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重症COVID-19患者凝血功能异常所致血栓形成的研究进展
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Abstract:
2019年12月左右，新型冠状病毒肺炎出现，这场新冠肺炎疫情传染性极强、传播速度极快，成为全球重大公共卫生事件，危及着全人类的健康。世界各国卫生组织竭尽全力抗击着这场疫情战役，虽然通过提高病例检测能力、社会防御意识和促进疫苗注射等因素可能在很大程度上对疫情进行了有效防控，但全球多个国家依旧已经或正在经历着多次暴发。绝大部分患者是可以痊愈的，但仍有部分患者转化为重症或危重症，严重者甚至死亡。对于重症新型冠状病毒肺炎患者，除了呼吸衰竭外，凝血功能异常引起的相关临床并发症也是使患者病情突然恶化，甚至死亡的重要原因之一。根据ISTH发布的弥散性血管内凝血病(DIC)标准，一些重度COVID-19感染患者可发生凝血功能障碍，并伴有爆发性凝血激活，导致广泛的微血管血栓形成和凝血因子消耗。已有研究结果显示，凝血功能异常与COVID-19患者的病重率和死亡率密切相关。本文通过对COVID-19患者中凝血功能异常和其发生的相关机制、治疗策略等方面进行综述，以便为COVID-19及之后可能出现的类似疾病的治疗提供参考方案。
In December 2019, a new type of Coronavirus pneumonia emerged, the epidemic is highly infectious, spread very fast, the crowd has a universal susceptibility to become a major global public health event, endangering the health of all mankind. Health organizations around the world are doing their best to fight the epidemic, although by improving case-detection capabilities, factors such as social defense awareness and self-protection ability, promotion of vaccination and herd immunity may have effectively prevented and controlled the epidemic to a large extent, but many countries around the world have still experienced or are experiencing multiple outbreaks. The vast majority of patients can be cured, but there are still some patients may be transformed into severe or critical illness, serious or even death. For severe Coronavirus pneumonia, in addition to respiratory failure, coagulation disorders caused by clinical complications is also a sudden deterioration of the disease, even one of the important causes of death. According to the disseminated intravascular coagulation (DIC) criteria issued by ISTH, some patients with severe COVID-19 infection can develop coagulation dysfunction with explosive coagulation activation, resulting in extensive microvascular thrombosis and coagulation factor depletion. Previous studies have shown that the coagulation disorders is closely related to the serious illness rate and death rate of patients with COVID-19. In this review, the mechanism and treatment strategies of coagulation disorders in COVID-19 patients were reviewed in order to provide reference for the treatment of COVID-19 and similar diseases.
| [1] | Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020) The Species Severe Acute Respiratory Syndrome-Related Coronavirus: Classifying 2019-nCoV and Naming It SARS-CoV-2. Nature Microbiology, 5, 536-544. https://doi.org/10.1038/s41564-020-0695-z |
| [2] | Chen, Y., Guo, Y., Pan, Y. and Zhao, Z.J. (2020) Structure Analysis of the Receptor Binding of 2019-nCoV. Biochemical and Biophysical Research Communications, 525, 135-140. https://doi.org/10.1016/j.bbrc.2020.02.071 |
| [3] | Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., et al. (2020) SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181, 271-280. https://doi.org/10.1016/j.cell.2020.02.052 |
| [4] | Cui, S., Chen, S., Li, X., Liu, S. and Wang, F. (2020) Prevalence of Venous Thromboembolism in Patients with Severe Novel Coronavirus Pneumonia. Journal of Thrombosis and Haemostasis, 18, 1421-1424. https://doi.org/10.1111/jth.14830 |
| [5] | Klok, F.A., Kruip, M.J.H.A., Van der Meer, N.J.M., Arbous, M.S., Gommers, D.A.M.P.J., et al. (2020) Incidence of Thrombotic Complications in Critically Ill ICU Patients with COVID-19. Thrombosis Research, 191, 145-147. https://doi.org/10.1016/j.thromres.2020.04.013 |
| [6] | Helms, J., Tacquard, C., Severac, F., Leonard-Lorant, I., Ohana, M., et al. (2020) High Risk of Thrombosis in Patients with Severe SARS-CoV-2 Infection: A Multicenter Prospective Cohort Study. Intensive Care Medicine, 46, 1089-1098. https://doi.org/10.1007/s00134-020-06062-x |
| [7] | Poissy, J., Goutay, J., Caplan, M., Parmentier, E. and Duburcq, T. (2020) Lille ICU Haemostasis COVID-19 Group. Pulmonary Embolism in Patients with COVID-19: Awareness of an Increased Prevalence. Circulation, 142, 184-186. |
| [8] | Tian, S., Hu, W., Niu, L., Liu, H., Xu, H. and Xiao, S.-Y. (2020) Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients with Lung Cancer. Journal of Thoracic Oncology, 15, 700-704. https://doi.org/10.1016/j.jtho.2020.02.010 |
| [9] | Tan, L., Wang, Q., Zhang, D., Ding, J., Huang, Q., Tang, Y.-Q., et al. (2020) Lymphopenia Predicts Disease Severity of COVID-19: A Descriptive and Predictive Study. Signal Transduction and Targeted Therapy, 5, Article No. 33. https://doi.org/10.1038/s41392-020-0148-4 |
| [10] | Favresse, J., Lippi, G., Roy, P.-M., Chatelain, B., Jacqmin, H., et al. (2018) D-Dimer: Preanalytical, Analytical, Postanalytical Variables, and Clinical Applications. Critical Reviews in Clinical Laboratory Sciences, 55, 548-577. https://doi.org/10.1080/10408363.2018.1529734 |
| [11] | Petrilli, C.M., Jones, S.A., Yang, J., Rajagopalan, H., O’Donnell, L., et al. (2020) Factors Associated with Hospital Admission and Critical Illness among 5279 People with Coronavirus Disease 2019 in New York City: Prospective Cohort Study. The BMJ, 369, m1966. https://doi.org/10.1136/bmj.m1966 |
| [12] | Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., et al. (2020) Epidemiological and Clinical Characteristics of 99 Cases of 2019 Novel Coronavirus Pneumonia in Wuhan, China: A Descriptive Study. The Lancet, 395, 507-513. https://doi.org/10.1016/S0140-6736(20)30211-7 |
| [13] | Yu, M., Nardella, A. and Pechet, L. (2000) Screening Tests of Disseminated Intravascular Coagulation: Guidelines for Rapid and Specific Laboratory Diagnosis. Critical Care Medicine, 28, 1777-1780. https://doi.org/10.1097/00003246-200006000-00013 |
| [14] | Guan, W.-J., Ni, Z.-Y., Hu, Y., Liang, W.-H., Ou, C.-Q., He, J.-X., et al. (2020) Clinical Characteristics of Coronavirus Disease 2019 in China. New England Journal of Medicine, 382, 1708-1720. https://doi.org/10.1056/NEJMoa2002032 |
| [15] | Tang, N., Li, D., Wang, X. and Sun, Z. (2020) Abnormal Coagulation Parameters Are Associated with Poor Prognosis in Patients with Novel Coronavirus Pneumonia. Journal of Thrombosis and Haemostasis, 18, 844-847. https://doi.org/10.1111/jth.14768 |
| [16] | Wan, Y., Shang, J., Graham, R., Baric, R.S. and Li, F. (2020) Receptor Recognition by the Novel Coronavirus from Wuhan: An Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. Journal of Virology, 94, e00127-20. https://doi.org/10.1128/JVI.00127-20 |
| [17] | Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y. and Zhou, Q. (2020) Structural Basis for the Recognition of SARS-CoV-2 by Full-Length Human ACE2. Science, 367, 1444-1448. https://doi.org/10.1126/science.abb2762 |
| [18] | Wang, J., Chen, S. and Bihl, J. (2020) Exosome-Mediated Transfer of ACE2 (Angiotensin-Converting Enzyme 2) from Endothelial Progenitor Cells Promotes Survival and Function of Endothelial Cell. Oxidative Medicine and Cellular Longevity, 2020, Article 4213541. https://doi.org/10.1155/2020/4213541 |
| [19] | Jose, R.J. and Manuel, A. (2020) COVID-19 Cytokine Storm: The Interplay between Inflammation and Coagulation. The Lancet Respiratory Medicine, 8, E46-E47. https://doi.org/10.1016/S2213-2600(20)30216-2 |
| [20] | Wichmann, D., Sperhake, J.-P., Lütgehetmann, M., Addo, M.M., Aepfelbacher, M., Püschel, K., Kluge, S., et al. (2020) Autopsy Findings and Venous Thromboembolism in Patients with COVID-19: A Prospective Cohort Study. Annals of Internal Medicine, 173, 268-277. https://doi.org/10.7326/M20-2003 |
| [21] | Fox, S.E., Akmatbekov, A., Harbert, J.L., Li, G., Quincy Brown, J. and Vander Heide, R.S. (2020) Pulmonary and Cardiac Pathology in African American Patients with COVID-19: An Autopsy Series from New Orleans. The Lancet Respiratory Medicine, 8, 681-686. https://doi.org/10.1016/S2213-2600(20)30243-5 |
| [22] | Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., et al. (2020) Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA, 323, 1061-1069. https://doi.org/10.1001/jama.2020.1585 |
| [23] | Barth, R.F., Buja, L.M. and Parwani, A.V. (2020) The Spectrum of Pathological Findings in Coronavirus Disease (COVID-19) and the Pathogenesis of SARS-CoV-2. Diagnostic Pathology, 15, Article No. 85. https://doi.org/10.1186/s13000-020-00999-9 |
| [24] | Levi, M. and Van der Poll, T. (2017) Coagulation and Sepsis. Thrombosis Research, 149, 38-44. https://doi.org/10.1016/j.thromres.2016.11.007 |
| [25] | Hottz, E.D., Azevedo-Quintanilha, I.G., Palhinha, L., Teixeira, L., Barreto, E.A., et al. (2020) Platelet Activation and Platelet-Monocyte Aggregate Formation Trigger Tissue Factor Expression in Patients with Severe COVID-19. Blood, 136, 1330-1341. https://doi.org/10.1182/blood.2020007252 |
| [26] | Levi, M. (2016) Platelets in Critical Illness. Seminars in Thrombosis and Hemostasis, 42, 252-257. https://doi.org/10.1055/s-0035-1570080 |
| [27] | Chrysanthopoulou, A., Kambas, K., Stakos, D., Mitroulis, I., Mitsios, A., et al. (2017) Interferon Lambda1/IL-29 and Inorganic Polyphosphate Are Novel Regulators of Neutrophil-Driven Thromboinflammation. The Journal of Pathology, 243, 111-122. https://doi.org/10.1002/path.4935 |
| [28] | Targosz-Korecka, M., Kubisiak, A., Kloska, D., Kopacz, A., Grochot-Przeczek, A. and Szymonski, M. (2021) Endothelial Glycocalyx Shields the Interaction of SARS-CoV-2spike Protein with ACE2 Receptors. Scientific Reports, 11, Article No. 12157. https://doi.org/10.1038/s41598-021-91231-1 |
| [29] | Prasad, M., Leon, M., Lerman, L.O. and Lerman, A. (2021) Viral Endothelial Dysfunction: A Unifying Mechanism for COVID-19. Mayo Clinic Proceedings, 96, 3099-3108. https://doi.org/10.1016/j.mayocp.2021.06.027 |
| [30] | Armstrong, S.M., Darwish, I. and Lee, W.L. (2013) Endothelial Activation and Dysfunction in the Pathogenesis of Influenza A Virus Infection. Virulence, 4, 537-542. https://doi.org/10.4161/viru.25779 |
| [31] | Gy？ngy？si, M., Alcaide, P., Asselbergs, F.W., Brundel, B.J.J.M., Camici, G.G., et al. (2023) Long COVID and the Cardiovascular System-Elucidating Causes and Cellular Mechanisms in Order to Develop Targeted Diagnostic and Therapeutic Strategies: A Joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases. Cardiovascular Research, 119, 336-356. https://doi.org/10.1093/cvr/cvac115 |
| [32] | Lippi, G., Plebani, M. and Henry, B.M. (2020) Thrombocytopenia Is Associated with Severe Coronavirus Disease 2019 (COVID-19) Infections: A Meta-Analysis. Clinica Chimica Acta, 506, 145-148. https://doi.org/10.1016/j.cca.2020.03.022 |
| [33] | Zhang, Y., et al. (2020) Mechanisms Involved in the Development of Thrombocytopenia in Patients with COVID-19. Thrombosis Research, 193, 110-115. https://doi.org/10.1016/j.thromres.2020.06.008 |
| [34] | Seyoum, M., Enawgaw, B. and Melku, M. (2018) Human Blood Platelets and Viruses: Defense Mechanism and Role in the Removal of Viral Pathogens. Thrombosis Journal, 16, Article No. 16. https://doi.org/10.1186/s12959-018-0170-8 |
| [35] | Ropa, J., Cooper, S., Capitano, M.L., Van’T Hof, W. and Broxmeyer, H.E. (2021) Human Hematopoietic Stem, Progenitor, and Immune Cells Respond ex vivo to SARS-CoV-2 Spike Protein. Stem Cell Reviews and Reports, 17, 253-265. https://doi.org/10.1007/s12015-020-10056-z |
| [36] | Assinger, A. (2014) Platelets and Infection—An Emerging Role of Platelets in Viral Infection. Frontiers in Immunology, 5, Article 649. https://doi.org/10.3389/fimmu.2014.00649 |
| [37] | Wool, G.D. and Miller, J.L. (2021) The Impact of COVID-19 Disease on Platelets and Coagulation. Pathobiology, 88, 15-27. https://doi.org/10.1159/000512007 |
| [38] | Morrell, C.N., Aggrey, A.A., Chapman, L.M. and Modjeski, K.L. (2014) Emerging Roles for Platelets as Immune and Inflammatory Cells. Blood, 123, 2759-2767. https://doi.org/10.1182/blood-2013-11-462432 |
| [39] | Thachil, J. (2020) What Does Monitoring Platelet Counts in COVID-19 Teach Us? Journal of Thrombosis and Haemostasis, 18, 2071-2072. https://doi.org/10.1111/jth.14879 |
| [40] | Duca, S.-T., Costache, A.-D., Miftode, R.-？., Mitu, O., Petri？, A.-O. and Costache, I.-I. (2022) Hypercoagulability in COVID-19: From an Unknown Beginning to Future Therapies. Medicine and Pharmacy Reports, 95, 236-242. https://doi.org/10.15386/mpr-2195 |
| [41] | Loo, J., Spittle, D.A. and Newnham, M. (2021) COVID-19, Immunothrombosis and Venous Thromboembolism: Biological Mechanisms. Thorax, 76, 412-420. https://doi.org/10.1136/thoraxjnl-2020-216243 |
| [42] | McDonald, B., Davis, R.P., Kim, S.-J., Tse, M., Esmon, C.T., Kolaczkowska, E., et al. (2017) Platelets and Neutrophil Extracellular Traps Collaborate to Promote Intravascular Coagulation during Sepsis in Mice. Blood, 129, 1357-1367. https://doi.org/10.1182/blood-2016-09-741298 |
| [43] | Santiesteban-Lores, L.E., Amamura, T.A., da Silva, T.F., Midon, L.M., Carneiro, M.C., Isaac, L., et al. (2021) A Double Edged-Sword—The Complement System during SARS-CoV-2 Infection. Life Sciences, 272, Article 119245. https://doi.org/10.1016/j.lfs.2021.119245 |
| [44] | Welsh, J.D., Hoofnagle, M.H., Bamezai, S., Oxendine, M., Lim, L., Hall, J.D., et al. (2019) Hemodynamic Regulation of Perivalvular Endothelial Gene Expression Prevents Deep Venous Thrombosis. Journal of Clinical Investigation, 129, 5489-5500. https://doi.org/10.1172/jci124791 |
| [45] | Colling, M.E., Tourdot, B.E. and Kanthi, Y. (2021) Inflammation, Infection and Venous Thromboembolism. Circulation Research, 128, 2017-2036. https://doi.org/10.1161/circresaha.121.318225 |
| [46] | Engelmann, B. and Massberg, S. (2012) Thrombosis as an Intravascular Effector of Innate Immunity. Nature Reviews Immunology, 13, 34-45. https://doi.org/10.1038/nri3345 |
| [47] | Jian, D., Wang, Y., Jian, L., Tang, H., Rao, L., Chen, K., et al. (2020) METTL14 Aggravates Endothelial Inflammation and Atherosclerosis by Increasing FOXO1 N6-Methyladeosine Modifications. Theranostics, 10, 8939-8956. https://doi.org/10.7150/thno.45178 |
| [48] | Zwaal, R.F.A. and Schroit, A.J. (1997) Pathophysiologic Implications of Membrane Phospholipid Asymmetry in Blood Cells. Blood, 89, 1121-1132. https://doi.org/10.1182/blood.v89.4.1121 |
| [49] | Dolhnikoff, M., Duarte-Neto, A.N., de Almeida Monteiro, R.A., da Silva, L.F.F., de Oliveira, E.P., Saldiva, P.H.N., et al. (2020) Pathological Evidence of Pulmonary Thrombotic Phenomena in Severe COVID-19. Journal of Thrombosis and Haemostasis, 18, 1517-1519. https://doi.org/10.1111/jth.14844 |
| [50] | Pellegrini, D., Kawakami, R., Guagliumi, G., Sakamoto, A., Kawai, K., Gianatti, A., et al. (2021) Microthrombi as a Major Cause of Cardiac Injury in COVID-19. Circulation, 143, 1031-1042. https://doi.org/10.1161/circulationaha.120.051828 |
| [51] | Lim, E.H.T., van Amstel, R.B.E., de Boer, V.V., van Vught, L.A., de Bruin, S., Brouwer, M.C., et al. (2023) Complement Activation in COVID-19 and Targeted Therapeutic Options: A Scoping Review. Blood Reviews, 57, Article 100995. https://doi.org/10.1016/j.blre.2022.100995 |
| [52] | Lim, M.S. and Mcrae, S. (2021) COVID-19 and Immunothrombosis: Pathophysiology and Therapeutic Implications. Critical Reviews in Oncology/Hematology, 168, Article 103529. https://doi.org/10.1016/j.critrevonc.2021.103529 |
| [53] | Esmon, C. (2006) Inflammation and the Activated Protein C Anticoagulant Pathway. Seminars in Thrombosis and Hemostasis, 32, 49-60. https://doi.org/10.1055/s-2006-939554 |
| [54] | Stoermer, K.A. and Morrison, T.E. (2011) Complement and Viral Pathogenesis. Virology, 411, 362-373. https://doi.org/10.1016/j.virol.2010.12.045 |
| [55] | Shang, J., Wan, Y., Luo, C., Ye, G., Geng, Q., Auerbach, A., et al. (2020) Cell Entry Mechanisms of SARS-CoV-2. Proceedings of the National Academy of Sciences, 117, 11727-11734. https://doi.org/10.1073/pnas.2003138117 |
| [56] | Tang, N., Bai, H., Chen, X., Gong, J., Li, D. and Sun, Z. (2020) Anticoagulant Treatment Is Associated with Decreased Mortality in Severe Coronavirus Disease 2019 Patients with Coagulopathy. Journal of Thrombosis and Haemostasis, 18, 1094-1099. https://doi.org/10.1111/jth.14817 |
| [57] | Weeks, L.D., Sylvester, K.W., Connors, J.M. and Connell, N.T. (2021) Management of Therapeutic Unfractionated Heparin in COVID-19 Patients: A Retrospective Cohort Study. Research and Practice in Thrombosis and Haemostasis, 5, e12521. https://doi.org/10.1002/rth2.12521 |
| [58] | Thachil, J., Wada, H. and Gando, S. (2020) ISTH Interim Guidance on Recognition and Management of Coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis, 18, 1023-1026. https://doi.org/10.1111/jth.14810 |
| [59] | Vaughn, V.M., Yost, M., Abshire, C., Flanders, S.A., Paje, D., Grant, P., et al. (2021) Trends in Venous Thromboembolism Anticoagulation in Patients Hospitalized with COVID-19. JAMA Network Open, 4, e2111788. https://doi.org/10.1001/jamanetworkopen.2021.11788 |
| [60] | Gozzo, L., Viale, P., Longo, L., Vitale, D.C. and Drago, F. (2020) The Potential Role of Heparin in Patients with COVID-19: Beyond the Anticoagulant Effect. A Review. Frontiers in Pharmacology, 11, Article 1307. https://doi.org/10.3389/fphar.2020.01307 |
| [61] | Gillot, C., Favresse, J., Mullier, F., Lecompte, T., Dogné, J.-M. and Douxfils, J. (2021) Netosis and the Immune System in COVID-19: Mechanisms and Potential Treatments. Frontiers in Pharmacology, 12, Article 708302. https://doi.org/10.3389/fphar.2021.708302 |
| [62] | Hou, Y.J., Okuda, K., Edwards, C.E., Martinez, D.R., Asakura, T., Dinnon, K.H., et al. (2020) SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. Cell, 182, 429-446. https://doi.org/10.1016/j.cell.2020.05.042 |
| [63] | Song, J., Wang, G., Zhang, W., Zhang, Y., Li, W.-Q., Zhou, Z., et al. (2020) Chinese Expert Consensus on Diagnosis and Treatment of Coagulation Dysfunction in COVID-19. Military Medical Research, 7, Article No. 19. https://doi.org/10.1186/s40779-020-00247-7 |
| [64] | Piazza, G. and Morrow, D.A. (2020) Diagnosis, Management, and Pathophysiology of Arterial and Venous Thrombosis in COVID-19. JAMA, 324, 2548-2549. https://doi.org/10.1001/jama.2020.23422 |
| [65] | The REMAP-CAP, ACTIV-4a, and ATTACC Investigators (2021) Therapeutic Anticoagulation with Heparin in Critically Ill Patients with COVID-19. New England Journal of Medicine, 385, 777-789. https://doi.org/10.1056/nejmoa2103417 |
| [66] | Warner, T.D., Nylander, S. and Whatling, C. (2011) Anti-Platelet Therapy: Cyclo-Oxygenase Inhibition and the Use of Aspirin with Particular Regard to Dual Anti-Platelet Therapy. British Journal of Clinical Pharmacology, 72, 619-633. https://doi.org/10.1111/j.1365-2125.2011.03943.x |
| [67] | Damman, P., Woudstra, P., Kuijt, W.J., de Winter, R.J. and James, S.K. (2011) P2Y12 Platelet Inhibition in Clinical Practice. Journal of Thrombosis and Thrombolysis, 33, 143-153. https://doi.org/10.1007/s11239-011-0667-5 |
| [68] | Huang, B., Chen, Z., Geng, L., Wang, J., Liang, H., Cao, Y., et al. (2019) Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways. Cell, 179, 1160-1176. https://doi.org/10.1016/j.cell.2019.10.027 |
| [69] | Liu, X., Li, Z., Liu, S., Sun, J., Chen, Z., Jiang, M., et al. (2020) Potential Therapeutic Effects of Dipyridamole in the Severely Ill Patients with COVID-19. Acta Pharmaceutica Sinica B, 10, 1205-1215. https://doi.org/10.1016/j.apsb.2020.04.008 |
| [70] | Iwata, K., Doi, A., Ohji, G., Oka, H., Oba, Y., Takimoto, K., et al. (2010) Effect of Neutrophil Elastase Inhibitor (Sivelestat Sodium) in the Treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS): A Systematic Review and Meta-Analysis. Internal Medicine, 49, 2423-2432. https://doi.org/10.2169/internalmedicine.49.4010 |
| [71] | Sakashita, A., Nishimura, Y., Nishiuma, T., Takenaka, K., Kobayashi, K., Kotani, Y., et al. (2007) Neutrophil Elastase Inhibitor (Sivelestat) Attenuates Subsequent Ventilator-Induced Lung Injury in Mice. European Journal of Pharmacology, 571, 62-71. https://doi.org/10.1016/j.ejphar.2007.05.053 |
| [72] | Miyoshi, S., Ito, R., Katayama, H., Dote, K., Aibiki, M., Hamada, H., et al. (2014) Combination Therapy with Sivelestat and Recombinant Human Soluble Thrombomodulin for ARDS and DIC Patients. Drug Design, Development and Therapy, 8, 1211-1219. https://doi.org/10.2147/dddt.s68030 |
| [73] | Sahebnasagh, A., Saghafi, F., Safdari, M., Khataminia, M., Sadremomtaz, A., Ghaleno, H.R., Bagheri, M., Bagheri, M.S., Habtemariam, S. and Avan, R. (2020) Neutrophil Elastase Inhibitor (Sivelestat), May Be a Promising Therapeutic Option for Management of Acute Lung Injury/Acute Respiratory Distress Syndrome or Disseminated Intravascular Coagulation in COVID-19. Journal of Clinical Pharmacy and Therapeutics, 45, 1515-1519. https://doi.org/10.1111/jcpt.13251 |
| [74] | Zizzo, G., Tamburello, A., Castelnovo, L., Laria, A., Mumoli, N., Faggioli, P.M., et al. (2022) Immunotherapy of COVID-19: Inside and beyond IL-6 Signalling. Frontiers in Immunology, 13, Article 795315. https://doi.org/10.3389/fimmu.2022.795315 |
| [75] | Matthay, M.A. and Luetkemeyer, A.F. (2021) IL-6 Receptor Antagonist Therapy for Patients Hospitalized for COVID-19: Who, When, and How? JAMA, 326, 483-485. https://doi.org/10.1001/jama.2021.11121 |
| [76] | Diurno, F., Numis, F.G., Porta, G., Cirillo, F. and Maddaluno, S. (2020) Eculizumab Treatment in Patients with COVID-19: Preliminary Results from Real Life ASL Napoli 2 Nord Experience. European Review for Medical and Pharmacological Sciences, 24, 4040-4047. |
| [77] | Annane, D., Heming, N., Grimaldi-Bensouda, L., Frémeaux-Bacchi, V., Vigan, M., Roux, A., et al. (2020) Eculizumab as an Emergency Treatment for Adult Patients with Severe COVID-19 in the Intensive Care Unit: A Proof-of-Concept Study. eClinicalMedicine, 28, Article 100590. https://doi.org/10.1016/j.eclinm.2020.100590 |
| [78] | Mastellos, D.C., Pires da Silva, B.G.P., Fonseca, B.A.L., Fonseca, N.P., Auxiliadora-Martins, M., Mastaglio, S., et al. (2020) Complement C3 vs C5 Inhibition in Severe COVID-19: Early Clinical Findings Reveal Differential Biological Efficacy. Clinical Immunology, 220, Article 108598. https://doi.org/10.1016/j.clim.2020.108598 |
