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Direct oral anticoagulants (DOACs) are increasingly used for the treatment of thrombosis. While inhibitors of factor IIa and factor Xa have shown effectiveness, the risk of bleeding remains a significant concern. Recently, direct factor XIa inhibitors-including asundexian and milvexian-have emerged as potential anticoagulation therapies, based on clinical observations that patients with factor XIa deficiencies seldom present with spontaneous bleeding tendencies. The interferences associated with DOACs in routine and specialised coagulation assays are well-described; however, the interferences associated with emerging FXIa inhibitors are largely uncharacterised. Here, we briefly report the impact of asundexian and milvexian in routine coagulation assays using in vitro plasma-based systems. Asundexian and milvexian induce concentration-dependent prolongations in APTT-based assays with curvilinear regressions, which may be suitable for the measurement of pharmacodynamic effects at peak levels ex vivo. We also report differential sensitivities of APTT-based assays-particularly at higher FXIa inhibitor concentrations-highlighting the clinical need for an extensive evaluation of interferences associated with FXIa inhibitors in coagulation assays.

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BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly prescribed for the prevention and treatment of thrombosis. However, DOACs are associated with extensive interference in coagulation assays. Herein, we evaluate raw activated charcoal (AC) as an adsorbent material, to minimise DOAC-associated interferences in routine and specialised coagulation parameters on CS-series analysers (Sysmex, Kobe, Japan). METHODS: Commercial human-derived non-anticoagulated plasma materials, with or without increasing concentrations of anticoagulant, were assayed for routine and specialised coagulation parameters before and after treatment with AC. RESULTS: Treatment of non-anticoagulated plasma with raw AC had minimal impact on routine and specialised coagulation parameters available on the CS-series; however, clinically relevant prolongations of certain activated partial thromboplastin time (APTT)-based assays were observed after treatment. Furthermore, in apixaban- and rivaroxaban-containing plasma material, AC efficiently adsorbed therapeutic and supratherapeutic DOAC concentrations; and, treatment with raw AC resolved DOAC-associated interferences on all affected routine and specialised coagulation parameters. CONCLUSIONS: Overall, raw AC efficiently adsorbed apixaban and rivaroxaban from human-derived plasma, without significantly affecting the majority of underlying routine and specialised coagulation parameters available on CS-series analysers.

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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented global healthcare crisis. While SARS-CoV-2-associated COVID-19 affects primarily the respiratory system, patients with COVID-19 frequently develop extrapulmonary manifestations. Notably, changes in the hematological system, including lymphocytopenia, neutrophilia and significant abnormalities of hemostatic markers, were observed early in the pandemic. Hematological manifestations have since been recognized as important parameters in the pathophysiology of SARS-CoV-2 and in the management of patients with COVID-19. In this narrative review, we summarize the state-of-the-art regarding the hematological and hemostatic abnormalities observed in patients with SARS-CoV-2-associated COVID-19, as well as the current understanding of the hematological system in the pathophysiology of acute and chronic SARS-CoV-2-associated COVID-19.

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SARS-CoV-2 cell-cell fusion and syncytiation is an emerging pathomechanism in COVID-19, but the precise factors contributing to the process remain ill-defined. In this study, we show that metalloproteases promote SARS-CoV-2 spike protein-induced syncytiation in the absence of established serine proteases using in vitro cell-cell fusion assays. We also show that metalloproteases promote S2'-activation of the SARS-CoV-2 spike protein, and that metalloprotease inhibition significantly reduces the syncytiation of SARS-CoV-2 variants of concern. In the presence of serine proteases, however, metalloprotease inhibition does not reduce spike protein-induced syncytiation and a combination of metalloprotease and serine protease inhibition is necessitated. Moreover, we show that the spike protein induces metalloprotease-dependent ectodomain shedding of the ACE2 receptor and that ACE2 shedding contributes to spike protein-induced syncytiation. These observations suggest a benefit to the incorporation of pharmacological inhibitors of metalloproteases into treatment strategies for patients with COVID-19.

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