Ингаляции гепарина у пациентов с новой коронавирусной инфекцией (обзор литературы)

УДК 578.834.1:612.115.35

Аннотация

Гепарин используется в клинической практике преимущественно как антикоагулянт. Однако спектр его эффектов значительно шире: противовоспалительный, антипролиферативный, гиполипидемический (как прямой, так и посредством повышения активности липопротеинлипазы), антикоагулянтный, противоотечный и др. Именно на противовоспалительное действие гепарина сделан акцент при терапии COVID-19. Одним из патогенетически обоснованных методов профилактики и терапии микрососудистого тромбоза в тканях легких может быть использование ингаляций нефракционированного гепарина, что позволяет реализовать как местное, так и системное действие этого препарата. Терапия ингаляциями гепарина не будет значительно увеличивать риск контаминации вирусом SARS-CoV-2 медицинского персонала при неукоснительном соблюдении стандартов и рекомендуемых мер индивидуальной защиты.

ЛИТЕРАТУРА

1. Qin C., Zhou L., Hu Z. et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020 Mar 12; ciaa248. DOI: 10.1093/cid/ciaa248. [Online ahead of print].

2. Huang C., Wang Y., Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. DOI: 10.1016/S0140-6736(20)30183-5.

3. Deng Y., Liu W., Liu K. et al. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chin Med J (Engl). 2020 Mar 20. DOI: 10.1097/CM9.0000000000000824. [Online ahead of print].

4. Tang N., Bai H., Chen X. et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094– 9. DOI: 10.1111/jth.14817.

5. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844–7. DOI: 10.1111/jth.14768.

6. Wang D., Hu B., Hu C. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–9. DOI: 10.1001/ jama.2020.1585. [Online ahead of print].

7. Castro C.Y. ARDS and diffuse alveolar damage: a pathologist’s perspective. Semin Thorac Cardiovasc Surg. 2006;18(1):13–9. DOI: 10.1053/j.semtcvs.2006.02.001.

8. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med. 2003;31(4 Suppl):S213–20. DOI: 10.1097/01.CCM.0000057846.21303.AB.

9. Burns A.R., Smith C.W., Walker D.C. Unique structural features that influence neutrophil emigration into the lung. Physiol Rev. 2003;83(2):309–36. DOI: 10.1152/physrev.00023.2002.

10. Blaisdell F.W. Pathophysiology of the respiratory distress syndrome. Arch Surg. 1974;108(1):44–9. DOI: 10.1001/archsurg.1974.01350250036009.

11. Tomashefski J.F., Davies P., Boggis C. et al. The pulmonary vascular lesions of the adult respiratory distress syndrome. Am J Pathol. 1983;112(1):112–26.

12. DixonB.Theroleofmicrovascularthrombosisinsepsis.AnaesthIntensive Care. 2004;32(5):619–29. DOI: 10.1177/0310057X0403200502.

13. Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020;18(5):1020–2. DOI: 10.1111/jth.14821.

14. Greene R., Zapol W.M., Snider M.T. et al. Early bedside detection of pulmonary vascular occlusion during acute respiratory failure. Am Rev Respir Dis. 1981;124(5):593–601. DOI: 10.1164/ arrd.1981.124.5.593.

15. Markart P., Nass R., Ruppert C. et al. Safety and tolerability of inhaled heparin in idiopathic pulmonary fibrosis. J Aerosol Med Pulm Drug Deliv. 2010;23(3):161–72. DOI: 10.1089/jamp. 2009.0780.
16. Dixon B., Schultz M.J., Hofstra J.J. et al. Nebulized heparin reduces levels of pulmonary coagulation activation in acute lung injury. Crit Care. 2010;14(5):445. DOI: 10.1186/cc9269.
17. Dixon B., Santamaria J.D., Campbell D.J. A phase 1 trial of nebulised heparin in acute lung injury. Crit Care. 2008;12(3):R64. DOI: 10.1186/cc6894.
18. Zhang H., Zhou P., Wei Y. et al. Histopathologic changes and SARSCoV-2 immunostaining in the lung of a patient with COVID-19. Ann Intern Med. 2020;172(9):629–32. DOI: 10.7326/M20–0533.
19. Tian S., Hu W., Niu L. et al. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two pPatients with lung cancer. J Thorac Oncol. 2020;15(5):700–4. DOI: 10.1016/j. jtho. 2020.02.010.
20. Lu R., Zhao X., Li J. et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565–74. DOI: 10.1016/ S0140–6736(20)30251–8.
21. Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7). Chin Med J. 2020;133(9):1087–95. DOI: 10.1097/ CM9.0000000000000819.
22. Yao X.H., Li T.Y., He Z.C. et al. A pathological report of three COVID-19 cases by minimal invasive autopsies. Zhonghua Bing Li Xue Za Zhi. 2020;49(5):411–7. [In Chinese]. DOI: 10.3760/ cma.j.cn112151-20200312-00193.
23. Zhang T., Sun L.X., Feng R.E. Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(0):E040. DOI: 10.3760/cma.j.cn112147-20200311-00312. [Online ahead of print].
24. Dolhnikoff M., Duarte-Neto A.N., de Almeida Monteiro R.A. et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020 Apr 15. DOI: 10.1111/ jth.14844. [Online ahead of print].
25. Ciceri F., Beretta L., ScandroglioA.M. et al. Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis. Crit Care Resusc. 2020 Apr 15. [Online ahead of print].
26. Juschten J., Tuinman P.R., Juffermans N.P. et al. Nebulized anticoagulants in lung injury in critically ill patients — an updated systematic review of preclinical and clinical studies. Ann Transl Med. 2017;5(22):1–12. DOI: 10.21037/atm.2017.08.23.
27. Kashefi N., Nathan J., Dissanaike S. Does a nebulized heparin/Nacetylcysteine protocol improve outcomes in adult smoke inhalation? Plast Reconstr Surg Glob Open. 2014;2(6):e165. DOI: 10.1097/GOX.0000000000000121.

28. McIntire A., Harris S., Whitten J. et al. Outcomes following the use of nebulized heparin for inhalation injury (HIHI Study). J Burn Care Res. 2017;38(1):45–52. DOI: 10.1097/BCR.0000000000000439.

29. Временные методические рекомендации. Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Версия 6 (28.04.2020). Министерство здравоохранения Российской Федерации, 2020. 165 с. Режим доступа: https://static-1.rosminzdrav.ru/system/attachments/attaches/000/050/116/original/28042020_%D0%9CR_COVID-19_v6.pdf. [Дата доступа: 25.05.2020].

30. Методические рекомендации. Анестезиолого-реанимационное обеспечение пациентов с новой коронавирусной инфекцией COVID-19. Федерация анестезиологов и реаниматологов, 2020. 183 с. Режим доступа: http://www.far.org.ru/recomendation. [Дата доступа: 25.05.2020].

31. Rostand K. S., Esko J. D. Microbial adherence to and invasion through proteoglycans. Infect Immun. 1997;65(1):1–8.

32. Mousavi S., Moradi M., Khorshidahmad T., Motamedi M. AntiInflammatory effects of heparin and its derivatives: a systematic review. Adv Pharmacol Sci. 2015;2015:507151. DOI: 10.1155/2015/507151.

33. Glas G.J., Serpa Neto A., Horn J. et al. Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis. Ann Intensive Care. 2016;6(1):33. DOI: 10.1186/ s13613-016-0138-4.

34. Porzionato A., Macchi V., Parenti A., De Caro R. The distribution of mast cells in the human area postrema. J Anat. 2004;204(2):141– 7. DOI: 10.1111/j.1469–7580.2004.00256.x.

35. Valent P., Baghestanian M., Bankl H.C. et al. New aspects in thrombosis research: possible role of mast cells as profibrinolytic and antithrombotic cells. Thromb Haemost. 2002;87(5):786–90.

36. Nader N.D., Knight P.R., Bobela I. et al. High-dose nitric oxide inhalation increases lung injury after gastric aspiration. Anesthesiology. 1999;91(3):741–9. DOI: 10.1097/00000542-199909000-00027.

37. Cadroy Y., Gaspin D., Dupouy D. et al. Heparin reverses the procoagulant properties of stimulated endothelial cells. Thromb Haemost. 1996;75(1):190–5.

38. Gori A.M., Pepe G., Attanasio M. et al. Tissue factor reduction and tissue factor pathway inhibitor release after heparin administration. Thromb Haemost. 1999;81(4):589–93.

39. Pepe G., Giusti B., Attanasio M. et al. Tissue factor and plasminogen activator inhibitor type 2 expression in human stimulated monocytes is inhibited by heparin. Semin Thromb Hemost. 1997;23(2):135–41.

40. Huber K., Resch I., Rosc D. et al. Heparin induced increase of t-PA antigen plasma levels in patients with unstable angina: no evidence for clinical benefit of heparinization during the initial phase of treatment. Thromb Res. 1989;55(6):779–84. DOI: 10.1016/0049– 3848(89)90308–3.

41. Barry D., Roger S., Antonio A. et al. Can nebulised heparin reduce time to extubation in SARS CoV 2. The CHARTER Study Protocol. medRxiv 2020.04.28.20082552. DOI: 10.1101/2020.04.28.20082552.

42. Belen-Apak F.B., Sarialioglu F. The old but new: Can unfractioned heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV2 by inhibition of host cell proteases? Med Hypotheses. 2020 Apr 20;142:109743. DOI: 10.1016/j.mehy.2020.109743. [Online ahead of print].

43. Cohoon K.P., Mahe G., Tafur A.J., Spyropoulos A.C. Emergence of institutional antithrombotic protocols for Coronavirus 2019. Res Pract Thromb Haemost. 28 April 2020. DOI: 10.1002/rth2.12358.

44. Idänpään-Heikkilä I., Simon P.M., Zopf D. et al. Oligosaccharides interfere with the establishment and progression of experimental pneumococcal pneumonia. J Infect Dis. 1997;176(3):704–12. DOI: 10.1086/514094.

45. Bryan R., Feldman M., Jawetz S.C. et al. The effects of aerosolized dextran in a mouse model of Pseudomonas aeruginosa pulmonary infection. J Infect Dis. 1999;179(6):1449–58. DOI: 10.1086/314755.

46. Liang O. D., Ascencio F., Fransson L. A., Wadstrom T. Binding of heparan sulfate to Staphylococcus aureus. Infect Immun. 1992;60(3):899–906. DOI:

47. Tsang K.W., Shum D.K., Chan S. et al. Pseudomonas aeruginosa adherence to human basement membrane collagen in vitro. Eur Respir J. 2003;21(6):932–8. DOI: 10.1183/09031936.03.00097302.
48. Martínez I., Melero J.A. Binding of human respiratory syncytial virus to cells: implication of sulfated cell surface proteoglycans. J Gen Virol. 2000;81(Pt 11):2715–22. DOI: 10.1099/0022-1317-81-11-2715.
49. Hosoya M., Balzarini J., Shigeta S., De Clercq E. Differential inhibitory effects of sulfated polysaccharides and polymers on the replication of various myxoviruses and retroviruses, depending on the composition of the target amino acid sequences of the viral envelope glycoproteins. Antimicrob Agents Chemother. 1991;35(12):2515–20. DOI: 10.1128/aac. 35.12.2515.
50. Ledson M., Gallagher M., Hart C.A., Walshaw M. Nebulized heparin in Burkholderia cepacia colonized adult cystic fibrosis patients. Eur Respir J. 2001;17(1):36–8. DOI: 10.1183/09031936.01.17100360.
51. Elsharnouby N. M., Eid H. E., Abou Elezz N. F., Aboelatta Y. A. Heparin/N-acetylcysteine: an adjuvant in the management of burn inhalation injury: a study of different doses. J Crit Care.2014;29(1):182.e1–4. 10.1016/j.jcrc. 2013.06.017.
52. Bandeshe H., Boots R., Dulhunty J. et al. Is inhaled prophylactic heparin useful for prevention and management of pneumonia in ventilated ICU patients?: The IPHIVAP investigators of the Australian and New Zealand Intensive Care Society Clinical Trials Group. J Crit Care. 2016;34:95–102. DOI: 10.1016/j.jcrc. 2016.04.005.
53. Mycroft-West C., Su D., Elli S. et al. The 2019 coronavirus (SARSCoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding. bioRxiv. 2020.02.29.971093. DOI: 10.1101/2020.02.29.971093.
54. Lang J., Yang N., Deng J. et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One. 2011;6(8):e23710. DOI: 10.1371/journal.pone.0023710.
55. Vicenzi E., Canducci F., Pinna D. et al. Coronaviridae and SARS-associated coronavirus strain HSR1. Emerg Infect Dis. 2004;10(3):413– 8. DOI: 10.3201/eid1003.030683.
56. de Haan C.A., Li Z., te Lintelo E. et al. Murine coronavirus with an extended host range uses heparan sulfate as an entry receptor. J Virol. 2005;79(22):14451–6. DOI: 10.1128/JVI.79.22.14451–14456.2005.
57. MaduI.G., ChuV.C., Lee H. et al. Heparan sulfate is a selective attachment factor for the avian coronavirus infectious bronchitis virus Beaudette. Avian Dis. 2007;51(1):45–51. DOI: 10.1637/0005–2086(2007)051[0045:HSIASA]2.0.CO;2.
58. Cagno V., Tseligka E.D., Jones S.T., Tapparel C. Heparan sulfate proteoglycans and viral attachment: true receptors or adaptation bias? Viruses. 2019;11(7):596. DOI: 10.3390/v11070596.
59. Milewska A., Zarebski M., Nowak P. et al. Human coronavirus NL63 utilizes heparan sulfate proteoglycans for attachment to target cells. J Virol. 2014;88(22):13221–30. DOI: 10.1128/JVI.02078–14.
60. Еременко А.А., Ройтман Е.В., Чаус Н.И. и др. Ингаляции гепарина для профилактики тромботических осложнений и ДВСсиндрома в раннем послеоперационном периоде у кардиохирургических больных. III Всероссийская конференция Ассоциации по изучению тромбозов, геморрагий и патологии сосудов имени А.А. Шмидта–Б.А. Кудряшова: тезисы докладов. М., 1997. 55–6.
61. Ройтман Е.В., Ефимов В.С., Анташев А.В. и др. Особенности нарушений гемокоагуляции у кардиохирургических больных и коррекция этих нарушений ингаляциями гепарина. В сборнике: материалы конференции «Прогресс и проблемы в лечении заболеваний сердца и сосудов». СПб., 1997. 52.
62. Воробьева Н.А. ДВС-синдром в реальной клинической практике. Архангельск: Пресс-Принт, 2015. 234 с.
63. Dixon B., Smith R., Santamaria J.D. et al. A trial of nebulised heparin to limit lung injury following cardiac surgery. Anaesth Intensive Care. 2016;44(1):28–33. DOI: 10.1177/0310057X1604400106.
64. Dixon B., Schultz M.J., Smith R. et al. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial. Crit Care. 2010;14(5): R180. DOI: 10.1186/cc9286.

65. McGinn K.A., Weigartz K., Lintner A. et al. Nebulized heparin with N-acetylcysteine and albuterol reduces duration of mechanical ventilation in patients with inhalation injury. J Pharm Pract. 2019;32(2):163–6. DOI: 10.1177/0897190017747143.

66. Yildiz-Pekoz A., Ozsoy Y. Inhaled heparin: therapeutic efficacy and recent formulations. J Aerosol Med Pulm Drug Deliv. 2017;30(3):143– 56. DOI: 10.1089/jamp. 2015.1273.

67. Bendstrup K.E., Chambers C.B., Jensen J.I., Newhouse M.T. Lung deposition and clearance of inhaled (99m)Tc-heparin in healthy volunteers. Am J Respir Crit Care Med. 1999;160(5 Pt 1):1653–8. DOI: 10.1164/ajrccm.160.5.9809123.

68. Chimenti L., Camprubí-Rimblas M., Guillamat-Prats R. et al. Nebulized heparin attenuates pulmonary coagulopathy and inflammation through alveolar macrophages in a rat model of acute lung injury. Thromb Haemost. 2017;117(11):2125–34. DOI: 10.1160/ TH17-05-0347.