Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi

Martinez de Lizarrondo et al., Circulation, doi:10.1161/CIRCULATIONAHA.117.027290, Aug 2017

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https://c19early.org/martinezdelizarrondo.html

N-acetylcysteine

15th treatment shown to reduce risk in February 2021, now with p = 0.000028 from 24 studies, recognized in 3 countries.

Lower risk for mortality, hospitalization, and cases.

No treatment is 100% effective. Protocols combine treatments.

6,100+ studies for 180 treatments. c19early.org

Experimental study in mice showing potent thrombolytic effects with N-acetylcysteine (NAC) in arterial thrombosis models. Authors hypothesize that NAC's thrombolytic mechanism involves destabilizing the VWF-dependent outer portion of thrombi, exposing the inner core to GpIIb/IIIa inhibition.

10 preclinical studies support the efficacy of N-acetylcysteine for COVID-19:

1 in silico study1

8 in vitro studies2-9

1 in vivo animal study5

Severe COVID-19 is marked by endotheliopathy with elevated von Willebrand factor (VWF) levels and platelet/VWF-rich microthrombi. N-acetylcysteine can reduce VWF multimers and lyse VWF-dependent clots in vivo, potentially helping to alleviate thrombosis associated with COVID-1910-12. N-acetylcysteine shows dose-dependent inhibition of SARS-CoV-24,7,9, shows anti-inflammatory and immunomodulatory effects against SARS-CoV-2-induced immune responses in combination with bromelain6, suppressed virus-induced reactive oxygen species and blocked viral replication in a humanized mouse model and in human lung cells5, may limit COVID-19 induced cardiac damage by boosting cellular antioxidant defenses and potentially mitigating the oxidative stress caused by spike protein-induced ROS production in cardiac fibroblasts3, and reduces disulfide bonds in proteins and exhibits antioxidant properties that may inhibit viral replication and modulate inflammatory responses2. NAC may be beneficial for COVID-19 by replenishing glutathione stores and reinforcing the glutathione peroxidase-4 pathway to inhibit ferroptosis, an oxidative stress-induced cell death pathway implicated in COVID-1913. NAC reinforces glutathione levels, reduces ROS, and minimizes ferroptosis and cytokine storm14.

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1. Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.scienceopen.com, doi.org.

2. Reis et al., Antiviral effect of Bromelain combined with acetylcysteine against SARS-CoV-2 Omicron variant, Scientific Reports, doi:10.1038/s41598-025-92242-y.nature.com, doi.org.

3. Van Tin et al., Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling, Cells, doi:10.3390/cells13161331.mdpi.com, doi.org.

4. Chaopreecha et al., Andrographolide attenuates SARS-CoV-2 infection via an up-regulation of glutamate-cysteine ligase catalytic subunit (GCLC), Phytomedicine, doi:10.1016/j.phymed.2024.156279.sciencedirect.com, doi.org.

5. Frasson et al., Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern, Journal of Molecular Cell Biology. doi:10.1093/jmcb/mjae004, academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjae004/7596546oup.com.

6. Ferreira et al., Taming the SARS-CoV-2-mediated proinflammatory response with BromAc®, Frontiers in Immunology, doi:10.3389/fimmu.2023.1308477.frontiersin.org, doi.org.

7. La Maestra et al., Inhibition of the Cell Uptake of Delta and Omicron SARS-CoV-2 Pseudoviruses by N-Acetylcysteine Irrespective of the Oxidoreductive Environment, Cells, doi:10.3390/cells11203313.mdpi.com, doi.org.

8. Goc et al., Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants, European Journal of Microbiology and Immunology, doi:10.1556/1886.2021.00022.akjournals.com, doi.org.

9. Akhter et al., The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2, Viruses, doi:10.3390/v13030425.mdpi.com, doi.org.

10. Martinez de Lizarrondo et al., Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi, Circulation, doi:10.1161/CIRCULATIONAHA.117.027290.ahajournals.org, doi.org.

11. Goshua et al., Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study, The Lancet Haematology, doi:10.1016/S2352-3026(20)30216-7.sciencedirect.com, doi.org.

12. Chen et al., N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice, Journal of Clinical Investigation, doi:10.1172/JCI41062.jci.org, doi.org.

13. Yuan et al., The role of cell death in SARS-CoV-2 infection, Signal Transduction and Targeted Therapy, doi:10.1038/s41392-023-01580-8.nature.com, doi.org.

14. Xie et al., The role of reactive oxygen species in severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection-induced cell death, Cellular & Molecular Biology Letters, doi:10.1186/s11658-024-00659-6.biomedcentral.com, doi.org.

Martinez de Lizarrondo et al., 15 Aug 2017, peer-reviewed, 11 authors. Contact: gauberti@cyceron.fr.

In vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper N-acetylcys..All

Potent Thrombolytic Effect of N -Acetylcysteine on Arterial Thrombi

PhD Sara Martinez De Lizarrondo, MD Clément Gakuba, PhD Bradley A Herbig, PhD Yohann Repessé, PhD Carine Ali, PhD Cécile V Denis, PhD Peter J Lenting, PhD Emmanuel Touzé, PhD Scott L Diamond, PhD Denis Vivien, PhD Maxime Gauberti

Circulation, doi:10.1161/circulationaha.117.027290

BACKGROUND: Platelet cross-linking during arterial thrombosis involves von Willebrand Factor (VWF) multimers. Therefore, proteolysis of VWF appears promising to disaggregate platelet-rich thrombi and restore vessel patency in acute thrombotic disorders such as ischemic stroke, acute coronary syndrome, or acute limb ischemia. N-Acetylcysteine (NAC, a clinically approved mucolytic drug) can reduce intrachain disulfide bonds in large polymeric proteins. In the present study, we postulated that NAC might cleave the VWF multimers inside occlusive thrombi, thereby leading to their dissolution and arterial recanalization. METHODS: Experimental models of thrombotic stroke induced by either intra-arterial thrombin injection or ferric chloride application followed by measurement of cerebral blood flow using a combination of laser Doppler flowmetry and MRI were performed to uncover the effects of NAC on arterial thrombi. To investigate the effect of NAC on larger vessels, we also performed ferric chloride-induced carotid artery thrombosis. In vitro experiments were performed to study the molecular bases of NAC thrombolytic effect, including platelet aggregometry, platelet-rich thrombi lysis assays, thromboelastography (ROTEM), and high-shear VWF string formation using microfluidic devices. We also investigated the putative prohemorrhagic effect of NAC in a mouse model of intracranial hemorrhage induced by in situ collagenase type VII injection. RESULTS: We demonstrated that intravenous NAC administration promotes lysis of arterial thrombi that are resistant to conventional approaches such as recombinant tissue-type plasminogen activator, direct thrombin inhibitors, and antiplatelet treatments. Through in vitro and in vivo experiments, we provide evidence that the molecular target underlying the thrombolytic effects of NAC is principally the VWF that cross-link platelets in arterial thrombi. Coadministration of NAC and a nonpeptidic GpIIb/IIIa inhibitor further improved its thrombolytic efficacy, essentially by accelerating thrombus dissolution and preventing rethrombosis. Thus, in a new large-vessel thromboembolic stroke model in mice, this cotreatment significantly improved ischemic lesion size and neurological outcome. It is important to note that NAC did not worsen hemorrhagic stroke outcome, suggesting that it exerts thrombolytic effects without significantly impairing normal hemostasis. CONCLUSIONS: We provide evidence that NAC is an effective and safe alternative to currently available antithrombotic agents to restore vessel patency after arterial occlusion.

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DOI record: { "DOI": "10.1161/circulationaha.117.027290", "ISSN": [ "0009-7322", "1524-4539" ], "URL": "http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027290", "abstract": "\n Background:\n \n Platelet cross-linking during arterial thrombosis involves von Willebrand Factor (VWF) multimers. Therefore, proteolysis of VWF appears promising to disaggregate platelet-rich thrombi and restore vessel patency in acute thrombotic disorders such as ischemic stroke, acute coronary syndrome, or acute limb ischemia.\n N\n -Acetylcysteine (NAC, a clinically approved mucolytic drug) can reduce intrachain disulfide bonds in large polymeric proteins. In the present study, we postulated that NAC might cleave the VWF multimers inside occlusive thrombi, thereby leading to their dissolution and arterial recanalization.\n \n \n \n Methods:\n Experimental models of thrombotic stroke induced by either intra-arterial thrombin injection or ferric chloride application followed by measurement of cerebral blood flow using a combination of laser Doppler flowmetry and MRI were performed to uncover the effects of NAC on arterial thrombi. To investigate the effect of NAC on larger vessels, we also performed ferric chloride–induced carotid artery thrombosis. In vitro experiments were performed to study the molecular bases of NAC thrombolytic effect, including platelet aggregometry, platelet-rich thrombi lysis assays, thromboelastography (ROTEM), and high-shear VWF string formation using microfluidic devices. We also investigated the putative prohemorrhagic effect of NAC in a mouse model of intracranial hemorrhage induced by in situ collagenase type VII injection.\n \n \n Results:\n We demonstrated that intravenous NAC administration promotes lysis of arterial thrombi that are resistant to conventional approaches such as recombinant tissue-type plasminogen activator, direct thrombin inhibitors, and antiplatelet treatments. Through in vitro and in vivo experiments, we provide evidence that the molecular target underlying the thrombolytic effects of NAC is principally the VWF that cross-link platelets in arterial thrombi. Coadministration of NAC and a nonpeptidic GpIIb/IIIa inhibitor further improved its thrombolytic efficacy, essentially by accelerating thrombus dissolution and preventing rethrombosis. Thus, in a new large-vessel thromboembolic stroke model in mice, this cotreatment significantly improved ischemic lesion size and neurological outcome. It is important to note that NAC did not worsen hemorrhagic stroke outcome, suggesting that it exerts thrombolytic effects without significantly impairing normal hemostasis.\n \n \n Conclusions:\n We provide evidence that NAC is an effective and safe alternative to currently available antithrombotic agents to restore vessel patency after arterial occlusion.\n ", "alternative-id": [ "10.1161/CIRCULATIONAHA.117.027290" ], "assertion": [ { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Received", "name": "received", "order": 0, "value": "2016-03-14" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Accepted", "name": "accepted", "order": 1, "value": "2017-04-26" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Published", "name": "published", "order": 2, "value": "2017-05-09" } ], "author": [ { "affiliation": [ { "name": "From Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Caen, France (S.M.d.L., C.G., Y.R., C.A., E.T., D.V., M.G.); CHU de Caen, Department of Anesthesiology and Critical Care Medicine, CHU de Caen Côte de Nacre, France (C.G.); Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia (B.A.H., S.L.D.); Laboratoire d’Hématologie, CHU de Caen, France (Y..." } ], "family": "Martinez de Lizarrondo", "given": "Sara", "sequence": "first" }, { "affiliation": [ { "name": "From Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Caen, France (S.M.d.L., C.G., Y.R., C.A., E.T., D.V., M.G.); CHU de Caen, Department of Anesthesiology and Critical Care Medicine, CHU de Caen Côte de Nacre, France (C.G.); Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia (B.A.H., S.L.D.); Laboratoire d’Hématologie, CHU de Caen, France (Y..." } ], "family": "Gakuba", "given": "Clément", "sequence": "additional" }, { "affiliation": [ { "name": "From Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Caen, France (S.M.d.L., C.G., Y.R., C.A., E.T., D.V., M.G.); CHU de Caen, Department of Anesthesiology and Critical Care Medicine, CHU de Caen Côte de Nacre, France (C.G.); Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia (B.A.H., S.L.D.); Laboratoire d’Hématologie, CHU de Caen, France (Y..." } ], "family": "Herbig", "given": "Bradley A.", "sequence": "additional" }, { "affiliation": [ { "name": "From Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Caen, France (S.M.d.L., C.G., Y.R., C.A., E.T., D.V., M.G.); CHU de Caen, Department of Anesthesiology and Critical Care Medicine, CHU de Caen Côte de Nacre, France (C.G.); Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia (B.A.H., S.L.D.); Laboratoire d’Hématologie, CHU de Caen, France (Y..." } ], "family": "Repessé", "given": "Yohann", "sequence": "additional" }, { "affiliation": [ { "name": "From Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Caen, France (S.M.d.L., C.G., Y.R., C.A., E.T., D.V., M.G.); CHU de Caen, Department of Anesthesiology and Critical Care Medicine, CHU de Caen Côte de Nacre, France (C.G.); Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia (B.A.H., S.L.D.); Laboratoire d’Hématologie, CHU de Caen, France (Y..." } ], "family": "Ali", "given": "Carine", "sequence": "additional" }, { "affiliation": [ { "name": "From Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Caen, France (S.M.d.L., C.G., Y.R., C.A., E.T., D.V., M.G.); CHU de Caen, Department of Anesthesiology and Critical Care Medicine, CHU de Caen Côte de Nacre, France (C.G.); Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia (B.A.H., S.L.D.); Laboratoire d’Hématologie, CHU de Caen, France (Y..." } ], "family": "Denis", "given": "Cécile V.", "sequence": "additional" }, { "affiliation": [ { "name": "From Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Caen, France (S.M.d.L., C.G., Y.R., C.A., E.T., D.V., M.G.); 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