• Thrombophilia in children: what and when is it necessary to test

Thrombophilia in children: what and when is it necessary to test

SOVREMENNAYA PEDIATRIYA.2018.7(95):39-46; doi 10.15574/SP.2018.95.39

Melnik A. A.
Specialized medical center «Optima-pharm», Kyiv, Ukraine

In recent decades an increase in the incidence of venous thromboembolism (VTE) and its connection with hereditary thrombophilia leading to increased thrombotic risks has been observed in children in all age categories. In the study of hereditary thrombophilia the most common tests are ATIII, protein C, protein S, factor V Leiden, and the mutation of factor II prothrombin. Testing of hereditary thrombotic risk factors should be individualized. Consultation and management of patients with VTE and identified markers of thrombophilia should be carried out by an experienced hematologist or specialist in the field of hemostasis.

Key words: thrombophilia, children, venous thromboembolism, risk factors, laboratory methods.


1. Albisetti M, Kellenberger CJ, Bergstrasser E et al. (2013). Port-acathrelated thrombosis and postthrombotic syndrome in pediatric oncology patients. J Pediatr. 163:340–6. https://doi.org/10.1016/j.jpeds.2013.06.076; PMid:23992671

2. Alioglu B, Avci Z, Tokel K, Atac FB, Ozbek N. (2008). Thrombosis in children with cardiac pathology: analysis of acquired and inherited risk factors. Blood Coagul Fibrinolysis. 19:294–304. https://doi.org/10.1097/MBC.0b013e3282fe73b1; PMid:18469551

3. Andrew M, David M, Adams M et al. (1994). Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood.83(5):1251–1257. PMid:8118029

4. Athale U, Chan KC. (2007). Thromboembolic complications in pediatric hematologic malignancies. Semin Thromb Hemost. 33:416–26. https://doi.org/10.1055/s-2007-976176; https://doi.org/10.1055/s-2007-976177; PMid:17525899

5. Athale U, Siciliano S, Thabane L, Pai N, Cox S, Lathia A, Khan A, Armstrong A, Chan AK. (2008). Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer.51:792–7. https://doi.org/10.1002/pbc.21734; PMid:18798556

6. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. (1994). Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 369:64–67. https://doi.org/10.1038/369064a0; PMid:8164741

7. Bonduel M, Sciuccati G, Hepner M, Torres AF, Pieroni G, Frontroth JP. (1999, Aug.). Prethrombotic disorders in children with arterial ischemic stroke and sinovenous thrombosis. Arch Neurol. 56(8):967–71. https://doi.org/10.1001/archneur.56.8.967; PMid:10448802

8. Boulet SL, Grosse SD, Thornburg CD, Yusuf H, Tsai J, Hooper WC. (2012). Trends in venous thromboembolism_related hospitalizations, 1994–2009. Pediatrics.130(4):e812-e820. https://doi.org/10.1542/peds.2012-0267; PMid:22987875 PMCid:PMC4527304

9. Branson HE, Katz J, Marble R, Griffin JH. (1983). Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet. 2:1165–1168. https://doi.org/10.1016/S0140-6736(83)91216-3

10. Buller HR, Sohne M, Middeldorp S. (2005). Treatment of venous thromboembolism. J Thromb Haem. 3:1554–1560. https://doi.org/10.1111/j.1538-7836.2005.01414.x; PMid:16102019

11. Casado-Flores J, Barja J, Martino R, Serrano A, Valdielso A. (2001, Jan.) Complications of central venous catheterization in critically ill children. Pediatr Crit Care Med. 2(1):57–62. https://doi.org/10.1097/00130478-200101000-00012; PMid:12797890

12. Chalmers EA. (2006). Epidemiology of venous thromboembolism in neonates and children. Thromb Res. 118(1):3–12. https://doi.org/10.1016/j.thromres.2005.01.010; PMid:16709473

13. Colman RW, Marder VJ, Clowes AW et al. (2006). Hemostasis and thrombosis. Basic principles and clinical practice. Philadelphia:1827. https://doi.org/10.1111/j.1538-7836.2006.02072.x; PMid:16961622

14. Comp PC, Esmon CT. (1984). Recurrent venous thromboembolism in patients with a partial deficiency of protein S. New England Journal of Medicine. 311:1525–1528. https://doi.org/10.1056/NEJM198412133112401; PMid:6239102

15. Cathie K, Levin M, Faust SN. (2008). Drug use in acute meningococcal disease. Arch Dis Child Educ Pract Ed 93:151–158. https://doi.org/10.1136/adc.2007.127696; PMid:18809693

16. De Bastos M, Stegeman BH, Rosendaal FR, Van Hylckama Vlieg A, Helmerhorst FM, Stijnen T, Dekkers OM. (2014). Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev. 3:3. https://doi.org/10.1002/14651858.CD010813.pub2

17. De Stefano V, Rossi E. (2013). Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups. Thromb Haemost. 110:697–705. https://doi.org/10.1160/TH13-01-0011; PMid:23846575

18. Egeberg O. (1965). Inherited antithrombin deficiency causing thrombophilia. Thrombosis et Diathesis Haemorrhagica. 13:516–530. https://doi.org/10.1055/s-0038-1656297; PMid:14347873

19. Eltayeb AA, Askar GA, Abu Faddan NH, Kamal TM. (2015). Prothrombotic risk factors and antithrombotic therapy in children with ischemic stroke. Ther Adv Neurol Disord. 8:71–81. https://doi.org/10.1177/1756285615573690; PMid:25922619 PMCid:PMC4356662

20. Faust S, Heyderman R, Levin M. (2000). Disseminated intravascular coagulation and purpura fulminans secondary to infection. Baillieres Best Pract Res Clin Haematol. 13(2):179–97. https://doi.org/10.1053/beha.2000.0067; PMid:10942620

21. Faust SN, Hevderman RS, Levin. (2001, Jul). Coagulation in severe sepsis: a central role for thrombomodulin and activated protein C. Crit Care Med. 29 (7):62–7. https://doi.org/10.1097/00003246-200107001-00022

22. Faust SN, Levin M, Harrison OB et al. (2001, Aug. 9). Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med. 345(6):408–16. https://doi.org/10.1056/NEJM200108093450603; PMid:11496851

23. Grace RF, Dahlberg SE, Neuberg D, Sallan SE, Connors JM, Neufeld EJ, Deangelo DJ, Silverman LB. (2011). The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol. 152:452–9. https://doi.org/10.1111/j.1365-2141.2010.08524.x; PMid:21210774 PMCid:PMC5763913

24. Green J, Doughtly L, Kaplan SS. et al. (2002). The tissue factor and plasminogen activator inhibitor type-1 response in pediatric sepsis-induced multiple organ failure. Throm Haemost. 87: 218–223. https://doi.org/10.1055/s-0037-1612976; PMid:11858480

25. Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. (1981). Deficiency of protein C in congenital thrombotic disease. Journal of Clinical Investigation. 68. 1370–1373. https://doi.org/10.1172/JCI110385

26. Hanmod SS, Jesudas R, Kulkarni R, Chitlur M. (2016). Neonatal hemostatic disorders: issues and challenges. Semin Thromb Hemost. 42:741–51. https://doi.org/10.1055/s-0036-1593415; PMid:27706533

27. Jordan FL, Nandorff A. (1956). The familial tendency in thromboembolic disease. Acta Medica Scandinavica. 156:267–275. https://doi.org/10.1111/j.0954-6820.1956.tb00084.x; PMid:13394174

28. Kerlin BA, Ayoob R, Smoyer WE. (2012). Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease. Clin J Am Soc Nephrol. 7:513–20. https://doi.org/10.2215/CJN.10131011; PMid:22344511 PMCid:PMC3302669

29. Klaassen ILM, van Ommen H, Middeltorp S. (2015). Manifestations and clinical impact of pediatric inherited thrombophilia. Blood. 125:1073–7. https://doi.org/10.1182/blood-2014-05-536060; PMid:25564402

30. Michot C, Garnier A, Neve M, Naudin J, Tsapis M, Dauger S. (2011). Neonatal renal venous thrombosis: the recent experience of Robert-Debre Hospital. Arch Pediatr. 18:1055–61. https://doi.org/10.1016/j.arcped.2011.07.011; PMid:21889320

31. Minnema MC, Pajkrt D, Wuillemin WA et al. (1998, Nov. 1). Activation of Clotting Factor XI Without Detectable Contact Activation in Experimental Human Endotoxemia. Blood. 92;9:3294–3301. PMid:9787166

32. Mitchell LG, Andrew M, Hanna K et al. (2003). A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase:results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer. 97: 508–16. https://doi.org/10.1002/cncr.11042; PMid:12518376

33. Moll S. (2006). Thrombophilias – practical implications and testing caveats. Journal of Thrombosis and Thrombolysis. 21:7–15. https://doi.org/10.1007/s11239-006-5570-0; PMid:16475036

34. Nelson RM, Botkjin JR, Kodish ED, Levetown M, Truman JT, Wilfond BS, Harrison CE, Kazura A, Krug 3rd E, Schwartz PA, Donovan GK, Fallat M, Porter IH, Steinberg D. (2001). Ethical issues with genetic testing in pediatrics. Pediatrics. 107:1451–1455. https://doi.org/10.1542/peds.107.6.1451

35. Nowak-Gottl U, von Krie R, Gobel U. (1997). Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed. 76(3):163–167. https://doi.org/10.1136/fn.76.3.F163

36. Nowak-Gottl U, Strater R, Heinecke A et al. (1999). Lipoprotein (a) and genetic polymorphism of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood.94:3678–82. PMid:10572079

37. Park CK, Paes BA, Nagel K et al. (2016, Jul 29). Neonatal central venous catheter thrombosis: diagnosis, management, and outcome. Blood Coagul Fibrinolysis.

38. Patnaik MM, Moll S. (2008, Nov.). Inherited antithrombin deficiency: a review. Haemophilia.14(6):1229–39. https://doi.org/10.1111/j.1365-2516.2008.01830.x; PMid:19141163

39. Paz-Priel I, Long L, Helman LJ, Mackall CL, Wayne AS. (2007). Thromboembolic events in children and young adults with pediatric sarcoma. J Clin Oncol. 25:1519–24. https://doi.org/10.1200/JCO.2006.06.9930; PMid:17442994

40. Pillai P, Bonny AE, O'Brien SH. (2013). Contraception-related venous thromboembolism in a pediatric institution. J Pediatr Adolesc Gynecol.26:186–8. https://doi.org/10.1016/j.jpag.2013.02.009; PMid:23566795

41. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. (1996). A common genetic variation in the 3ў-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 88:3698–3703. PMid:8916933

42. Raffini L, Huang YS, Witmer C, Feudtner C. (2009). Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics.124(4):1001–1008. https://doi.org/10.1542/peds.2009-0768; PMid:19736261

43. Revel-Vilk, Chan A, Bauman M, Massicotte P. (2003). Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost. 1:915–21. https://doi.org/10.1046/j.1538-7836.2003.00158.x; PMid:12871356

44. Saracco P, Bagna R, Gentilomo C et al. (2016). Neonatal Working Group of Registro Italiano Trombosi Infantili (RITI). Clinical Data of Neonatal Systemic Thrombosis. J Pediatr. 171:60–61. https://doi.org/10.1016/j.jpeds.2015.12.035; PMid:26787378

45. Srur E, Vargas C, Salas S, Parra JA, Bianchi V, Mezzano D et al. (2004, Dec.). Primary thrombophilia. Report of 93 cases and 12 asymptomatic relatives. Rev Med Chil. 132(12):1466–73. PMid:15743157

46. Tormene D, Simioni P, Prandoni P et al. (2002). The incidence of venous thromboembolismin thrombophilic children: a prospective cohort study. Blood. 100:2403–5. https://doi.org/10.1182/blood-2002-04-1186; PMid:12239149

47. Tormene D, Gavossos S, Rosette V, Simioni P. (2006). Thrombosis and thrombophilia in children. Semin Thromb Hemost.32:724–87. https://doi.org/10.1055/s-2006-951457; PMid:17024600

48. Tosetto A, Iorio A, Marcucci M et al. (2012). Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost. 10:1019–25. https://doi.org/10.1111/j.1538-7836.2012.04735.x; PMid:22489957

49. Tormene D, Pagnan A, Prandoni P, Simioni P. (2004). Screening for thrombophilia in children: a puzzling decision with unclear implications. J Thromb Haemost; 2:1193–4. https://doi.org/10.1111/j.1538-7836.2004.00755.x; PMid:15219210

50. Tourovska K, Dulicek P, Vanicek H, Slavik Z. (2000). Thrombosis in childhood – etiologic role of congenital thrombolitic conditions. Cas Lek Cek Mar 15. 139(5):137–42.

51. Tuckuviene R, Christensen AL, Chan AK, Athale U. (2012). Body mass index and thromboembolism in children with hematologic malignancies. Pediatr Blood Cancer.59:320–2. https://doi.org/10.1002/pbc.23355; PMid:22223230

52. Van Deventer SJ, Buller HR, ten Cate JW et al. (1990, Dec.). Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood.15;76 (12):2520–6.

53. Van Ommen CH, Heijboer H, Bu uller HR, Hirasing RA, Heijmans HS, Peters M. (2001). Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands. J Pediatr.139(5):676–681. https://doi.org/10.1067/mpd.2001.118192; PMid:11713446

54. Van Ommen CH, Middeldorp S. (2011). Thrombophilia in childhood: to test or not to test? Semin Thromb Hemost. 37:794–801. https://doi.org/10.1055/s-0031-1297170; PMid:22187402

55. Voorberg J, Roelse J, Koopman R, Buller H, Berends F, ten Cate JW, Mertens, K, van Mourik JA. (1994). Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet. 343:1535–1536. https://doi.org/10.1016/S0140-6736(94)92939-4

56. Wertz DC. (2003). Ethical, social and legal issues in pharmacogenomics. The Pharmacogenomics Journal. 3:194–196. https://doi.org/10.1038/sj.tpj.6500188; PMid:12931132

57. Yang JY, Chan AK. (2013). Pediatric thrombophilia. Pediatr Clin North Am. 60: 1443–62. https://doi.org/10.1016/j.pcl.2013.09.004; PMid:24237981

Article received: May 23, 2018. Accepted for publication: Nov 03, 2018.