Advertisement

Neonatology pp 1431-1453 | Cite as

Pathophysiology of Coagulation and Deficiencies of Coagulation Factors in Newborn

  • Paola Saracco
  • Rodney P. A. Rivers
Reference work entry

Abstract

The hemostatic system of the neonate is dynamically evolving and different from older children and very different from the adult. The main points of difference between neonatal and adult hemostasis are as follows:
  • Platelets show significant differences in function.

  • Bleeding times are shorter through increased activity of von Willebrand factor (VWF).

  • Many procoagulant and inhibitor levels are gestationally dependent.

  • Reduced procoagulant and inhibitor reserve.

  • Relatively impaired fibrinolysis.

  • This neonatal coagulopathy impacts both the diagnosis and management of hemorrhagic or thrombotic events in neonates. Diagnostic laboratories should use age-analyzer and reagent-appropriate references ranges.

References

  1. Andrew M, Paes B, Milner R et al (1987) Development of the human coagulation system in the full-term infant. Blood 70(1):165–172PubMedGoogle Scholar
  2. Andrew BM, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L (1992) Maturation of the hemostatic system during childhood. Blood 80(8):1998–2005PubMedGoogle Scholar
  3. Asselta R, Peyvandi F (2009) Factor V deficiency. Semin Thromb Hemost 35(4):382–389.  https://doi.org/10.1055/s-0029-1225760CrossRefPubMedGoogle Scholar
  4. Attard C, van der Straaten T, Karlaftis V, Monagle P, Ignjatovic V (2013) Developmental haemostasis: age-specific differences in the quantity of haemostatic proteins. J Thromb Haemost 11(10).  https://doi.org/10.1111/jth.12372
  5. Baker-Groberg SM, Lattimore S, Recht M, McCarty OJT, Haley KM (2016) Assessment of neonatal platelet adhesion, activation, and aggregation. J Thromb Haemost 14(4):815–827.  https://doi.org/10.1111/jth.13270CrossRefPubMedPubMedCentralGoogle Scholar
  6. Barnard DR, Simmons MA, Hathaway WE (1979) Coagulation studies in extremely premature infants. Pediatr Res 13(12):1330–1335CrossRefGoogle Scholar
  7. Bolton-Maggs PHB, Perry DJ, Chalmers EA et al (2004) The rare coagulation disorders – review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia 10(5):593–628.  https://doi.org/10.1111/j.1365-2516.2004.00944.xCrossRefPubMedGoogle Scholar
  8. Chalmers EA, Williams M, Brennand J, Liesner R, Collins P, Richards M (2011) Guideline on the management of haemophilia in the fetus and neonate. Br J Haematol 154(2):208–215.  https://doi.org/10.1111/j.1365-2141.2010.08545.xCrossRefPubMedGoogle Scholar
  9. Clarke P, Mitchell SJ, Wynn R et al (2006) Vitamin K prophylaxis for preterm infants: a randomized, controlled trial of 3 regimens. Pediatrics 118(6):e1657–e1666.  https://doi.org/10.1542/peds.2005-2742CrossRefPubMedGoogle Scholar
  10. Cvirn G, Gallistl S, Muntean W (1999) Effects of antithrombin and protein C on thrombin generation in newborn and adult plasma. Thromb Res 93(4):183–190CrossRefGoogle Scholar
  11. Cvirn G, Gallistl S, Koestenberger M, Kutschera J, Leschnik B, Muntean W (2002) Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma. Thromb Res 105(5):433–439CrossRefGoogle Scholar
  12. Cvirn G, Kutschera J, Wagner T et al (2009) Collagen/endogenous thrombin-induced platelet aggregation in cord versus adult whole blood. Neonatology 95(2):187–192.  https://doi.org/10.1159/000155613CrossRefPubMedGoogle Scholar
  13. Duga S, Salomon O (2009) Factor XI deficiency. Semin Thromb Hemost 35(04):416–425.  https://doi.org/10.1055/s-0029-1225764CrossRefPubMedGoogle Scholar
  14. Forman KR, Diab Y, Wong ECC, Baumgart S, Luban NLC, Massaro AN (2014) Coagulopathy in newborns with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia: a retrospective case-control study. BMC Pediatr 14(1):277.  https://doi.org/10.1186/1471-2431-14-277CrossRefPubMedPubMedCentralGoogle Scholar
  15. Girolami A, Scandellari R, Scapin M, Vettore S (2008) Congenital bleeding disorders of the vitamin K-dependent clotting factors. Vitam Horm 78:281–374.  https://doi.org/10.1016/S0083-6729(07)00014-3CrossRefPubMedGoogle Scholar
  16. Golding J, Paterson M, Kinlen LJ (1990) Factors associated with childhood cancer in a national cohort study. Br J Cancer 62(2):304–308CrossRefGoogle Scholar
  17. Golding J, Greenwood R, Birmingham K, Mott M (1992) Childhood cancer, intramuscular vitamin K, and pethidine given during labour. BMJ 305(6849):341–346CrossRefGoogle Scholar
  18. Goodeve A (2008) Molecular genetic testing of hemophilia A. Semin Thromb Hemost 34(6):491–501.  https://doi.org/10.1055/s-0028-1103360CrossRefPubMedGoogle Scholar
  19. Hathaway W, Corrigan J (1991) Report of scientific and standardization subcommittee on neonatal hemostasis. Normal coagulation data for fetuses and newborn infants. Thromb Haemost 65(3):323–325CrossRefGoogle Scholar
  20. Holmberg L, Henriksson P, Ekelund H, Astedt B (1974) Coagulation in the human fetus. Comparison with term newborn infants. J Pediatr 85(6):860–864CrossRefGoogle Scholar
  21. Ignjatovic V, Mertyn E, Monagle P (2011) The coagulation system in children: developmental and pathophysiological considerations. Semin Thromb Hemost 37(7):723–729.  https://doi.org/10.1055/s-0031-1297162CrossRefPubMedGoogle Scholar
  22. Ignjatovic V, Kenet G, Monagle P (2012) Developmental hemostasis: recommendations for laboratories reporting pediatric samples. J Thromb Haemost 10(2):298–300.  https://doi.org/10.1111/j.1538-7836.2011.04584.xCrossRefPubMedGoogle Scholar
  23. Israels SJ, Rand ML, Michelson AD (2003) Neonatal platelet function. Semin Thromb Hemost 29(4):363–372.  https://doi.org/10.1055/s-2003-42587CrossRefPubMedGoogle Scholar
  24. Jensen AH, Josso F, Zamet P, Monset-Couchard M, Minkowski A (1973) Evolution of blood clotting factor leves in premature infants during the first 10 days of life: a study of 96 cases with comparison between clinical status and blood clotting factor levels. Pediatr Res 7(7):638–644.  https://doi.org/10.1203/00006450-197307000-00007CrossRefPubMedGoogle Scholar
  25. Karimi M, Bereczky Z, Cohan N, Muszbek L (2009) Factor XIII deficiency. Semin Thromb Hemost 35(4):426–438.  https://doi.org/10.1055/s-0029-1225765CrossRefPubMedGoogle Scholar
  26. Keir AK, Stanworth SJ (2016) Neonatal plasma transfusion: an evidence-based review. Transfus Med Rev 30(4):174–182.  https://doi.org/10.1016/j.tmrv.2016.07.001CrossRefPubMedGoogle Scholar
  27. Kulkarni R, Lusher J (2001) Perinatal management of newborns with haemophilia. Br J Haematol 112(2):264–274.  https://doi.org/10.1046/j.1365-2141.2001.02362.xCrossRefPubMedGoogle Scholar
  28. Kulkarni R, Soucie JM (2011) Pediatric hemophilia: a review. Semin Thromb Hemost 37(07):737–744.  https://doi.org/10.1055/s-0031-1297164CrossRefPubMedGoogle Scholar
  29. Laffan M, Lester W, O’Donnell J et al (2014) The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 167(4):453–465.  https://doi.org/10.1016/j.virol.2008.08.028.MacropinocytosisCrossRefPubMedPubMedCentralGoogle Scholar
  30. Lancellotti S, De Cristofaro R (2009) Congenital prothrombin deficiency. Semin Thromb Hemost 35(04):367–381.  https://doi.org/10.1055/s-0029-1225759CrossRefPubMedGoogle Scholar
  31. Ljung RCR (2008) Intracranial haemorrhage in haemophilia A and B. Br J Haematol 140(4):378–384.  https://doi.org/10.1111/j.1365-2141.2007.06949.xCrossRefPubMedGoogle Scholar
  32. Mariani G, Bernardi F (2009) Factor VII deficiency. Semin Thromb Hemost 35(4):400–406.  https://doi.org/10.1055/s-0029-1225762CrossRefPubMedGoogle Scholar
  33. McCarthy PT, Shearer MJ, Crampton O (1986) Vitamin K content of human liver at different ages. Rec Adv New Dev Hemostaseol Haemost 16:84.  https://doi.org/10.1002/j.1552-4604.1988.tb03106.xCrossRefGoogle Scholar
  34. Menegatti M, Peyvandi F (2009) Factor X deficiency. Semin Thromb Hemost 35(4):407–415.  https://doi.org/10.1055/s-0029-1225763CrossRefPubMedGoogle Scholar
  35. Mihatsch WA, Braegger C, Bronsky J et al (2016) Prevention of vitamin K deficiency bleeding in newborn infants: a position paper by the ESPGHAN committee on nutrition. J Pediatr Gastroenterol Nutr 63(1):123–129.  https://doi.org/10.1097/MPG.0000000000001232CrossRefPubMedGoogle Scholar
  36. de Moerloose P, Neerman-Arbez M (2009) Congenital fibrinogen disorders. Semin Thromb Hemost 35(04):356–366.  https://doi.org/10.1055/s-0029-1225758CrossRefPubMedGoogle Scholar
  37. Naderi M, Dorgalaleh A, Alizadeh S et al (2014) Clinical manifestations and management of life-threatening bleeding in the largest group of patients with severe factor XIII deficiency. Int J Hematol 100(5):443–449.  https://doi.org/10.1007/s12185-014-1664-1CrossRefPubMedGoogle Scholar
  38. Neary E, McCallion N, Kevane B et al (2015) Coagulation indices in very preterm infants from cord blood and postnatal samples. J Thromb Haemost 13(11):2021–2030.  https://doi.org/10.1111/jth.13130CrossRefPubMedGoogle Scholar
  39. Nichols WL, Hultin MB, James AH et al (2008) Von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) expert panel report (USA). Haemophilia 14(2):171–232.  https://doi.org/10.1111/j.1365-2516.2007.01643.xCrossRefPubMedGoogle Scholar
  40. Pakvasa MA, Winkler AM, Hamrick SE, Josephson CD, Patel RM (2017) Observational study of haemostatic dysfunction and bleeding in neonates with hypoxic-ischaemic encephalopathy. BMJ Open 7(2):e013787.  https://doi.org/10.1136/bmjopen-2016-013787CrossRefPubMedPubMedCentralGoogle Scholar
  41. Parker L, Cole M, Craft AW, Hey EN (1998) Neonatal vitamin K administration and childhood cancer in the north of England: retrospective case-control study. BMJ 316(7126):189–193CrossRefGoogle Scholar
  42. Passmore SJ, Draper G, Brownbill P, Kroll M (1998) Case-control studies of relation between childhood cancer and neonatal vitamin K administration. BMJ 316(7126):178–184CrossRefGoogle Scholar
  43. Peyvandi F, Makris M (2017) Inhibitor development in haemophilia. Haemophilia 23:3–3.  https://doi.org/10.1111/hae.13145CrossRefPubMedGoogle Scholar
  44. Peyvandi F, Menegatti M (2016) Treatment of rare factor deficiencies in 2016. Hematology 2016(1):663–669.  https://doi.org/10.1182/asheducation-2016.1.663CrossRefPubMedGoogle Scholar
  45. Peyvandi F, Palla R, Menegatti M, Mannucci PM (2009) Introduction: rare bleeding disorders: general aspects of clinical features, diagnosis, and management. Semin Thromb Hemost 35(4):349–355.  https://doi.org/10.1055/s-0029-1225757CrossRefPubMedGoogle Scholar
  46. Peyvandi F, Bolton-Maggs PH, Batorova A, De Moerloose P (2012) Rare bleeding disorders. Haemophilia 18(Suppl. 4):148–153.  https://doi.org/10.1111/j.1365-2516.2012.02841.xCrossRefPubMedGoogle Scholar
  47. Peyvandi F, Garagiola I, Biguzzi E (2016) Advances in the treatment of bleeding disorders. J Thromb Haemost 14(11):2095–2106.  https://doi.org/10.1111/jth.13491CrossRefPubMedGoogle Scholar
  48. Pichler E, Pichler L (2008) The neonatal coagulation system and the vitamin K deficiency bleeding – a mini review. Wien Med Wochenschr 158(13–14):385–395.  https://doi.org/10.1007/s10354-008-0538-7CrossRefPubMedGoogle Scholar
  49. Piotrowski A, Dabrowska-Wojciak I, Mikinka M et al (2010) Coagulation abnormalities and severe intraventricular hemorrhage in extremely low birth weight infants. J Matern Fetal Neonatal Med 23(7):601–606.  https://doi.org/10.1080/14767050903229614CrossRefPubMedGoogle Scholar
  50. Powell JS (2015) Longer-acting clotting factor concentrates for hemophilia. J Thromb Haemost 13(Suppl 1):S167–S175.  https://doi.org/10.1111/jth.12912CrossRefPubMedGoogle Scholar
  51. Puckett RM, Offringa M (2000) Prophylactic vitamin K for vitamin K deficiency bleeding in neonates. Offringa M, ed. Cochrane Database Syst Rev (4):CD002776.  https://doi.org/10.1002/14651858.CD002776
  52. Punzalan RC, Gottschall JL (2016) Use and future investigations of recombinant and plasma-derived coagulation and anticoagulant products in the neonate. Transfus Med Rev 30(4):189–196.  https://doi.org/10.1016/j.tmrv.2016.07.002CrossRefPubMedGoogle Scholar
  53. Radicioni M, Mezzetti D, Del Vecchio A, Motta M (2012) Thromboelastography: might work in neonatology too? J Matern Fetal Neonatal Med 25(Suppl 4):18–21.  https://doi.org/10.3109/14767058.2012.714996CrossRefPubMedGoogle Scholar
  54. Salonvaara M, Riikonen P, Vahtera E, Mahlamäki E, Heinonen K, Kekomäki R (2004) Development of selected coagulation factors and anticoagulants in preterm infants by the age of six months. Thromb Haemost 92(4):688–696.  https://doi.org/10.1160/TH03-12-0769CrossRefPubMedGoogle Scholar
  55. Sankar MJ, Chandrasekaran A, Kumar P, Thukral A, Agarwal R, Paul VK (2016) Vitamin K prophylaxis for prevention of vitamin K deficiency bleeding: a systematic review. J Perinatol 36(Suppl 1):S29–S35.  https://doi.org/10.1038/jp.2016.30CrossRefPubMedPubMedCentralGoogle Scholar
  56. Saxonhouse MA, Manco-Johnson MJ (2009) The evaluation and management of neonatal coagulation disorders. Semin Perinatol 33(1):52–65.  https://doi.org/10.1053/j.semperi.2008.10.007CrossRefPubMedGoogle Scholar
  57. Schulte R, Jordan LC, Morad A, Naftel RP, Wellons JC, Sidonio R (2014) Rise in late onset vitamin K deficiency bleeding in young infants because of omission or refusal of prophylaxis at birth. Pediatr Neurol 50(6):564–568.  https://doi.org/10.1016/j.pediatrneurol.2014.02.013CrossRefPubMedGoogle Scholar
  58. Sewell EK, Forman KR, Wong ECC, Gallagher M, Luban NLC, Massaro AN (2017) Thromboelastography in term neonates: an alternative approach to evaluating coagulopathy. Arch Dis Child Fetal Neonatal Ed 102(1):F79–F84.  https://doi.org/10.1136/archdischild-2016-310545CrossRefPubMedGoogle Scholar
  59. Shearer MJ (2009) Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev 23(2):49–59.  https://doi.org/10.1016/j.blre.2008.06.001CrossRefPubMedGoogle Scholar
  60. Street AM, Ljung R, Lavery SA (2008) Management of carriers and babies with haemophilia. Haemophilia 14(Suppl. 3):181–187.  https://doi.org/10.1111/j.1365-2516.2008.01721.xCrossRefPubMedGoogle Scholar
  61. Sutor AH, von Kries R, Cornelissen EA, McNinch AW, Andrew M, Vitamin K (1999) Deficiency bleeding (VKDB) in infancy. ISTH pediatric/perinatal subcommittee. International society on thrombosis and haemostasis. Thromb Haemost 81(3):456–461CrossRefGoogle Scholar
  62. Urban D, Pluthero FG, Christensen H et al (2017) Decreased numbers of dense granules in fetal and neonatal platelets. Haematologica 102(2):e36–e38.  https://doi.org/10.3324/haematol.2016.152421CrossRefPubMedPubMedCentralGoogle Scholar
  63. von Kries R, Becker A, Göbel U (1987) Vitamin K in the newborn: influence of nutritional factors on acarboxy-prothrombin detectability and factor II and VII clotting activity. Eur J Pediatr 146(2):123–127CrossRefGoogle Scholar
  64. Van Winckel M, De Bruyne R, Van De Velde S, Van Biervliet S (2009) Vitamin K, an update for the paediatrician. Eur J Pediatr 168(2):127–134.  https://doi.org/10.1007/s00431-008-0856-1CrossRefPubMedGoogle Scholar
  65. Venkatesh V, Curley A, Khan R et al (2013) A novel approach to standardised recording of bleeding in a high risk neonatal population. Arch Dis Child Fetal Neonatal Ed 98(3):F260–F263.  https://doi.org/10.1136/archdischild-2012-302443CrossRefPubMedGoogle Scholar
  66. Watzka M, Geisen C, Scheer M et al (2014) Bleeding and non-bleeding phenotypes in patients with GGCX gene mutations. Thromb Res 134(4):856–865.  https://doi.org/10.1016/j.thromres.2014.07.004CrossRefPubMedGoogle Scholar
  67. Widdershoven J, Motohara K, Endo F, Matsuda I, Monnens L (1986) Influence of the type of feeding on the presence of PIVKA-II in infants. Helv Paediatr Acta 41(1–2):25–29PubMedGoogle Scholar
  68. Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD (2009) Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. J Perinatol 29(2):130–136.  https://doi.org/10.1038/jp.2008.141CrossRefPubMedGoogle Scholar
  69. Witmer CM, Huang Y-S, Lynch K, Raffini LJ, Shah SS (2011) Off-label recombinant factor VIIa use and thrombosis in children: a multi-center cohort study. J Pediatr 158(5):820–825.e1.  https://doi.org/10.1016/j.jpeds.2010.10.038CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Pediatric Hematology, Department of PediatricsUniversity Hospital Città della Salute e della ScienzaTorinoItaly
  2. 2.Section of Paediatrics, Department of MedicineImperial CollegeLondonUK

Personalised recommendations