Changes in Hemostasis during Liver Transplantation in Children

The objective: to assess changes of clinical and laboratory hemostasic parameters in children at the stages of orthotopic liver transplantation.

Subjects and Methods. A single-centre, prospective, pilot study of coagulation test scores was performed in 20 children aged 0 to 11 years with hepatoblastoma after a course of PRETEX IV chemotherapy who underwent liver transplantation from a related donor.

Results. Children from 0 to 11 years old with hepatoblastoma, after chemotherapy, retain the normal functional activity of the hemostasis system at the pre-hepatic stage of transplantation: APTT 34.6 (34.45; 38.65) s; prothrombin index (PI) 83.53 (74.09; 87.87) %; INR 1.22 (1.16; 1.42) in the 0‒2 year group, APTT 40.45 (34.9; 41, 68), PI 75.57 (64.41; 80.45) %, and INR 1.39 (1.36; 1.87) in the group aged 3‒11 years. Severe hypocoagulation develops by the end of the hepatic stage and in the first 15 minutes after the start of arterial blood flow through the graft: CT and CFT from 195.0 (189.0; 228.5) s and 163.0 (129.5; 171.5) s to 537.0 (456.0; 1,651.5) s and 468.0 (324.5; 611.5) s (p < 0.05), respectively, in the INTEM test. Hypocoagulation at this time develops due to deficiency of coagulation factors and the release of endogenous glycosaminoglycans from the endothelium transplant, as indicated by an increase in CT and CFT to 666.0 (468.5; 2,209.5) s and 254.5 (203.25; 305.75) s in INTEM, CT to 525.0 (389.0; 2028.0) s with p < 0.05 in HEPTEM in children under the age group of up to 2. Within 1 hour after the start of arterial blood flow, the effects of systemic heparinoid effects persist, which is confirmed by the dynamics of CT 360.0 (219.5; 2,116.5) s with up to 960.0 (560.5; 1,440.5) s with p < 0.05 in the EXTEM test.

Conclusion. Changes in hemostasis system parameters during surgery make it possible to judge about rapidly developing coagulation and anticoagulation disorders in children of the presented age groups. Specific changes in the coagulation profile at the stages of liver transplantation in children under the age of 11 inclusive, make it possible to do without routine correction of changes in the hemostasis system.

1. Ventslovayte N.D., Efremova N.А., Goryacheva L.G. et al. Liver transplantation in children: the experience of last decades, current problems and solutions. Detskiye Infektsii, 2020, vol. 19, no. 2, pp. 52–56. (In Russ.) doi: 10.22627/2072-8107-2020-19-2-52-57.

2. Minov А.F., Dzyadzko А.M., Rummo O.O. Hemostatic disorders in liver diseases. Vestnik Transplantologii I Iskusstvennykh Organov, 2010, vol. 2, no. 12, pp. 82–91. (In Russ.) doi: 10.15825/1995-1191-2010-2-82-91.

3. Nosovskiy А.M., Pikhlak А.E., Logachev V.А. et al. Small sample statistics in medical research. Rossiyskiy Meditsinskiy Journal, 2013, no. 6, pp. 57-60. (In Russ.)

4. Timerbulatov Sh.V., Fayazov R.R., Smyr R.А. et al. Determination of volume and degree of acute blood loss. Meditsinsky Vestnik Bashkirostana, 2012, vol. 2, no. 7, pp. 69-72. (In Russ.)

5. Arnold K., Xu Y. E., Liao Y. et al. Synthetic anticoagulant heparan sulfate attenuates liver ischemia reperfusion injury. Scient. Rep., 2020, no. 1 (10), pp. 1-10. C. 17187. doi:10.1038/s41598-020-74275-7.

6. Cleland S., Corredor C., Ye J.J. et al. Massive haemorrhage in liver transplantation: Consequences, prediction and management. World J. Transplant., 2016, no. 2 (6), pp. 291–305. doi:10.5500/wjt.v6.i2.291.

7. Cuenca A.G., Kim H.B., Vakili K. Pediatric liver transplantation. Semin. Pediatr. Surg., 2017, no. 4 (26), pp. 217–223. doi: 10.1053/j.sempedsurg.2017.07.014.

8. Feltracco P., Brezzi M., Barbieri S. et al. Blood loss, predictors of bleeding, transfusion practice and strategies of blood cell salvaging during liver transplantation. World J. Hepatol., 2013, no. 1 (5), pp. 1–15. doi:10.4254/wjh.v5.i1.

9. Field A., Poole T., Bamber J.H. ROTEM(®) sigma reference range validity. Anaesthesia, 2019, no. 8 (74), pp. 1062–1071. doi:10.1111/anae.14711.

10. Fyodorova T., Rogachevsky A., Strelnikova A. et al. Massive hemorrhages in pregnant women with placenta previa and accreta: A transfusiologist’s view. Sklifosovsky J. Emerg. Med. Care, 2018, no. 3 (7), pp. 253–259. doi:10.23934/2 223-9022-2018-7-3-253-259.

11. Gautier S., Monakhov A., Tsiroulnikova O. et al. Split liver transplantation: a single center experience. Alman. Clin. Med., 2020, no. 3 (48), pp. 162–170. doi:10.18786/2072-0505-2020-48-031.

12. Görlinger K. ROTEM-guided Bleeding Management in complex Pediatric Surgery and Obstetrics. Hospital del Nino, San Borja, Lima, Peru. 2018, doi:10.13140/RG.2.2.14719.30885.

13. Görlinger K., Pérez-Ferrer A., Dirkmann D. et al. The role of evidence-based algorithms for rotational thromboelastometry-guided bleeding management. Korean J. Anesthesiol., 2019, no. 4 (72), pp. 297–322. doi:10.4097/kja.19169.

14. Hartmann M., Warde C., Dirkmann D. et al. Safety of coagulation factor concentrates guided by ROTEMTM-analyses in liver transplantation: Results from 372 procedures. BMC Anesthesiol., 2019, no. 1 (19), pp. 1–11. doi: 10.1186/s12871-019-0767-x.

15. Henry Z., Northup P.G. The Rebalanced hemostasis system in end-stage liver disease and its impact on liver transplantation. Intern. Anesthesiol. Clin., 2017, no. 2 (55), pp. 107–120. doi:10.1097/AIA.0000000000000139.

16. Kinney E.L. Primer of biostatistics. 1987, pp. 847.

17. Kloesel B., Kovatsis P.G., Faraoni D. et al. Incidence and predictors of massive bleeding in children undergoing liver transplantation: A single-center retrospective analysis. Paediat. Anaesth., 2017, no. 7 (27), pp. 718–725. doi:10.1111/pan.13162.

18. Li J.-P., Kusche-Gullberg M. Heparan sulfate: biosynthesis, structure, and function. Intern. Rev. Cell Molec. Biol., 2016, vol. 325, pp. 215–273. doi:10.1016/bs.ircmb.2016.02.009.

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

20. Malhotra S., Sibal A., Goyal N. Pediatric liver transplantation in India: 22 years and counting. Indian Pediatr., 2020, no. 12 (57), pp. 1110-1113.

21. Meirelles Júnior R.F., Salvalaggio P., Rezende M.B. et al Liver transplantation: history, outcomes and perspectives. Einstein (São Paulo, Brazil), 2015, no. 1 (13), pp. 149–152. doi:10.1590/S1679-45082015RW3164.

22. Metcalf R.A., Pagano M.B., Hess J.R. et al A data-driven patient blood management strategy in liver transplantation. Vox Sanguinis, 2018, no. 113 (5), pp. 421–429. doi:10.1111/vox.12650.

23. Nacoti M., Corbella D., Fazzi F. et al. Coagulopathy and transfusion therapy in pediatric liver transplantation. World J. Gastroenter., 2016, no. 6 (22), pp. 2005–2023. doi:10.3748/wjg.v22.i6.2005

24. Schmidt A., Israel A., Refaai M. The utility of thromboelastography to guide blood product transfusion. Am. J. Clin. Pathol., 2019, no. 4 (152), pp. 407– 422. doi:10.1093/ajcp/aqz074.

25. Schumacher C., Eismann H., Sieg L. et al. Use of rotational thromboelastometry in liver transplantation is associated with reduced transfusion requirements. Experim. Clin. Transplant.: Official Journal of the Middle East Society for Organ Transplantation, 2019, no. 2 (17), pp. 222–230. doi:10.6002/ect.2017.0236.

26. Tan E.K., Tan B.K., Fong H.C. et al. Impact of microsurgical anastomosis of hepatic artery on arterial complications and survival outcomes after liver transplantation. Transplant. Proc., 2021, no. 1 (53), pp. 65–72. doi:10.1016/j. transproceed.2020.08.017.

27. Villarreal J.A., Yoeli D., Ackah. et al. Intraoperative blood loss and transfusion during primary pediatric liver transplantation: A single-center experience. Pediatric Transplant., 2019, no. 4 (23), pp. e13449. doi:10.1111/petr.13449.

28. Vitin A.A., Tomescu D., Azamfirei L. Hemodynamic optimization strategies in anesthesia care for liver transplantation. Liver Cirrhosis – Update and Current Challenges, 2017, pp. 173‒195. doi:10.5772/intechopen.68416.

29. Whiting D., Di Nardo J.A. TEG and ROTEM: technology and clinical applications. Am. J. Hematol., 2014, no. 2 (89), pp. 228–232. doi:10.1002/ajh.23599.

30. Wikkelso A., Wetterslev J., Moller A.M. et al. Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding. The Cochrane Database of Systematic Reviews, 2016, no. 8 (2016), pp. CD007871. doi:10.1002/14651858. CD007871.pub3.

31. Zulueta M.M.L., Chyan C.L., Hung S.C. Structural analysis of synthetic heparan sulfate oligosaccharides with fibroblast growth factors and heparin-binding hemagglutinin. Curr. Opin. Struct. Biol., 2018, vol. 50, pp. 126–133. doi:10.1016/j. sbi.2018.03.003.