Факторы риска тромботических осложнений и антитромботическая терапия кардиохирургических пациентов детского возраста

Современное развитие кардиохирургической помощи пациентам детского и неонатального возраста претерпевает стремительный рост. Выполняемые сложные этапные реконструктивные вмешательства, частое использование инвазивного мониторинга сопряжены с высоким риском развития венозных и артериальных тромбозов.

Кардиохирургический пациент является по-своему уникальным, поскольку требует контролируемой антикоагуляции во время искусственного кровообращения. И конечно же большинство кардиохирургических пациентов предполагает антитромботическое сопровождение на протяжении всего периоперационного периода. Помимо медикаментозной поддержки оправданным считается реализация мер по управлению сосудистым доступом с целью минимизации рисков тромбоэмболических осложнений, которые могут оказывать влияние как на функциональный статус пациентов, так и на общую и межстадийную летальность.

Целью настоящего обзора явилась систематизация имеющихся данных о факторах риска, способствующих развитию тромботических осложнений у пациентов с врождёнными пороками сердца.

Информационный поиск проводился с использованием Интернет-ресурсов (PubMed, Web of Science, eLibrary. ru); в анализ были включены литературные источники за период 2015–2020 гг. По результатам проведённого анализа литературных данных были описаны возраст-ассоциированные особенности системы гемостаза у пациентов с врождёнными пороками сердца, и связанные с патофизиологией дефектов и выполняемых реконструктивных вмешательств. Освещены вопросы патофизиологии унивентрикулярных врождённых пороков сердца и сопряжённые с ними факторы риска развития тромбоза. Кроме того, обсуждаются аспекты интраоперационного антитромботического сопровождения, а также меры по профилактике тромбоэмболических осложнений в данной популяции пациентов.

Координированные действия гематологов, кардиологов, анестезиологов и кардиохирургов позволят достичь тонкого баланса между рисками кровотечения и тромбоза в популяции пациентов детского возраста, подвергаемых сердечно-сосудистым вмешательствам. 

1. Liu Y, Chen S, Zühlke L, Black GC, Choy M-K, Li N, et al. Global birth prevalence of congenital heart defects 1970-2017: Updated systematic review and meta-analysis of 260 studies. IntJ Epidemiol. 2019; 48(2): 455-463. doi: 10.1093/ije/dyz009

2. Gilboa SM, Devine OJ, Kucik JE, Oster ME, Riehle-Colarusso T, Nembhard WN, et al. Congenital heart defects in the United States: Estimating the magnitude of the affected population in 2010. Circulation. 2016; 134(2): 101-109. doi: 10.1161/CIRCULATIONAHA.115.019307

3. Карахалис Н.Б., Ефимочкин Г.А., Шадрин А.К., Синьков С.В. Антитромботическая терапия у детей. Анестезиология и реаниматология. 2018; 63(1): 46-53. doi: 10.18821/0201-7563-2018-63-1-46-55

4. Young G, Male C, van Ommen CH. Anticoagulation in children: Making the most of little patients and little evidence. Blood Cells Mol Dis. 2017; 67: 48-53. doi: 10.1016/j.bcmd.2017.05.003

5. Romantsik O, Bruschetti M, Zappettini S, Ramenghi LA, Calevo MG. Heparin for the treatment of thrombosis in neonates. Cochrane Database Syst Rev. 2016; 11(11): CD012185. doi: 10.1002/14651858.CD012185.pub2

6. Williams MD, Chalmers EA, Gibson BES. The investigation and management of neonatal haemostasis and thrombosis. Br J Haematol. 2002; 119(2): 295-309. doi: 10.1046/j.1365-2141.2002.03674.x

7. Chin VM, Holland M-LL, Parker MM, Holtby HM, O’Leary JD. Antithrombin activity and heparin response in neonates and infants undergoing congenital cardiac surgery: A retrospective cohort study. Can J Anaesth. 2016; 63(1): 38-45. doi: 10.1007/s12630-015-0500-2

8. Toulon P. Developmental hemostasis: laboratory and clinical implications. Int J Lab Hem. 2016; 38(1): 66-77. doi: 10.1111/ijlh.12531

9. Glatz AC, Keashen R, Chang J, Balsama L-A, Dori Y, Gillespie MJ, et al. Outcomes using a clinical practice pathway for the management of pulse loss following pediatric cardiac catheterization. Catheter Cardiovasc Interv. 2015; 85(1): 111-117. doi: 10.1002/ccd.25686

10. Alexander J, Yohannan T, Abutineh I, Agrawal V, Lloyd H, Zurakowski D, et al. Ultrasound-guided femoral arterial access in pediatric cardiac catheterizations: A prospective evaluation of the prevalence, risk factors, and mechanism for acute loss of arterial pulse. Catheter Cardiovasc Interv. 2016; 88(7): 1098-1107. doi: 10.1002/ccd.26702

11. Bacciedoni V, Attie M, Donato H, Comité Nacional de Hematología, Oncología y Medicina Transfusional. Thrombosis in newborn infants. Arch Argent Pediatr. 2016; 114(2): 159-166. doi: 10.5546/aap.2016.eng.159

12. Silvey M, Brandão LR. Risk factors, prophylaxis, and treatment of venous thromboembolism in congenital heart disease patients. Front Pediatr. 2017; 19(5): 146. doi: 10.3389/fped.2017.00146

13. Biss TT. Venous thromboembolism in children: is it preventable? Semin Thromb Hemost. 2016; 42(6): 603-611. doi: 10.1055/s-0036-1581100

14. Haley KM. Neonatal venous thromboembolism. Front Pediatr. 2017; 5: 136. doi: 10.3389/fped.2017.00136

15. Карахалис Н.Б., Каде А.Х., Братова А.В. Возраст-зависимые изменения параметров системы гемостаза у пациентов педиатрической популяции кардиохирургического профиля. Инновационная Медицина Кубани. 2020; 17(1): 23-29. doi: 10.35401/2500-0268-2020-17-1-23-29

16. Sherrod BA, McClugage SG, Mortellaro VE, Aban IB, Rocque BG. Venous thromboembolism following inpatient pediatric surgery: Analysis of 153,220 patients. J Pediatr Surg. 2019; 54(4): 631-639. doi: 10.1016/j.jpedsurg.2018.09.017

17. Hehir DA, Easley RB, Byrnes J. Noncardiac challenges in the cardiac ICU: Feeding, growth, and gastrointestinal complications, anticoagulation, and analgesia. World J Pediatr Congenit Heart Surg. 2016; 7(2): 199-209. doi: 10.1177/2150135115615847

18. Emani S, Trainor R, Zurakowski D, Baird CW, Fynn-Thompson FE, Pigula FA, et al. Aspirin unresponsiveness predicts thrombosis in high-risk pediatric patients after cardiac surgery. J Thorac Cardiovasc Surg. 2014; 148(3): 810-814. doi: 10.1016/j.jtcvs.2014.06.016

19. Callegari A, Christmann M, Albisetti M, Kretschmar O, Quandt D. Single ventricle physiology patients and coagulation abnormalities: Is there a relationship with hemodynamic data and postoperative course? A pilot study. Clin Appl Thromb Hemost. 2019; 25: 1-8. doi: 10.1177/1076029619888695

20. Bailly D, Boskkov L, Zubair M, Rogers VJ, Lantz G, Armsby L, et al. Congenital cardiac lesions involving systolic flow abnormalities are associated with platelet dysfunction in children. Ann Thorac Surg. 2014; 98(4): 1419-1424. doi: 10.1016/j.athoracsur.2014.05.035

21. Loeffelbein F, Funk D, Nakamura L, Zieger B, Grohmann J, Siepe M, et al. Shear-stress induced acquired von Willebrand syndrome in children with congenital heart disease. Interact Cardiovasc Thorac Surg. 2014; 19: 926-932. doi: 10.1093/icvts/ivu.305

22. Romlin B, Söderlund F, Wåhlander H, Nilsson B, Baghaei F, Jeppsson A. Platelet count and function in paediatric cardiac surgery: A prospective observational study. Br J Anaesth. 2014; 113(5): 847-854. doi: 10.1093/bja/aeu194

23. Attard C, Huang J, Monagle P, Ignjatovic V. Pathophysiology of thrombosis and anticoagulation post Fontan surgery. Thromb Res. 2018; 172: 204-213. doi: 10.1016/j.thromres.2018.04.011

24. Bhatt MD, Paes BA, Chan AK. How to use unfractionated heparin to treat neonatal thrombosis in clinical practice. Blood Coagul Fibrinolysis. 2016; 27(6): 605-614. doi: 10.1097/MBC.0000000000000469

25. Massicotte MP, Bauman M. Developmental hemostasis and ventricular assist devices: A troubled relationship. Prog Pediatr Cardiol. 2017; 47: 14-20. doi: 10.1016/j.ppedcard.2017.08.006

26. Sasikumar N, Hermuzi A, Fan CS, Lee K-J, Chaturvedi R, Hickey E, et al. Outcomes of Blalock-Taussig shunts in current era: A single center experience. Congenit Heart Dis. 2017; 12(6): 808- 814. doi: 10.1111/chd.12516

27. Bove T, Vandekerckhove K, Panzer J, De Groote K, De Wolf D, François K. Disease-specific outcome analysis of palliation with the modified Blalock-Taussig shunt. World J Pediatr Congenit Heart Surg. 2015; 6(1): 67-74. doi: 10.1177/2150135114558690

28. Perez ER, Riveros R. Mathematical analysis and physical profile of Blalock-Taussig shunt and Sano modification procedure in hypoplastic left heart syndrome: Review of the literature and implications for the anesthesiologist. Semin Cardiothorac Vasc Anesth. 2017; 21(2): 152-164. doi: 10.1177/1089253216687857

29. Agarwal A, Firdouse M, Brar N, Yang A, Lambiris P, Chan AK, et al. Incidence and management of thrombotic and thromboembolic complications following the Norwood procedure: A literature review. Clin Appl Thromb Hemost. 2017; 23(8): 911-921. doi: 10.1177/1076029616679506

30. Agarwal A, Firdouse M, Brar N, Yang A, Lambiris P, Chan AK, et al. Incidence and management of thrombotic and thromboembolic complications following the superior cavopulmonary anastomosis procedure: A literature review. Clin Appl Thromb Hemost. 2018; 24(3): 405-415. doi: 10.1177/1076029617739702

31. Manlhiot C, Brandão LR, Schwartz SM, Sivarajan VB, Williams S, Collins TH, et al. Management and outcomes of patients with occlusive thrombosis after pediatric cardiac surgery. J Pediatr. 2016; 169: 146-153. doi: 10.1016/j.jpeds.2015.10.046

32. Firdouse M, Agarwal A, Chan AK, Mondal T. Thrombosis and thromboembolic complications in Fontan patients: A literature review. Clin Appl Thromb Hemost. 2014; 20(5): 484-492. doi: 10.1177/1076029613520464

33. Idorn L, Jensen AS, Juul K, Reimers JI, Johansson PI, Sørensen KE, et al. Thromboembolic complications in Fotan patients: Population-based prevalence and exploration of the etiology. Pediatr Cardiol. 2013; 34(2): 262-272. doi: 10.1007/s00246-012-0431-4

34. McCrindle BW, Manlhiot C, Cochrane A, Roberts R, Hughes M, Szechtman B, Weintraub R, et al. Factors associated with thrombotic complications after the Fontan procedure: A secondary analysis of a multicentre, randomized trial of primary thromboprophylaxis for 2 years after the Fontan procedure. J Am Coll Cardiol. 2013; 61(3): 346-353. doi: 10.1016/j.jacc.2012.08.1023

35. Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med. 2008; 358(8): 771-783. doi: 10.1056/NEJMoa0707571

36. Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano C, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med. 2008; 358(8): 784-793. doi: 10.1056/NEJMoa0707768

37. Pasquali SK, Li JS, He X, Jacobs ML, O’Brien SM, Hall M, et al. Comparative analysis of antifibrinolytic medications in pediatric heart surgery. J Thorac Cardiovasc Surg. 2012; 143(3): 550-557. doi: 10.1016/j.jtcvs.2011.06.048

38. Taroni D, Rahe C, Cybulski KA. Use of antifibrinolytics in pediatric cardiac surgery: Where are we now? Paediatr Anaesth. 2019; 29(5): 435-440. doi: 10.1111/pan.13533 39. Dhir A. Antifibrinolytics in cardiac surgery. Ann Card Anaesth. 2013; 16(2): 117-125. doi: 10.4103/0971-9784-109749

39. Nouraei SM. What are the optimal dose of administration and time of drainage for topical tranexamic acid in patients undergoing cardiac surgery? Korean J Thorac Cardiovasc Surg. 2017; 50(6): 477-478. doi: 10.5090/kjtcs.2017.50.6.477

40. Faraoni D, Goobie SM. New insights about the use of tranexamic acid in children undergoing cardiac surgery: From pharmacokinetics to pharmacodynamics. Anesth Analg. 2012; 117(4): 760-762. doi: 10.1213/ANE.0b013e3182a22278

41. Myles PS, Smith JA, Painter T. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med. 2017; 376(19): 1893. doi: 10.1056/NEJMc1703369

42. Wesley MC, Pereira LM, Scharp LA, Emani SM, McGowan FX Jr., DiNardo JA. Pharmacokinetics of tranexamic acid in neonates, infants, and children undergoing cardiac surgery with cardiopulmonary bypass. Anesthesiology. 2015; 122(4): 746- 758. doi: 10.1097/0000000000000570

43. Eaton MP, Alfieris GM, Sweeney DM, Angona RE, Cholette JM, Venuto C, et al. Pharmacokinetics of ε-aminocapronic acid in neonates undergoing cardiac surgery with cardiopulmonary bypass. Anesthesiology. 2015; 122(5): 1002-1009. doi: 10.1097/ALN.0000000000000616

44. Rastogi A, Agarwal A, Goyal P, Priya V, Dhiraaj S, Haldar R. Ultrasound guided internal jugular vein cannulation in infants: Comparative evaluation of novel modified short axis out of plane approach with conventional short axis of plane approach. Indian J Anaesth. 2018; 62(3): 208-213. doi: 10.4103/ija.IJA_676_17

45. Kutty S, Jacobs ML, Thompson WR, Danford DA. Fontan circulation of the next generation: Why it’s necessary, what it might look like. J Am Heart Assoc. 2020; 9(1): e013691. doi: 10.1161/JAHA.119.013691

46. Murphy LD, Benneyworth BD, Moser EAS, Hege KM, Valentine KM, Mastropietro CW. Analysis of patient characteristics and risk factors for thrombosis after surgery for congenital heart disease. Pediatr Crit Care Med. 2018; 19(12): 1146-1152. doi: 10.1097/PCC.0000000000001743

47. Mir A, Frank S, Journeycake J, Wolovitis J, Guleserian K, Heistein L, et al. Aspirin resistance in single-ventricle physiology: Aspirin prophylaxis is not adequate to inhibit platelets in the immediate postoperative period. Ann Thorac Surg. 2015; 99(6): 2158- 2164. doi: 10.1016/j.athoracsur.2015.02.026

48. Saini A, Joshi AD, Cowan KM, et al. High acetylsalicylic acid dosing in infants after modified Blalock-Taussig shunt. Cardiol Young. 2019; 29(3): 389-397. doi: 10.1017/S1047951118002536

49. Hanke CA, Stiller B, Nakamura L, et al. Prophylactic use of clopidogrel in paediatric cardiac patients. Klin Padiatr. 2012; 224(3): 166-169. doi: 10.1055/s-0032-1306345

50. Wessel D, Berger F, Li J, Dähnert I, Rakhit A, Fontecave S, et al. Clopidogrel in infants with systemic-to-pulmonary shunts. N Engl J Med. 2013; 368(25): 2377-2384. doi: 10.1056/NEJMoa1114588

51. Lander H, Zammert M, FitzGerald D. Anticoagulation management during cross-clamping and bypass. Best Pract Res Clin Anaesthesiol. 2016; 30(3): 359-370. doi: 10.1016/j.bpa.2016.07.002

52. Monagle P, Newall F. Management of thrombosis in children and neonates: Practical use of anticoagulants in children. Hematol Educ Program. 2018; 2018(1): 399-404. doi: 10.1182/asheducation-2018.1.399

53. Klaassen ILM, Sol JJ, Suijker MH, Fijnvandraat K, van de Wetering MD, van Ommen CH. Are Low-Molecular-Weight-Heparins safe and effective in children? A systematic review. Blood Rev. 2019; 33: 33-42. doi: 10.1016/j.blre.2018.06.003

54. Radulescu VC. Anticoagulation therapy in children. Semin Thromb Hemost. 2017; 43(8): 877-885. doi: 10.1055/s-0036-1598004

55. Payne RM, Burns KM, Glatz AC, Li D, Li X, Monagle P, et al. A multi-national trial of a direct oral anticoagulant in children with cardiac disease: Design and rationale of the Safety of ApiXaban on Pediatric Heart disease On the prevention of Embolism (SAXOPHONE) study. Am Heart J. 2019; 217: 52-63. doi: 10.1016/j.ahj.2019.08.002

56. Esch JJ, Hellinger A, Friedman KG, VanderPluym CJ. Apixaban for treatment of intracardiac thrombosis in children with congenital heart disease. Interact Cardiovasc Thorac Surg. 2020; 30(6): ivaa041. doi: 10.1093/icvts/ivaa041

57. Paden ML, Rycus PT, Thiagarajan RR, ELSO Registry. Update and outcomes in extracorporeal life support. Semin Perinatol. 2014; 38(2): 65-70. doi: 10.1053/j.semperi.2013.11.002

58. Stocker CF, Horton SB. Anticoagulation strategies and difficulties in neonatal and paediatric extracorporeal membrane oxygenation (ECMO). Perfusion. 2016; 31(2): 95-102. doi: 10.1177/0267659115590626

59. Saini A, Spinella PC. Management of anticoagulation and hemostasis for pediatric extracorporeal membrane oxygenation. Clin Lab Med. 2014; 34(3): 655-673. doi: 10.1016/j.cll.2014.06.014

60. Cashen K, Meert K, Dalton H. Anticoagulation in neonatal ECMO: An enigma despite a lot of effort! Front Pediatr 2019; 13(7): 366. doi: 10.3389/fped.2019.00366

61. Dalton HJ, Garcia-Filion P, Holubkov R, Moler FW, Shanley T, Heidemann S, et al. Association of bleeding and thrombosis with outcome in extracorporeal life support. Pediatr Crit Care Med. 2015; 16(2): 167-174. doi: 10.1097/PCC.0000000000000317

62. Barbaro RP, Paden ML, Guner YS, Raman L, Ryerson LM, Alexander P, et al. Pediatric Extracorporeal Life Support Organization Registry International Report 2016. ASAIO J. 2017; 63(4): 456-463. doi: 10.1097/MAT.0000000000000603

63. Fraser CD Jr., Jaquiss RDB, Rosenthal DN, Humpl T, Canter CE, Blackstone EH, et al. Prospective trial of a pediatric ventricular assist device. N Engl J Med. 2012; 367(6): 532-541. doi: 10.1056/NEJMoa1014164

64. Rosenthal DN, Lancaster CA, McElhinney DB, Chen S, Stein ML, Lin A, et al. Impact of a modified anti-thrombotic guideline on stroke in children supported with a pediatric ventricular assist device. J Heart Lung Transplant. 2017; 36(11): 1250-1257. doi: 10.1016/j.healun.2017.05.020

65. Steiner ME, Bomgaars LR, Massicotte MP, Berlin Heart EXCOR Pediatric VAD IDE study investigators. Antithrombotic therapy in a prospective trial of a pediatric ventricular assist device. ASAIOJ. 2016; 62(6): 719-727. doi: 10.1097/MAT.0000000000000434

66. Maltais S, Kilic A, Nathan S, Keebler M, Emani S, Ransom J, et al. Prevention of HeartMate II pump thrombosis through clinical management: The PREVENT multi-center study. J Heart Lung Transplant. 2017; 36(1): 1-12. doi: 10.1016/j.healun.2016.10.001

67. Chang YM, Huang SC, Chen SJ, Wu E-T, Wang J-K, Wu M-H. An usual cause of chylothorax after Norwood stage one reconstruction. Thorac Cardiovasc Surg. 2009; 57(2): 120-122. doi: 10.1055/s-2008-1038668

68. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Torbicki A, Simonneau G, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Force for the Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur HeartJ. 2016; 37(1): 67-119. doi: 10.1093/eurheartj/ehv317

69. Hansmann G, Apitz C, Abdul-Khaliq H, Alastalo T-P, Beerbaum P, Bonnet D, et al. Executive Summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. European Paediatric Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016; 102(2): ii86-ii100. doi: 10.1136/heartjnl-2015-309132

70. Irdem A, Baspinar O, Kervancioglu M, Kilinç M. Intracardiac thrombus in children with dilated cardiomyopathy. Turk Kardiol Dern Ars. 2014; 42(2): 161-167. doi: 10.5543/tkda.2014.81593

71. Chen K, Williams S, Chan AKC, Mondal TK. Thrombosis and embolism in pediatric cardiomyopathy. Blood Coagul Fibrinolysis. 2013; 24(3): 221-230. doi: 10.1097/MBC.0b013e32835bfd85

72. Hepponstall M, Chan A, Monagle P. Anticoagulation therapy in neonates, children and adolescents. Blood Cells Mol Dis. 2017; 67: 41-47. doi: 10.1016/j.bcmd.2017.05.008

73. Moudgil A. Renal venous thrombosis in neonates. Curr Pediatr Rev. 2014; 10(2): 101-106. doi: 10.2174/15733963100214 0513101845

74. Bidadi B, Nageswara Rao AA, Kaur D, Khan SP, Rodriguez V. Neonatal renal vein thrombosis: Role of anticoagulation – an institutional review. Pediatr Hematol Oncol. 2016; 33(1): 59-66. doi: 10.3109/08880018.2015.1132801