Эволюция взглядов и современные представления о состоянии системы гемостаза при циррозе печени

Цель: изучить состояние отдельных звеньев системы гемостаза при циррозе печени по данным современной литературы.

В обзоре представлен анализ данных литературы, освещающей состояние системы гемостаза при циррозе печени. В полемическом стиле изложены патофизиологические и патогенетические механизмы, лежащие в основе нарушений, возникающих в различных звеньях системы гемостаза при этом заболевании. Подвергнуты анализу литературные данные, касающиеся достаточно мало изученного аспекта цирроза печени – гиперкоагуляции. С позиции современных представлений и с учетом особенностей нарушений гемостаза постулирована патогенетическая значимость эндотелия сосудов и эндотелиальной дисфункции, а также роли медиаторов воспаления в развитии коагулопатии и синдрома внутрисосудистого свертывания крови у больных циррозом печени.

1. Lisman T., Porte R.J. Pathogenesis, prevention and management of bleeding and thrombosis in patients with liver disease. Res. Pract. Thromb. Hemost. 2017; 1 (2): 150–161. https://doi.org/10.1002/ rth2. 12028

2. Lentschener C., Flaujac C., Ibrahim F., Gouin-Thibault I., Bazin M., Sogni Ph., Samama C.-M. Assessment of homeostasis in patients with cirrhosis: relevance of the ROTEM tests? A prospective, cross-sectional study. Eur. J. Anaesthesiol. 2016; 33 (2): 126–133. https://doi.org/10.1097/EJA.0000000000000322

3. Богушевич С.А. Клинико-гемостазиологические нарушения в патогенезе циррозов печени различной этиологии: автореф. дис. … канд. мед. наук. Томск, 2013. 23 с.

4. Корой П.В. Клинико-патогенетическое и прогностическое значение нарушений гемостатического гомеостаза при хронических заболеваниях печени: дис. ... докт. мед. наук. Ставрополь, 2011. 333 с.

5. Somani V., Amarapurkar D., Shah A. Thromboelastography for asessing the risk of bleeding in patients with cirrhosis-moving closer. J. Clin. Exp. Hepatol. 2017; 7 (4): 284–289. https://doi.org/10.1016/j.jceh. 2017.03.001

6. Ларина Н.Н., Галимзянов Х.М., Левитан Б.Н., Иванников В.В. Патология системы гемостаза и этиология циррозов печени. Астраханский медицинский журнал. 2011; 6 (1): 77–79.

7. Минов А.Ф., Дзядзько А.М., Руммо О.О. Нарушения гемостаза при заболеваниях печени. Вестник трансплантологии и искусственных органов. 2010; 12 (2): 82–91.

8. Mackavey C.I., Hankes R. Hemostasis, coagulation abnormalities and liver disease. Crit. Care Nurs. Clin. North Am. 2013; 25 (4): 435–446. https://doi.org/10.1016/j.ccell.2013.09.001

9. Tripodi A., Primignani M., Chantarangkul V., Lemma L., Jovani M., Rebulla P., Mannucci P. Global hemostasis tests in patients with cirrhosis before and after prophylactic platelet transfusion. Liver Int. 2013; 33 (3): 362–367. https://doi.org/10.1111/liv.12038

10. Tripodi A. Hemostasis abnormalities in cirrhosis. Curr. Opin. Hematol. 2015; 22 (5): 406–412. https://doi.org/10.1097/MOH.0000000000000164

11. Hugenholtz G.C., Adelmeijer J., Meijers J.C., Porte R.J., Stravitz R.T., Lisman T. An unbalance between von Willebrand factor and ADAMTS 13 in acute liver failure: implications for hemostasis and clinical outcome. Hepatology. 2013; 58 (2): 752–761. https://doi.org/10.1002/hep.26372. PMID: 23468040

12. Kleiegris M.-C., Boc M.H.A., Roest M., Heskens Y., ten CateHoek A., Van Deursen C., Spronk H.M.H., Reitsma P.H., De Groot P.G., ten Cate H., Koek G. Cirrhosis patients have a coagulopathy that is associated with decreased clot formation capacity. J. Thromb. Haemost. 2014; 12 (10): 1647–1657. https://doi.org/10.1111/j.th.12706

13. Mucino-Bermejo J., Carrillo-Esper R., Mendez-Sanchez N., Uribe M. Thrombosis and hemorrhage in the critically ill cirrhotic patients: five years retrospective prevalence study. Ann. Hepatol. 2015; 14 (1): 93–98. PMID: 25536646

14. Wan J., Roberts L.N., Hendrix W., Konings J., Ow T.-W., Rabinowich L., Barbouti O., de Laat B., Arya R., Patel V.C., Roest M., Lisman T., Bernal W. Whole blood thromb in generation profiles of patients with cirrhosis explored with a near patient assay. J. Thromb. Haemost. 2020; 18 (4): 834–843. https://doi.org/10.1111/jth14751

15. Drolz A., Horvatits T., Roedl K., Rutter K., Staufer K., Kneidinger N., Holzinger U., Zauner Ch., Schellonogowski P., Heinz G., Perkmann T., Kluge S., Trauner M., Fuhrmann V. Coagulation parameters and major bleeding in critically ill patients with cirrhosis. Hepatology. 2016; 64 (2): 556–568. https://doi.org/10.1002/hep.28628

16. Roberts J.R., Bamba K. Balanced coagulopathy in cirrhosisclinical implycations: a teachable moment. JAMA Intern. Med. 2014; 174 (11): 1723–1724. https://doi.org/10.1001/jamainternmed 2014.4023

17. Leonardi T., De Maria N., Villa E. Anticoagulation in cirrhosis; a new paradigm? Clin. Mol. Hepatol. 2017; 23 (1): 13–21. https://doi.org/10.3350/cmh.2016.0110

18. Hungenholtz G.C.G., Macrae F., Abdelmeijer J., Dulfez S., Porte R.J., Lisman T., Ariens R.A. Procoagulant changes in fibrin clot structure in patients with cirrhosis area ssociated with oxidative modifications of fibrinogen. J. Thromb. Haemost. 2016; 14 (5): 1054–1066. https://doi.org/10.1111/jth.13278

19. Kujovich J.L. Coagulopathy in liver disease: a balancing act. Hemotology Am. Soc. Hemotol. Educ. Program. 2015; 2015: 243–249. https://doi.org/10.1182/asheducation-2015.1.243

20. Intagliata N., Henry Z., Maitland H., Shah N.L., Argo C.K., Northup P.G., Caldvell S.H. Direct oral anticoagulations in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation. Dig. Dis. Sci. 2016; 61 (6): 1721–1727. https://doi.org/10.1007/s10620-015-4012-2

21. Shatzel J., Dulai P.S., Harbin D., Cheung H., Reid T.N., Kim J., James S.L., Khine H., Batman S., Whyman J., Dickson R.S., Ornstein D.L. Safety and efficacy of pharmacological thromboprophylaxis for hospitalized patients with cirrhosis. A single center retrospective cohort study. J. Thromb. Haemost. 2015; 13 (7): 1245–1253. https://doi.org/10.1111/jth13000

22. De Pierti L., Bianchini M., Montaltti R., De Maria N., DiMaria T., Begliomini B., Gerunda G.E., di Beneditto F., Garsia-Tsao G., Villa E. Thromboelastography guided blood product use before invasive procedures in cirrhosis with severe coagulopathy. A randomized controlled trial. Hepatology. 2016; 63 (2): 566–573. https://doi.org/10.1002/hep.28148

23. Stine J.G., Niccum B.A., Zummet A.N., Intagliata N., Caldwell H.S., Argo K.C., Northup P.G. Increased risk of venous thromboembolism in hospitalized patients with cirrhosis due to non-alcoholic steatohepatis. Clin. Transpl. Gastroenterol. 2018; 9 (3): 140. https://doi.org/10.1038-s41424-018-0002-y

24. Qi X., De Stefano V., Li H., Dai J., Guo X., Fan D. Anticoagulation for the treatment of portal vein thrombosis in liver cirrhosis: a systemic review and meta-analysis of observational studies. Eur. J. Intern. Med. 2015; 26 (1): 23–29. https://doi.org/10.1016/j.ejim.2014.12.002.26

25. Delgado M.G., Seijo S., Yepes I., Achecar L., Catalina M.V., Garcia-Criado A. et al. Efficacy and safety of anticoagulation in patients with cirrhosis and portal vein thrombosis. Clin. Gastroenterol. Hepatol. 2012; 10 (7): 776–783. https://doi.org/10.1016/j.cgh.2012.01.012

26. Ambrosino P., Tarantino L., Di Minno G., Paternoster M., Graziano V., Petitto M., Nasto A., Di Minno M.N.D. The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis. Thromb. Haemost. 2017; 117 (1): 139–148. https://doi.org/10.1160/TH 16-06-0450

27. Kinjo N., Kawanaka H., Akahoshi T., Matsumoto Y., Kamori M., Nagao Y., Hashimoto N., Uehara H., Tomikawa M., Shirabe K., Maehara Y. Portal vein thrombosis in liver cirrhosis. World J. Hepatol. 2014; 6 (2): 64–71. https://doi.org/10.4254/wjh.v6.i2.64. PMID: 24575165

28. Harrison M. The misunderstood coagulopathy of liver disease: a review for the acute setting. West J. Emerg. Med. 2018; 19 (5): 863–871. https://doi.org/10.5811/westjem.2018.7.37893

29. Lisman T., Kleiss S., Patel V.C., Fisher C., Adelmeijer J., Bos S., Singanayagam A., Stoy S.H., Shawcross D.L., Bernal W. In vitro efficacy of pro-anticoagulant strategies in compensated and acute patients with cirrhosis. Liver Int. 2018; 38 (11): 1988–1996. https://doi.org/10.1111/liv.13882

30. Sinegre T., Duron C., Lecomte T., Pereira B., Massoulier S., Lamblin G., Abergel A., Leberton A. Increased factor VIII plays a significant role plasma hypercoaguiability phenotype of patients with cirrhosis. J. Thromb. Haemost. 2018; 16 (6): 1132–1140. https://doi.org/10.1111/jth.14011

31. Saerbruch T., Wong F. Treatment of oesophageal varices in liver cirrhosis. Digeston. 2019; 99 (4): 261–266. https://doi.org/19.1159/000492076

32. Villanueva C., Graupera I., Aracil C., Alvarado E., Mianana J., Puente A., Hernandez-Gea V., Ardevol A., Pavel O., Colomo A., Concepcion M., Poca M., Torras X., Rene J.M., Guarner C. A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis. Hepatology. 2017; 65 (5): 1693–1707. https://doi.org/10.1002/hep. 29056

33. Sauerbruch T., Mengel M., Dollinger M., Zipprich A., Rössle M., Pauther E., Wiest R., Caca K., Hoffmeister A., Lutz H., Schoo R., Lorenzen H., Trebicka J., Appenrodt B., Schepke M., Fimmers R. Prevention of rebleeding from oesophageal varices in patients with cirrhosis receiving smalldiameter stents versus hemodinamically controlled medical therapy. Gastroenterology. 2015; 149 (3): 660–668e1. https://doi.org/10.1053/j.gastro.2015.05.011

34. Pfisterer N., Dexheimer C., Fuchs E.M., Bucsics T., Schwabl P., Mandorfer M. Betablockers do not increase efficacy of band ligation in primary propylaxis but they improve survival in secondary prophylaxis of variceal bleeding. Aliment. Pharmacol. Ther. 2018; 47 (7): 966–979. https://doi.org/10.1111/apt.14485

35. Jakab S.S., Garcia-Tsao G. Screening and surveillance of varices in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 2019; 17 (1): 26–29. https://doi.org/10.1016/j.cgh.2018.03.012

36. Wong G.L.H., Liang L.Y., Kwok R., Hui A.J., Tse Y.-K., Chan H.L.-Yu., Wong V.W.-S. Low risk of variceal bleeding in patients with cirrhossis after variceal screening stratified by liver/spleen stiffness. Hepatology. 2019; 70 (3): 971–981. https://doi.org/10.1002/hep.30522

37. Yang Z.J., Costa K.A., Novelli E.M., Smith R.E. Venous thromboembolism in cirrhosis. Clin. Appl. Thromb. Hemost. 2014; 20 (2): 169–178. https://doi.org/10.1177/1076029612461846.

38. Iwakiri Y., Shah V., Rockey D.C. Vascular pathology in chronic liver disease and cirrhosis-current status and future directions. J. Hepatol. 2014; 61 (4): 912–924. https://doi.org/10.1016/j.jhep.2014.05.047

39. Tripodi A., Chantarangkul V., Primignani M., Clerici M., Dellera A., Aghemo A., Mannucci P.M. Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with freshfrozen plasma. Intern. Emerg. Med. 2012; 7 (2): 139–144. https://doi.org/10.1007/s11739-011-0528-4

40. Lisman T., Violi F. Cirrhosis as a risk factor for venous thrombosis. Tromb. Haemost. 2017; 117 (1): 3–5. https://doi.org/10.1160/TH.16-10-0782

41. Lisman T., Bos S., Intagliata N.M. Mexanisms of enhanced thrombin-generating capacity in patients with cirrhosis. J. Thromb. Haemost. 2018: 16 (6): 1128–1131. https://doi.org/10.1111/j.th.14020

42. Monereo Minoz M., Aguilera Garcia S.G., De la Barreda Hausser S., Gonzales-Reimere E. Cryptogenetic liver cirrhosis and prothrombotic mutations. A mere association? Rev. Esp. Enfermed. Dig. 2016; 108 (9): 588–591. https://doi.org/10.17235/reed.2015.3871/2015

43. Kremers R.M., Kleinegris M.-C., Ninivaggi M., De Laat B., Ten Cate Hugo, Koek H.G., Wagenvoord R.J., Hemker C.H. Decreased prothrombin conversion and reduced thrombin inactivation explain rebalanced thrombin generation in liver cirrhosis. PLoS One. 2017; 12 (5): e0177020. https://doi.org/10.1371/journal.pone 0177020

44. Younossi Z.M., Stepanova M., Afendy M., Fang Y., Younossi Y., Mir H. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin. Gastroenterol. Hepatol. 2011; 9 (6): 524–530. https://doi.org/10.1016/j.cgh.2011.03.020

45. Oleary J.G., Greenbero C.H. AGA clinical practice update coagulation in cirrhosis. Gastroenterology. 2019; 157 (1): 34–43. https://doi.org/10.1053/j.gastro. 2019.03. 070

46. Tripodi A., Primignani M., Lemma L., Chantarangkul V., Mannuccio P.M. Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis. J. Hepatol. 2013; 59 (2): 265–270. https://doi.org/10.1016/j.hep.2013.03.036

47. Yilmaz V.T., Dincer D., Arci B., Cetinkaya R. Significant association between serum levels of von Willibrand factor (vWF) antigen with stages of cirrhosis. Eur. J. Med. 2015; 47 (1): 21–25. https://doi.org/10.5152/eajm. 2014.00.16

48. Kalambokis G.N., Oikonomou A., Christon L., Tsianos E.V., Christodoulou D., Baltayiannis G. Von Willebrand factor and procoagulant imbalance predict outcome in patients with cirrhosis and thromocitopenia. J. Hepatol. 2016; 65 (5): 921–929. https://doi.org/10.1016/j.jhep.2016.06.002

49. Afdhal N.H., Dusheiko G.M., Glannini E.G., Chen P.-J., Han K.-H., Mohsin A., Rodzdnez-Torres M., Rugina S., Bakulin I., Lawitz E., Shiffman M.L., Tayyab G.-U.-N., Poordad F., Kamel J.M., Brainsky A., Geib J., Vasey S.V., Patwardhan R., Campbell F.M., Theodore D. Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy. Gastroenterology. 2014; 146 (2): 442–452e1. https://doi.org/10.1053/j.gastro.2013.10.012. Epub 2013 Oct 12

50. Temel T., Cansu D.U., Temel H.E., Ozakyol A.H. Serum thrombopoietin levels and its relationship with thrombocytopenia in patients with cirrhosis. Hepat. Mon. 2014; 14 (5): e18556. https://doi.org/10.5812/hepatmon18556

51. Iwakiri Y., Kim M.Y. Nitric oxide in liver diseases. Trends Pharmacol. Sci. 2015; 36 (8): 524–536. https://doi.org/10.1016/j.tips.2015.05.001

52. Rassi A.B., Damico A.E., Tripodi A., Da Rocha T.R., Migta Y.B., Ferreira M.C., Carrilho J.F., Farias A.Q. Fresh frozen plasma transfusion in patients with cirrhosis and coagulopathy: effect on conventional coagulation tests and thrombomodulinmodified thrombin generation. J. Hepatol. 2020; 72 (1): 85–94. https://doi.org/10.1016/j.jhep2019.09.008

53. Sinegre Th., Abergel A., Sapin A.F., Lamblin G., MarquesVerdier A., Duron C., Leberton A. Low sensitivity to the action of thrombomodulin in cirrhotic patients. Interest of thrombinography. Ann. Biol. Clin. (Paris). 2016; 74 (2): 203–212. https://doi.org/10.1684/abc.2015.1111

54. Vairappan B. Endothelial dysfunction in cirrhosis: role of inflammation and oxydative stress. World J. Hepatol. 2015; 7 (3): 443–459. https://doi.org/104254/wjh.v.7.i.3.443

55. Di Pascoli M., Divi M., Rodrigeuz-Vilarrupla A., Rosado E., Garcia-Sancho J., Vilaseca M., Bosch J., Garcia-Pagan J.C. Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats. J. Hepatol. 2013; 58 (5): 904–910. https://doi.org/10.1016/j.jhep.2012.12.012

56. Rodriguez-Vilarrupla A., Lavina B., Garcia-Caldero H., Russo L., Rosado E., Roglans N., Boch J., Garcia-Pagain J.C. PPAR α activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhosis rats. Hepatology. 2012; 56 (5): 1033–1039. https://doi.org/10.1016/j.jhep.2011.12.008

57. Wani Z.A., Bhat R.A., Bhadoria A.S., Maiwall R. Extrahepatic portal vein obstruction and portal vein thrombosis in special situations: need for a new classificcation. Saudi J. Gastroenterol. 2015; 21 (3): 129–138. https://doi.org/10.4103/1309-3767.157550

58. Chen H., Liu L., Qi X., He C., Wu F., Fan D., Han G. Efficacy and safety of anticoagulation in more advanced portal vein thrombosis in patients with liver cirrhosis. Eur. J. Gastroenterol. Hepatol. 2016; 28 (1): 82–89. https://doi.org/10.1097/MEG.0000000000000482

59. Girleanu I., Trifan A., Stancin C., Sfarti C. Portal vein thrombosis in cirrhotic patients – it is always the small pieces that make the big picture. World J. Gastroenterol. 2018; 24 (39): 4419–4427. https://doi.org/10.3748/wjg.24i394419

60. Primignani M., Tosetti G., La Mura V. Therapeutic and clinical aspects of portal vein thrombosis in patients with cirrhosis. World J. Hepatol. 2015; 7 (29): 2906–2912. https://doi.org/10.4254/wjhv.7.i.29.2906