Wiener Medizinische Wochenschrift

, Volume 158, Issue 13–14, pp 385–395 | Cite as

The neonatal coagulation system and the vitamin K deficiency bleeding – a mini review

  • Ewald Pichler
  • Ludwig PichlerEmail author


Coagulation factors do not cross the placental barrier but are synthesized independently by the conceptus. At birth, activities of the vitamin K dependent factors II, VII, IX, and X and the concentrations of the contact factors XI and XII are reduced to about 50% of normal adult values. The levels of the factors V, VIII, XIII, and fibrinogen are similar to adult values. Plasma concentrations of the naturally occurring anticoagulant proteins (antithrombin, protein C, and protein S) are significantly lower at birth than during the adult years. Plasminogen is reduced by approximately 50%. Platelet counts are within the normal range, regarding function, however, neonatal platelets seem to be hyporeactive. The von Willebrand factor contains large multimers and its concentration is increased. Properties and functions of vitamin K as well as requirement and plasma concentrations in newborns are reviewed. Regarding vitamin K deficiency bleeding (VKDB), the classical nomenclature is used: "early" (presenting within the first 24 h of life), "classical" (day 1–7 after birth), and "late" (8 days to 6 months). After the presentation of the history of vitamin K prophylaxis, vitamin K levels are described as can be expected after the administration of prophylactic doses at various routes. Subsequently, the actual schedule of vitamin K prophylaxis as recommended by the "Österreichische Gesellschaft für Kinder- und Jugendheilkunde" is given as follows: i) the oral treatment of healthy full-term babies and orally fed preterm babies, ii) the parenteral treatment of small preterm and sick full-term babies, and iii) the treatment of mothers under medication with enzyme-inducing drugs with vitamin K during the last 15–30 days of pregnancy. The regimes of prophylactic vitamin K treatment of different countries are also given. Finally, the therapeutic use of vitamin K is addressed; the potential use of fresh-frozen plasma, prothrombin complex preparations, and recombinant factor VIIa is discussed.


Placental barrier Neonatal coagulation system Vitamin K deficiency bleeding Vitamin K prophylaxis 

Das neonatale Gerinnungssystem und die Vitamin K Mangelblutung – eine kurze Übersicht


Die vorliegende Übersicht versucht einen Bogen zu spannen von der Blutgerinnung und den Gerinnungsfaktoren des Neugeborenen über die Rolle des Vitamin K in der Gerinnung hin zu den verschiedenen Formen der Vitamin K Mangelblutung des Neugeborenen sowie deren Prophylaxe und Therapie. Gerinnungsfaktoren überschreiten nicht die Plazentabarriere, sondern werden vom Fetus gebildet. Bei der Geburt sind die Faktoren des Vitamin K-abhängigen Prothrombinkomplexes (II, VII, IX und X) sowie die Kontaktfaktoren XI und XII auf etwa 50 % des Erwachsenen-Normalwertes reduziert. Die Faktoren V, VIII, XIII und Fibrinogen dagegen liegen in ähnlicher Konzentration wie beim Erwachsenen vor. Die antikoagulatorischen Proteine wie Antithrombin, Protein C und Protein S sind signifikant erniedrigt. Plasminogen ist um etwa 50 % erniedrigt. Die Plättchen liegen im Erwachsenen-Normalbereich, sind jedoch hyporeaktiv. Die Konzentration des von Willebrand Faktors, der große Multimere aufweist, ist erhöht. Die Eigenschaften und die Funktionen von Vitamin K werden ebenso besprochen, wie der Bedarf und die Plasmakonzentrationen des Neugeborenen. Bei Darstellung der Vitamin K Mangelblutung wird die "alte" Nomenklatur beibehalten: frühe Form, klassische Form und späte Form. Für die Vitamin K Prophylaxe wird ein kurzer historischer Rückblick gegeben, anschließend werden die Vitamin K Plasmaspiegel nach gebräuchlichen Dosierungen beschrieben und schließlich wird die für Österreich empfohlene Prophylaxe wiedergegeben. Die für andere Länder gültigen Empfehlungen sind in einer Tabelle zusammengefaßt. Den Schluß stellt eine kurze Darstellung der Therapie der Vitamin K Mangelblutung dar.


Plazentabarriere Gerinnungssystem des Neugeborenen Vitamin K Mangelblutung Vitamin K Prophylaxe 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Cohen SG. The placental transmission of antibodies and serum γ-globulins. J Infect Dis, 87: 291–298, 1950PubMedGoogle Scholar
  2. Avrech OM, Samra Z, Lazarovich Z, Caspi E, Jacobovich A, Sompolinski D. Efficacy of the placental barrier for immunoglobulins: correlation between maternal and fetal immunoglobulin levels. Int Arch Allergy Immunol, 103: 160–165, 1994PubMedGoogle Scholar
  3. Szirmai E. Der plazentare Übergang der Koagulationsfaktoren und die Hypoprothrombinämie der Neugeborenen. Zentrbl Gynäkol, 74: 1051–1056, 1952Google Scholar
  4. Szirmai E. Der plazentare Übergang der Gerinnungsfaktoren und die Koagulationsbeziehungen zwischen Mutter und Frucht. Folia Haematol Int Mag Klin Morphol Blutforsch, 74: 207–220, 1956PubMedGoogle Scholar
  5. Cade JF, Hirsh J, Martin M. Placental barrier to coagulation factors: its relevance to the coagulation defect at birth and to haemorrhage in the newborn. Brit Med J, 2: 281–283, 1969PubMedGoogle Scholar
  6. Reverdiau-Moalic P, Delahousse B, Body G, Bardos P, Leroy J, Guel Y. Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood, 88: 900–906, 1996PubMedGoogle Scholar
  7. Chalmers EA. Haemophilia and the newborn. Blood Rev, 18: 85–92, 2004PubMedCrossRefGoogle Scholar
  8. Male Ch, Johnston M, Sparling C, Brooker LA, Andrew M, Massicotte P. The influence of developmental haemostasis on the laboratory diagnosis and management of haemostatic disorders during infancy and childhood. Clin Lab Med, 19: 39–69, 1999PubMedGoogle Scholar
  9. Lane PA, Hathaway WE. Vitamin K in infancy. J Pediatr, 106: 351–359, 1985PubMedCrossRefGoogle Scholar
  10. Muntean W, Belohradksky BH, Klose HJ, Riegel K. Faktor-VIII-Aktivität und Faktor-VIII-assoziiertes Antigen bei Neugeborenen. Klin Pädiat, 189: 412–416, 1977Google Scholar
  11. Schwarz HP, Muntean W, Watzke H, Richter B, Griffin JH. Low total protein S antigen but high protein S activity due to decreased C4b-binding protein in neonates. Blood, 71: 562–565, 1988PubMedGoogle Scholar
  12. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P. Development of the human coagulation system in the full-term infant. Blood, 70: 165–172, 1987PubMedGoogle Scholar
  13. Schmidt B, Ofosu FA, Mitchell L, Brooker LA, Andrew M. Anticoagulant effects of heparin in neonatal plasma. Pediatr Res, 25: 405–408, 1989PubMedCrossRefGoogle Scholar
  14. Andrew M, Schmidt B, Mitchell L, Paes B, Ofosu F. Thrombin generation in newborn plasma is critically dependent on the concentration of prothrombin. Thromb Haemost, 63: 27–30, 1990PubMedGoogle Scholar
  15. Muntean W, Leschnik B, Baier K, Cvirn G, Gallistl S. In vivo thrombin generation in neonates. J Thromb Haemost, 2: 2071–2072, 2004PubMedCrossRefGoogle Scholar
  16. Cvirn G, Gallistl S, Leschnik B, Muntean W. Low tissue factor pathway inhibitor (TFPI) with low antithrombin allows sufficient thrombin generation in neonates. J Thromb Haemost, 1: 263–268, 2003PubMedCrossRefGoogle Scholar
  17. Saleh AA, Alshameeri RS, O'Brien JM, Munkarah AR, Dombrovski MP, Bottoms SF, Cotton DB, Mammen EF. Maternal and neonatal primary hemostasis. Thromb Res, 73: 125–129, 1994PubMedCrossRefGoogle Scholar
  18. Israels SJ, Daniels M, McMillan EM. Deficient collagen-induced activation in the newborn platelet. Pediatr Res, 27: 337–343, 1990PubMedCrossRefGoogle Scholar
  19. Michelson AD. Platelet function in the newborn. Sem Thromb Hemost, 24: 507–512, 1998Google Scholar
  20. Grosshaupt B, Muntean W, Sedlmayr P. Hyporeactivity of neonatal platelets is not caused by preactivation during birth. Eur J Pediatr, 156: 944–948, 1997PubMedCrossRefGoogle Scholar
  21. Weinstein MJ, Blanchard R, Moake JL, Vosburgh E, Moise K. Fetal and neonatal von Willebrand factor (vWF) is unusually large and similar to the vWF in patients with thrombotic thrombocytopenic purpura. Br J Haematol, 72: 68–72, 1989PubMedCrossRefGoogle Scholar
  22. Rehak Th, Cvirn G, Gallistl S, Leschnik B, Köstenberger M, Katzer, Ribitsch V, Muntean W. Increased shear stress- and ristocetin-induced binding of von Willebrand factor to platelets in cord compared with adult plasma. Thromb Haemost, 92: 682–687, 2004PubMedGoogle Scholar
  23. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood, 80: 1998–2005, 1992PubMedGoogle Scholar
  24. Victora C. Vitamin K deficiency and haemorrhagic disease of the newborn: a public health problem in less developed countries? UNICEF Staff Working Papers; Evaluation, Policy and Planning Series, Number EVL-97-005; UNICEF, New York, 1997Google Scholar
  25. Sutor AH, Kries R von, Cornelissen EAM, McNinch AW, Andrew M. Vitamin K deficiency bleeding (VKDB) in infancy. Thromb Haemost, 81: 456–461, 1999PubMedGoogle Scholar
  26. FAO/WHO. Vitamin K. In: Human vitamin and mineral requirements. Report of a joint FAO/WHO expert consultation Bangkok, Thailand. Publishing and Multimedia Service, Rome, pp 133–150, 2002Google Scholar
  27. Cranenburg ECM, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost, 98: 120–125, 2007PubMedGoogle Scholar
  28. FNB (Food and Nutrition Board)/IOM (Institue of Medicine). Vitamin K. In: Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. The National Academic Press, Washington, pp 162–196, 2002Google Scholar
  29. Shearer MJ. Vitamin K metabolism and nutriture. Blood Rev, 6: 92–104, 1992PubMedCrossRefGoogle Scholar
  30. Shearer MJ, Rahim S, Barkhan P, Stimmler L. Plasma vitamin K1 in mothers and their newborn babies. Lancet, ii: 460–463, 1982CrossRefGoogle Scholar
  31. Oldenburg J, Brederlow B von, Fregin A, Rost S, Wolz W, Eberl W, Eber S, Lenz E, Schwaab R, Brackmann HH, Effenberg W, Harbrecht U, Schurgers LJ, Vermeer C, Müller CR. Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. Thromb Haemost, 84: 937–941, 2000PubMedGoogle Scholar
  32. American Academy of Pediatrics, Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics, 112: 191–192, 2003CrossRefGoogle Scholar
  33. Hey E. Effect of maternal anticonvulsant treatment on neonatal blood coagulation. Arch Dis Child Fetal Neonatal Ed, 81: F208–F210, 1999PubMedGoogle Scholar
  34. Bovill EG, Soll RF, Bhushan F, Landesman M, Freije M, Church W, McAuliffe T, Davidson K, Sadowski J. Vitamin K1 metabolism and the production of descarboxy prothrombin and protein C in the term and premature neonate. Blood, 81: 77–83, 1993PubMedGoogle Scholar
  35. Koppe JG, Pluim E, Olie K. Breastmilk, PCBs, dioxins and vitamin K deficiency: discussion paper. J Royal Soc Med, 82: 416–419, 1989Google Scholar
  36. Haroon Y, Shearer MJ, Rahim S, Gunn WG, McEnery G, Barkhan P. The content of phylloquinone (vitamin K1) in human milk, cow's milk and infant formula foods determined by high-performance liquid chromatography. J Nutr, 112: 1105–1117, 1982PubMedGoogle Scholar
  37. McNinch AW, Tripp JH. Haemorrhagic disease of the newborn in the British isles: two year prospective study. Brit Med J, 303: 1105–1109, 1991PubMedGoogle Scholar
  38. Kries R von. Vitamin K prophylaxis – a useful public health measure? Paediatr Perinat Epidemiol, 6: 7–13, 1992PubMedCrossRefGoogle Scholar
  39. Hanawa Y, Maki M, Murate B, Matsuyama E, Yamamoto Y, Nagao T, Yamada K, Ikeda I, Terao T, Mikami S, Shiraki K, Komazawa M, Shirahata A, Tsuji Y, Motohara K, Tsukimoto I, Sawada K. The second nation-wide survey in Japan of vitamin K deficiency in infancy. Eur J Pediatr, 147: 472–477, 1988PubMedCrossRefGoogle Scholar
  40. Ungchusak K, Tishyadhigama S, Choprapawon C, Sawadiwutipong W, Varintarawat S. Incidence of idiopathic vitamin K deficiency in infants: a national, hospital based, survey in Thailand, 1983. J Med, Assoc Thai, 71: 417–421, 1988Google Scholar
  41. Danielsson N, Hoa DP, Thang NV, Vos T, Loughnan PM. Intracranial haemorrhage due to late onset vitamin K deficiency bleeding in Hanoi province, Vietnam. Arch Dis Child Fetal Neonatal Ed, 89: F546–F550, 2004PubMedCrossRefGoogle Scholar
  42. American Academy of Pediatrics, Committee on Nutrition. Vitamin K compounds and the water-soluble analogues: use in therapy and prophylaxis in pediatrics. Pediatrics, 28: 501–506, 1961Google Scholar
  43. Loughnan PM, McDougall PN. Epidemiology of late onset haemorrhagic disease: a pooled data analysis. J Paediatr Child Health, 29: 177–181, 1993PubMedCrossRefGoogle Scholar
  44. Allison AC. Danger of vitamin K to newborn. Lancet, i: 669, 1955CrossRefGoogle Scholar
  45. Meyer TC, Angus J. The effect of large doses of "Synkavit" in the newborn. Arch Dis Child, 31: 212–215, 1956PubMedGoogle Scholar
  46. Hey E. Vitamin K – what, why, and when. Arch Dis Child Fetal Neonatal Ed, 88: F80–F83, 2003PubMedCrossRefGoogle Scholar
  47. Golding J, Paterson M, Kinlen LJ. Factors associated with childhood cancer in a national cohort study. Brit J Cancer, 62: 304–308, 1990PubMedGoogle Scholar
  48. Golding J, Greenwood R, Birminham K, Mott M. Childhood cancer, intramuscular vitamin K, and pethidine given during labour. Brit Med J, 305: 341–346, 1992PubMedGoogle Scholar
  49. American Academy of Pediatrics. AAP publications reaffirmed, May 2006. Pediatrics, 118: 1266, 2006CrossRefGoogle Scholar
  50. McNinch AW, Upton C, Samuels M, Shearer MJ, McCarthy P, Tripp JH, L'e Orme R. Plasma concentrations after oral or intramuscular vitamin K1 in neonates. Arch Dis Child, 60: 814–818, 1985PubMedGoogle Scholar
  51. Schubiger G, Tonz O, Grüter J, Shearer MJ. Vitamin K1 concentration in breast-fed neonates after oral or intramuscular administration of a single dose of a new mixed-micellar preparation of phylloquinone. J Pediatr Gastroenterol Nutr, 16: 435–439, 1993PubMedCrossRefGoogle Scholar
  52. Raith W, Fauler G, Pichler G, Muntean W. Plasma concentrations after intravenous administration of phylloquinone (vitamin K1) in preterm and sick neonates. Thromb Res, 99: 467–472, 2000PubMedCrossRefGoogle Scholar
  53. Stoeckel K, Joubert PH, Grüter J. Elimination half-life of vitamin K1 in neonates is longer than is generally assumed: implications for the prophylaxis of haemorrhagic disease of the newborn. Eur J Clin Pharmacol, 49: 421–423, 1996PubMedCrossRefGoogle Scholar
  54. Costakos DT, Porte M. Did "Controversies concerning vitamin K and the newborn" cover all the controversies? Pediatrics, 113: 1466–1467, 2004PubMedCrossRefGoogle Scholar
  55. Hansen KN, Ebbesen F. Neonatal vitamin K prophylaxis in Denmark: three year's experience with oral administration during the first three month of life with one oral administration at birth. Acta Paediatr, 85: 1137–1139, 1996PubMedCrossRefGoogle Scholar
  56. Cornelissen M, Kries R von, Loughan P, Schübinger G. Prevention of vitamin K deficiency bleeding: efficacy of different multiple oral dose schedules of vitamin K. Eur J Pediatr, 156: 126–130, 1997PubMedCrossRefGoogle Scholar
  57. Kries R von, Hachmeister A, Göbel U. Oral mixed micellar vitamin K for prevention of late vitamin K deficiency bleeding. Arch Dis Child Fetal Neonatal Ed, 88: F109–F112, 2003PubMedCrossRefGoogle Scholar
  58. Zwiauer K. Vorschlag zur Vitamin K-Prophylaxe bei Neugeborenen. Mschr Kinderheilk, 151: 563–564, 2003Google Scholar
  59. Mandelbrot L, Guillaumont M, Leclercq M, Lefrère JJ, Gozin D, Daffos F, Forestier F. Placental transfer of vitamin K1 and its implication in fetal hemostasis. Thromb Haemost, 60: 39–43, 1988PubMedGoogle Scholar
  60. Cornelissen M, Steegers-Theunissen R, Kollée L, Eskes T, Motohara K, Monnens L. Supplementation of vitamin K in pregnant woman receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol, 168: 884–888, 1993PubMedGoogle Scholar
  61. Schubiger G, Laubscher B, Bänziger O. Vitamin K-Prophylaxe bei Neugeborenen: neue Empfehlungen. Available at: Accessed June 16, 2006
  62. Orme ML, Lewis PJ, Swiet M de, Serlin MJ, Sibeon R, Baty JD, Breckenridge AM. May mothers given warfarin breast-feed their infants? Br Med J, 1: 1564–1565, 1977PubMedGoogle Scholar
  63. Williams MD, Chalmers EA, Gibson BE. The investigation and management of neonatal haemostasis and thrombosis. Br J Haematol, 119: 295–309, 2002PubMedCrossRefGoogle Scholar
  64. O'Shaugnessy DF, Atterbury C, Maggs PB, Murphy M, Thomas D, Yates S, Williamson LM. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Brit Soc Haematol, 126: 11–28, 2004CrossRefGoogle Scholar
  65. Dempfle C-E, Gulba D, Kirchmaier CM, Klamroth R, Korte W, Lorenz R, Peck-Radosavljecic M, Veldman A, Zotz RB. Klinische Bewertung potentieller Einsatzbereiche von rekombinantem Faktor VIIa bei internistischen und pädiatrischen Erkrankungen. Empfehlungen einer Expertengruppe. Med Klin, 102: 70–81, 2007CrossRefGoogle Scholar
  66. Brady KM, Easley RB, Tobias JD. Recombinant activated factor VII (rFVIIa) treatment in infants with hemorrhage. Pediatr Anesth, 16: 1042–1046, 2006CrossRefGoogle Scholar
  67. Hünseler C, Kribs A, Eifinger F, Roth B. Recombinant activated factor seven in acute life-threatening bleeding in neonates: report on three cases and review of literature. J Perinatol, 26: 706–713, 2006PubMedCrossRefGoogle Scholar
  68. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Castle V, Powers P. Development of the human coagulation system in the healthy premature infant. Blood, 72: 1651–1657, 1988PubMedGoogle Scholar
  69. Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol, 12: 95–104, 1990PubMedCrossRefGoogle Scholar
  70. Kries R von, Hachmeister A, Göbel U. Can 3 oral 2mg doses of vitamin K effectively prevent late vitamin K deficiency bleeding? Eur J Pediatr, 158(Suppl 3): S183–S186, 1999PubMedCrossRefGoogle Scholar
  71. American Academy of Pediatrics. Nutritional needs of preterm infants. In: Kleinman RE, Pediatric Nutrition Handbook. 4th ed., American Academy of Pediatrics, Elk Grove, IL, pp 66–68, 1998Google Scholar
  72. Commonwealth of Australia, National Health and Medical Research Council. Joint statement and recommendations on vitamin K administration to newborn infants to prevent vitamin K deficiency bleeding in infancy. ISBN 0642450676, 2000Google Scholar
  73. Mahasandana C, Isarangkura P. Vitamin K prophylaxis: its role in reducing infant morbidity and mortality. Haemophilia, 10(Suppl 3): 92, 2004Google Scholar
  74. Autret-Leca E, Jonville-Béra A-P. Vitamin K in neonates. How to administer, when and to whom. Paediatr Drugs, 3: 1–8, 2001PubMedCrossRefGoogle Scholar
  75. Ito K, Goto K, Sugiura T, Muramatsu K, Ando T, Maniwa H, Yokoyama T, Sugiyama K, Togari H. Polymorphisms of the factor VII gene associated with low activities of vitamin K-dependent coagulation factors in one-month-old infants. Tohoku J Exp Med, 211: 1–8, 2007PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department Toxicology/PharmacologyOctapharma PPGmbHViennaAustria
  2. 2.Department of PaediatricsLandeskrankenhaus KlagenfurtKlagenfurtAustria

Personalised recommendations