Goal-oriented therapy of coagulopathy in liver transplantation in children (literature review)

Introduction. Methods for correcting perioperative blood loss and hemostasis disorders in children during liver transplantation are still controversial and are largely conducted empirically by specialists. Additional difficulties are imposed by the features of a continuously growing and developing organism, as well as the following hemostasis system.

The objective was to analyze modern approaches to the correction of hemostasis disorders in children in the perioperative period of liver transplantation.

Materials and methods. The analysis of literary sources indexed for the period from 2000 to 2024 in the databases PubMed, Google Scholar, Cochrane MEDLINE and E-Library (for Russian authors).

Results. The analysis of the literature has shown that at present, in liver transplantation in children, a personalized approach prevails in choosing the tactics of infusion – transfusion therapy and correction of developing changes in the hemostasis system. Modern approaches are aimed at the fastest possible identification of specific perioperative disorders of pro- and anticoagulant factors directly «at the patient’s bedside» and targeted correction of each specific element.

Conclusion. Despite the active development and improvement of approaches to correcting perioperative hemostasis disorders during liver transplantation, improving pharmacotherapy protocols, minimizing the time to obtain laboratory data and reducing the influence of the human factor on the interpretation of results and treatment choice, the study of the hemostasis system and correction of its disorders is still very far from the final stage.

1. Budnik I. A., Morozova O. L., Tsymbal A. A. et al. The effect of fibrinogen concentrates, factor XIII and a thrombin-activated fibrinolysis inhibitor on the density and fibrinolytic stability of a blood clot in a hyperfibrinolysis model. Pathological physiology and experimental therapy, 2017, vol. 61, no. 4, pp. 44–50. (In Russ.).

2. Bulanov A. Yu., Yatskov K. V., Shulutko E. M. et al. Endogenous heparin-like syndrome: an analysis of clinical observations. Anesthesiology and intensive care, 2012, no. 7, pp. 3. (In Russ.).

3. Galstyan G. M., Berkovsky A. L., Zhuravlev V. V. Are fibrinogen preparations needed in Russia? Anesthesiology and intensive care, 2014, no. 3, pp. 49–59. (In Russ.).

4. Dziadzko A. M., Shcherba A. E., Rummo O. O. Ischemic reperfusion injury of the liver. Medical Journal, 2013, no. 1, pp. 27–31. (In Russ.).

5. Minov A. F., Dziadzko A. M., Rummo O. O. Hemostasis disorders in liver diseases. Bulletin of Transplantology and artificial organs, 2010, no. 2 –12, pp. 82–91. (In Russ.).

6. Morozov Yu. A., Mednikov R. V., Chernova M. A. Disorders of the hemostasis system in liver pathology and their diagnosis. Hemorrhagic diathesis, thrombosis, thrombophilia, 2014, vol. 1, pp. 82–91. (In Russ.).

7. Reshetnyak V. I., Zhuravel S. V., Kuznetsova N. K. et al. The hemostasis system is normal and during liver transplantation (review). General resuscitation, 2018, vol. 5, pp. 14, pp. 58–84. (In Russ.).

8. Khurtin V. V., Berkovsky A. L., Sergeeva E. V. et al. Obtaining a scientific concontabrinogen. Mathematics and Phraseology, 2019, vol. 64, pp. 1, pp. 73–78. (In Russ.).

9. Agarwal S. The prevalence of a heparin-like effect shown on the thromboelastograph in patients undergoing liver transplantation. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 2008, no. 6, vol. 14, pp. 855–860. https://doi.org/10.1002/lt.21437.

10. Andrew M. Development of the human coagulation system in the full-term infant. Blood, 1987, vol. 70, pp. 1, no. 165–172. PMID: 3593964.

11. Bhalla S. Preoperative risk evaluation and optimization for patients with liver disease. Gastroenterology report, 2024, vol. 12, pp. 071. https://doi.org/10.1093/gastro/goae071.

12. Bos S. Efficacy of pro- and anticoagulant strategies in plasma of patients undergoing hepatobiliary surgery. Journal of thrombosis and haemostasis: JTH, 2020, vol. 11, no. 18, pp. 2840–2851. https://doi.org/10.1111/jth.15060.

13. Boylan J. F. Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology, 1996, vol. 85, no. 5, pp. 1043–1048. https://doi.org/10.1097/00000542–199611000–00012.

14. Chavez-Tapia N. C. Prophylactic activated recombinant factor VII in liver resection and liver transplantation: systematic review and meta–analysis. PloS one, 2011, vol. 7, pp. 6, no. e22581. https://doi.org/10.1371/journal.pone.0022581.

15. Dalmau A. The prophylactic use of tranexamic acid and aprotinin in orthotopic liver transplantation: a comparative study. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 2004, vol. 10, no. 2, pp. 279–284. https://doi.org/10.1002/lt.20075.

16. Dios Domínguez C. De, Pérez Cadena L. G., Pérez Cadena M. G. Does tranexamic acid reduce transfusion requirements in children with cerebral palsy undergoing osteotomies? A systematic review and meta-analysis. Journal of orthopaedics, 2024, vol. 58, pp. 66–74. https://doi.org/10.1016/j.jor.2024.06.036.

17. Feltracco P. Blood loss, predictors of bleeding, transfusion practice and strategies of blood cell salvaging during liver transplantation. World Journal of Hepatology, 2013, vol. 5, no. 1, pp. 1–15. https://doi.org/10.4254/wjh.v5.i1.1.

18. Freitas Dutra V. de. A challenge for blood management: A patient presenting anti–Vel antibody undergoing orthotopic liver transplantation. Transfusion medicine (Oxford, England), 2023, pp. 33, vol. 5, pp. 426–427. https://doi.org/10.1111/tme.12996.

19. Gomes M. Safety of fibrinogen concentrate in non-trauma and non-obstetric adult patients during perioperative care: systematic review and meta-analysis. Journal of Clinical Medicine, 2024, no. 12, pp. 13. https://doi.org/10.3390/jcm13123482.

20. Görlinger K. ROTEM-guided bleeding management in complex pediatric surgery and obstetrics, 2018, no. 2, pp. 317–318. . https://doi.org/10.13140/RG.2.2.14719.30885.

21. Hartmann M., Szalai C., Saner F. H. Hemostasis in liver transplantation: Pathophysiology, monitoring, and treatment. World journal of gastroenterology, 2016, vol. 22, pp. 4, pp. 1541–1550. https://doi.org/10.3748/wjg.v22.i4.1541.

22. Himmelreich G. Pathophysiologic role of contact activation in bleeding followed by thromboembolic complications after implantation of a ventricular assist device. ASAIO journal (American Society for Artificial Internal Organs: 1992, 1995, vol. 41, no. 3, pp. M790–4. https://doi.org/10.1097/00002480–199507000–00122.

23. Hoffman M., Monroe D. M. A cell-based model of hemostasis. Thrombosis and Haemostasis, 2001, no. 6, 85, pp. 958–965.

24. Hukkinen M. Antithrombin supplementation for prevention of vascular thrombosis after pediatric liver transplantation. Journal of pediatric surgery, 2022, vol. 57, no. 11, pp. 666–675.

25. Hung H. C. Protein S for portal vein thrombosis in cirrhotic patients waiting for liver transplantation. Journal of clinical medicine, 2020, vol. 9, no. 4, pp. 1181. https://doi.org/10.3390/jcm9041181.

26. Ker K. Tranexamic acid for postpartum bleeding: a systematic review and individual patient data meta-analysis of randomised controlled trials. Lancet (London, England), 2024, vol. 10463, no. 404, pp. 1657–1667. https://doi.org/10.1016/S0140–6736(24)02102–0.

27. Kilercik H. Factors affecting intraoperative blood transfusion requirements during living donor liver transplantation. Journal of clinical medicine, 2024, no. 19, pp. 13.

28. Kim B. R. Continuous versus intermittent infusion of human antithrombin III concentrate in the immediate postoperative period after liver transplantation. Clinical and translational science, 2023, vol. 16, no. 7, pp. 1177–1185.

29. Kim J. H. Comparison of fibrinogen concentrate and cryoprecipitate on major thromboembolic events after living donor liver transplantation. Journal of clinical medicine, 2023, no. 23, pp. 12. https://doi.org/10.3390/jcm12237496.

30. Koh A. Safety and efficacy of tranexamic acid to minimise perioperative bleeding in hepatic surgery: a systematic review and meta-analysis. World journal of surgery, 2022, vol. 46, no. 2, pp. 441–449. https://doi.org/10.1007/s00268–021–06355–2.

31. Kong H.-Y., Zhao X., Wang K.-R. Intraoperative management and early post-operative outcomes of patients with coronary artery disease who underwent orthotopic liver transplantation. Hepatobiliary & pancreatic diseases international: HBPD INT, 2020, vol. 19, no. 1, pp. 12–16. https://doi.org/10.1016/j.hbpd.2019.12.003.

32. Krom R. J. Incidence of postreperfusion hyperfibrinolysis in liver transplantation by donor type and observed treatment strategies. Anesthesia and analgesia, 2023, vol. 136, no. 3, pp. 518–523. https://doi.org/10.1213/ANE.0000000000006302.

33. Lisman T., Porte R. J. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood, 2010, vol. 116, no. 6, pp. 878–885. https://doi.org/10.1182/blood-2010-02-261891.

34. Lubkin D. T., Does an early, balanced resuscitation strategy reduce the incidence of hypofibrinogenemia in hemorrhagic shock? Trauma surgery & acute care open, 2024, vol. 9, no. 1, pp. 878–885. https://doi.org/10.1136/tsaco-2023-001193.

35. Martinelli E. S. The debate on antifibrinolytics in liver transplantation: always, never, or sometimes? Brazilian journal of anesthesiology (Elsevier), 2024, vol. 74, no. 6, pp. 844562. https://doi.org/10.1016/j.bjane.2024.844562.

36. Massicotte L. Development of a predictive model for blood transfusions and bleeding during liver transplantation: an observational cohort study. Journal of cardiothoracic and vascular anesthesia, 2018, vol. 32, no. 4, pp. 1722–1730. https://doi.org/10.1053/j.jvca.2017.10.011.

37. Nacoti M. Coagulopathy and transfusion therapy in pediatric liver transplantation. World Journal of Gastroenterology, 2016, vol. 22, no. 6, pp. 2005–2023. https://doi.org/10.3748/wjg.v22.i6.2005.

38. Osuna M. Changes in coagulation potential over time after administration of recombinant activated factor VII in an emicizumab-treated hemophilia A patient with inhibitors. International journal of hematology, 2024, vol. 120, no. 5, pp. 639–644. https://doi.org/10.1007/s12185-024-03828-7.

39. Sabate A., Caballero M., Pérez L. Comments on: tranexamic acid administration during liver transplantation is not associated with lower blood loss or with reduced utilization of red blood cell transfusion. Anesthesia and analgesia, 2024, vol. 139, no. 4, pp. c32–c33. https://doi.org/10.1213/ANE.0000000000007029.

40. Scheffert J. L. Timing of factor VIIa in liver transplantation impacts cost and clinical outcomes. Pharmacotherapy, 2013, vol. 33, no. 5, pp. 483–488. https://doi.org/10.1002/phar.1230.

41. Schuetze S. M., Linenberger M. Acquired protein S deficiency with multiple thrombotic complications after orthotopic liver transplant. Transplantation, 1999, vol. 67, no. 10, pp. 1366–1369. https://doi.org/10.1097/00007890–199905270–00013.

42. Senzolo M. Heparin-like effect in liver disease and liver transplantation. Clinics in liver disease, 2009, vol. 13, no. 1, pp. 43–53. https://doi.org/10.1016/j.cld.2008.09.004.

43. Shalaby S. Endothelial damage of the portal vein is associated with heparin–like effect in advanced stages of cirrhosis. Thrombosis and haemostasis, 2020, vol. 120, no. 8, pp. 1173–1181. https://doi.org/10.1055/s–0040–1713169.

44. Sogaard K. K. Portal vein thrombosis; risk factors, clinical presentation and treatment. BMC gastroenterology, 2007, vol. 7, pp. 34. https://doi.org/10.1186/1471-230X-7-34.

45. Tirotta C. F. A Randomized pilot trial assessing the role of human fibrinogen concentrate in decreasing cryoprecipitate use and blood loss in infants undergoing cardiopulmonary bypass. Pediatric cardiology, 2022, vol. 43, no. 7, pp. 1444–1454. https://doi.org/10.1007/s00246-022-02866-4.

46. Toulon P. Developmental hemostasis: laboratory and clinical implications. International journal of laboratory hematology, 2016, vol. 38, suppl. 1, pp. 66–77. https://doi.org/10.1111/ijlh.12531.

47. Vandyck K. B. Coagulation management during liver transplantation: monitoring and decision making for hemostatic interventions. Current opinion in organ transplantation, 2023, vol. 28, no. 6, pp. 404–411. https://doi. org/10.1097/MOT.0000000000001101.

48. Yank V. Systematic review: benefits and harms of in–hospital use of recombinant factor VIIa for off-label indications. Annals of internal medicine, 2011, vol. 154, no. 8, pp. 529–540. https://doi.org/10.7326/0003–4819–154–8–201104190–00004.

49. Warnaar N., Molenaar I. Q., Colquhoun S. D. et al. Intraoperative pulmonary embolism and intracardiac thrombosis complicating liver transplantation: a systematic review. Journal of Thrombosis and Haemostasis, 2008, vol. 2, pp. 297–302. https://doi.org/10.1111/j.1538–7836.2008.02831.x.