to high bleeding risks of current anticoagulants. Objective To characterise prothrombotic risks in non-hospitalised COVID-19 patients after recovery and investigate novel anticoagulants with a favourable efficacy-safety profile in preventing COVID-19-associated coagulopathy. Methods We recruited 138 SARS-CoV-2-naïve participants and 111 community-managed COVID-19 patients at a median of 72 days post-diagnosis. All participants underwent assessment of full blood count, thrombin generation, clot formation, platelet activation, and plasma biomarkers. A human ex vivo thrombosis model using Badimon perfusion chambers was established to mimic thrombus formation in macro- and micro-vessels under high- and low-shear rate of blood from participants with hypercoagulable features. Results Approximately 9.0% of post-acute COVID-19 patients exhibited persistent hypercoagulability (median OR 1.2, IQR 0.8-2.1). Compared to controls, patients showed enhanced thrombin generation, with higher peak concentration (P < 0.0001) and shorter time to peak (P < 0.0001). Extrinsic and intrinsic coagulation kinetics were accelerated, reflected by shorter prothrombin time (P = 0.0034) and activated partial thromboplastin time (P = 0.0015). D-dimer was elevated in 30.6% (> 0.5 mg/L) and 4.5% (> 1.0 mg/L) of patients, indicating fibrinolytic activity in individuals. Platelet activation was increased as stimulated P-selectin–positive platelets was markedly higher (P = 0.0190), and platelet–monocyte aggregates were elevated irrespective of agonist exposure (P <0.0001). In contrast, biomarkers of endotheliopathy and systemic inflammation were not significantly different. For ex vivo thrombosis testing, 15 participants with marked prothrombotic features were studied as blood donors. Under low shear force, compared to saline, two novel anticoagulants, ultravariegin (thrombin inhibitor) and P1395M (factor XIa inhibitor), reduced thrombus area by 30.1% (P <0.0001) and 18.5% (P = 0.0114), respectively. A low-dose combination with one-fifth of each monotherapy dose reduced thrombi by 30.6% (P < 0.0001), while enaxoparin as a positive control reduced by 15.4% (P = 0.0341). Under high shear force, thrombus reductions were 16.8% (ultravariegin, P = 0.0002), 8.0% (P1395M, P = 0.0093), and 17.3% (combination, P < 0.0001), versus 14.8% with enoxaparin (P < 0.0001). Conclusions Persistent prothrombotic risks exist in a subset of non-hospitalised COVID-19 patients after recovery. Ultravariegin and P1395M, as mono- or low-dose dual-therapy, may offer potent strategies to prevent COVID-19-associated coagulopathy. Bleeding risks may potentially be limited through combining anticoagulants at reduced doses.