Antiviral anticoagulation

Pryzdial, Edward L. G.; Sutherland, Michael R.; Lin, Bryan H.; Horwitz, Marc S.

doi:10.1002/rth2.12406

Cited by 13 publications

(11 citation statements)

References 177 publications

(336 reference statements)

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“…In this direction, factor Xa (FXa), a serine protease in the common coagulation pathway, is known to play a crucial role in coagulation by inducing the formation of thrombin, which eventually leads to the formation of cross-linked blood clots [ 9 – 11 ]. FXa has also been linked to inflammation [ 12 ] and viral infections [ 13 ]. In fact, direct FXa inhibitors have been reported to promote a host of pharmacological effects, including anticoagulant activity, anti-inflammatory activity, and antiviral activity (Fig.…”

Section: Introductionmentioning

confidence: 99%

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Al‐Horani

2020

Am J Cardiovasc Drugs

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Human factor Xa (FXa) is a serine protease of the common coagulation pathway. FXa is known to activate prothrombin to thrombin, which eventually leads to the formation of cross-linked blood clots. While this process is important in maintaining hemostasis, excessive thrombin generation results in a host of thrombotic conditions. FXa has also been linked to inflammation via protease-activated receptors. Together, coagulopathy and inflammation have been implicated in the pathogenesis of viral infections, including the current coronavirus pandemic. Direct FXa inhibitors have been shown to possess anti-inflammatory and antiviral effects, in addition to their established anticoagulant activity. This review summarizes the pharmacological activities of direct FXa inhibitors, their pharmacokinetics, potential drug-drug interactions and adverse effects, and the details of clinical trials involving direct FXa inhibitors in coronavirus disease 2019 (COVID-19) patients. Key Points Factor Xa is a serine protease in the common coagulation pathway, the excessive stimulation of which leads to a host of thrombotic conditions. Factor Xa has also been linked to inflammation as well as viral infections. In addition to their established anticoagulant properties, factor Xa inhibitors have exhibited significant anti-inflammatory and antiviral effects in several testing settings. Currently, there are > 10 clinical trials for evaluating the potential of factor Xa inhibitors in coronavirus disease 2019 (COVID-19) patients. Strategies to administer these drugs parenterally may facilitate their use in critically ill COVID-19 patients.

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Section: Introductionmentioning

confidence: 99%

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Al‐Horani

2020

Am J Cardiovasc Drugs

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“…Therefore, for patients regularly assuming DOACs, clinicians have recommended to replace DOACs with heparin to avoid drug–drug interactions (Testa et al, 2020 ). However, in COVID-19 patients, the coagulation function is heavily unbalanced leading to hypercoagulation and the development of life-threatening coagulopathies, which may negatively affect the prognosis (Han et al, 2020 ; Pryzdial et al, 2020 ). Indeed, the alteration of blood clotting and inflammation are two frequently coupled manifestations of viral infections.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, the alteration of blood clotting and inflammation are two frequently coupled manifestations of viral infections. Therefore, DOACs such as apixaban have shown an antiviral activity on herpes simplex virus type 1 and have been proposed as a possible therapeutic strategy to control COVID-19 (Pryzdial et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Repurposing Known Drugs as Covalent and Non-covalent Inhibitors of the SARS-CoV-2 Papain-Like Protease

et al. 2020

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In the absence of an approved vaccine, developing effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals is essential to tackle the current pandemic health crisis due to the coronavirus disease 2019 (COVID-19) spread. As any traditional drug discovery program is a time-consuming and costly process requiring more than one decade to be completed, in silico repurposing of existing drugs is the preferred way for rapidly selecting promising clinical candidates. We present a virtual screening campaign to identify covalent and non-covalent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) showing potential multitarget activities (i.e., a desirable polypharmacology profile) for the COVID-19 treatment. A dataset including 688 phase III and 1,702 phase IV clinical trial drugs was downloaded from ChEMBL (version 27.1) and docked to the recently released crystal structure of PLpro in complex with a covalently bound peptide inhibitor. The obtained results were analyzed by combining protein–ligand interaction fingerprint similarities, conventional docking scores, and MM-GBSA–binding free energies and allowed the identification of some interesting candidates for further in vitro testing. To the best of our knowledge, this study represents the first attempt to repurpose drugs for a covalent inhibition of PLpro and could pave the way for new therapeutic strategies against COVID-19.

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“…35 The thrombopathy may be a response to direct virus-induced damage to vascular endothelial cells 64 and/or the virus acquiring TF from host cells, both triggering coagulation activation. 50,52,53,71…”

Section: Does Complement Activation Trigger Venous Thromboembolism mentioning

confidence: 99%

“…Although many of these patients have elevated D‐dimer and fibrinogen, they also commonly have increased C‐reactive protein and IL‐6, consistent with a vigorous inflammatory response 35 . The thrombopathy may be a response to direct virus‐induced damage to vascular endothelial cells 64 and/or the virus acquiring TF from host cells, both triggering coagulation activation 50,52,53,71 . However, it is also possible that complement contributes.…”

Section: Other Considerationsmentioning

confidence: 99%

Is the COVID‐19 thrombotic catastrophe complement‐connected?

Conway

Pryzdial

2020

Journal of Thrombosis and Haemostasis

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In December 2019, the world was introduced to a new betacoronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for its propensity to cause rapidly progressive lung damage, resulting in high death rates. As fast as the virus spread, it became evident that the novel coronavirus causes a multisystem disease (COVID-19) that may involve multiple organs and has a high risk of thrombosis associated with striking elevations in pro-inflammatory cytokines, D-dimer, and fibrinogen, but without disseminated intravascular coagulation. Postmortem studies have confirmed the high incidence of venous thromboembolism, but also notably revealed diffuse microvascular thrombi with endothelial swelling, consistent with a thrombotic microangiopathy, and inter-alveolar endothelial deposits of complement activation fragments. The clinicopathologic presentation of COVID-19 thus parallels that of other thrombotic diseases, such as atypical hemolytic uremic syndrome (aHUS), that are caused by dysregulation of the complement system. This raises the specter that many of the thrombotic complications arising from SARS-CoV-2 infections may be triggered and/or exacerbated by excess complement activation. This is of major potential clinical relevance, as currently available anti-complement therapies that are highly effective in protecting against thrombosis in aHUS, could be efficacious in COVID-19. In this review, we provide mounting evidence for complement participating in the pathophysiology underlying the thrombotic diathesis associated with pathogenic coronaviruses, including SARS-CoV-2. Based on current knowledge of complement, coagulation and the virus, we suggest lines of study to identify novel therapeutic targets and the rationale for clinical trials with currently available anticomplement agents for COVID-19.

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Antiviral anticoagulation

Cited by 13 publications

References 177 publications

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Repurposing Known Drugs as Covalent and Non-covalent Inhibitors of the SARS-CoV-2 Papain-Like Protease

Is the COVID‐19 thrombotic catastrophe complement‐connected?

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