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

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

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Zusammenfassung

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.

Summary

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.

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Literatur

  • Cohen SG. The placental transmission of antibodies and serum γ-globulins. J Infect Dis, 87: 291–298, 1950

    PubMed  CAS  Google Scholar 

  • 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, 1994

    PubMed  CAS  Google Scholar 

  • Szirmai E. Der plazentare Übergang der Koagulationsfaktoren und die Hypoprothrombinämie der Neugeborenen. Zentrbl Gynäkol, 74: 1051–1056, 1952

    CAS  Google Scholar 

  • Szirmai E. Der plazentare Übergang der Gerinnungsfaktoren und die Koagulationsbeziehungen zwischen Mutter und Frucht. Folia Haematol Int Mag Klin Morphol Blutforsch, 74: 207–220, 1956

    PubMed  CAS  Google Scholar 

  • 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, 1969

    PubMed  CAS  Google Scholar 

  • 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, 1996

    PubMed  CAS  Google Scholar 

  • Chalmers EA. Haemophilia and the newborn. Blood Rev, 18: 85–92, 2004

    Article  PubMed  Google Scholar 

  • 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, 1999

    PubMed  CAS  Google Scholar 

  • Lane PA, Hathaway WE. Vitamin K in infancy. J Pediatr, 106: 351–359, 1985

    Article  PubMed  CAS  Google Scholar 

  • Muntean W, Belohradksky BH, Klose HJ, Riegel K. Faktor-VIII-Aktivität und Faktor-VIII-assoziiertes Antigen bei Neugeborenen. Klin Pädiat, 189: 412–416, 1977

    CAS  Google Scholar 

  • 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, 1988

    PubMed  CAS  Google Scholar 

  • 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, 1987

    PubMed  CAS  Google Scholar 

  • Schmidt B, Ofosu FA, Mitchell L, Brooker LA, Andrew M. Anticoagulant effects of heparin in neonatal plasma. Pediatr Res, 25: 405–408, 1989

    Article  PubMed  CAS  Google Scholar 

  • 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, 1990

    PubMed  CAS  Google Scholar 

  • Muntean W, Leschnik B, Baier K, Cvirn G, Gallistl S. In vivo thrombin generation in neonates. J Thromb Haemost, 2: 2071–2072, 2004

    Article  PubMed  CAS  Google Scholar 

  • 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, 2003

    Article  PubMed  CAS  Google Scholar 

  • 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, 1994

    Article  PubMed  CAS  Google Scholar 

  • Israels SJ, Daniels M, McMillan EM. Deficient collagen-induced activation in the newborn platelet. Pediatr Res, 27: 337–343, 1990

    Article  PubMed  CAS  Google Scholar 

  • Michelson AD. Platelet function in the newborn. Sem Thromb Hemost, 24: 507–512, 1998

    CAS  Google Scholar 

  • Grosshaupt B, Muntean W, Sedlmayr P. Hyporeactivity of neonatal platelets is not caused by preactivation during birth. Eur J Pediatr, 156: 944–948, 1997

    Article  PubMed  CAS  Google Scholar 

  • 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, 1989

    Article  PubMed  CAS  Google Scholar 

  • 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, 2004

    PubMed  CAS  Google Scholar 

  • Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood, 80: 1998–2005, 1992

    PubMed  CAS  Google Scholar 

  • 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, 1997

  • Sutor AH, Kries R von, Cornelissen EAM, McNinch AW, Andrew M. Vitamin K deficiency bleeding (VKDB) in infancy. Thromb Haemost, 81: 456–461, 1999

    PubMed  CAS  Google Scholar 

  • 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, 2002

  • Cranenburg ECM, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost, 98: 120–125, 2007

    PubMed  CAS  Google Scholar 

  • 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, 2002

    Google Scholar 

  • Shearer MJ. Vitamin K metabolism and nutriture. Blood Rev, 6: 92–104, 1992

    Article  PubMed  CAS  Google Scholar 

  • Shearer MJ, Rahim S, Barkhan P, Stimmler L. Plasma vitamin K1 in mothers and their newborn babies. Lancet, ii: 460–463, 1982

    Article  Google Scholar 

  • 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, 2000

    PubMed  CAS  Google Scholar 

  • American Academy of Pediatrics, Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics, 112: 191–192, 2003

    Article  Google Scholar 

  • Hey E. Effect of maternal anticonvulsant treatment on neonatal blood coagulation. Arch Dis Child Fetal Neonatal Ed, 81: F208–F210, 1999

    PubMed  CAS  Google Scholar 

  • 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, 1993

    PubMed  CAS  Google Scholar 

  • Koppe JG, Pluim E, Olie K. Breastmilk, PCBs, dioxins and vitamin K deficiency: discussion paper. J Royal Soc Med, 82: 416–419, 1989

    CAS  Google Scholar 

  • 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, 1982

    PubMed  CAS  Google Scholar 

  • McNinch AW, Tripp JH. Haemorrhagic disease of the newborn in the British isles: two year prospective study. Brit Med J, 303: 1105–1109, 1991

    PubMed  CAS  Google Scholar 

  • Kries R von. Vitamin K prophylaxis – a useful public health measure? Paediatr Perinat Epidemiol, 6: 7–13, 1992

    Article  PubMed  CAS  Google Scholar 

  • 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, 1988

    Article  PubMed  CAS  Google Scholar 

  • 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, 1988

    CAS  Google Scholar 

  • 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, 2004

    Article  PubMed  CAS  Google Scholar 

  • 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, 1961

    Google Scholar 

  • Loughnan PM, McDougall PN. Epidemiology of late onset haemorrhagic disease: a pooled data analysis. J Paediatr Child Health, 29: 177–181, 1993

    Article  PubMed  CAS  Google Scholar 

  • Allison AC. Danger of vitamin K to newborn. Lancet, i: 669, 1955

    Article  Google Scholar 

  • Meyer TC, Angus J. The effect of large doses of "Synkavit" in the newborn. Arch Dis Child, 31: 212–215, 1956

    PubMed  CAS  Google Scholar 

  • Hey E. Vitamin K – what, why, and when. Arch Dis Child Fetal Neonatal Ed, 88: F80–F83, 2003

    Article  PubMed  CAS  Google Scholar 

  • Golding J, Paterson M, Kinlen LJ. Factors associated with childhood cancer in a national cohort study. Brit J Cancer, 62: 304–308, 1990

    PubMed  CAS  Google Scholar 

  • Golding J, Greenwood R, Birminham K, Mott M. Childhood cancer, intramuscular vitamin K, and pethidine given during labour. Brit Med J, 305: 341–346, 1992

    PubMed  CAS  Google Scholar 

  • American Academy of Pediatrics. AAP publications reaffirmed, May 2006. Pediatrics, 118: 1266, 2006

    Article  Google Scholar 

  • 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, 1985

    PubMed  CAS  Google Scholar 

  • 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, 1993

    Article  PubMed  CAS  Google Scholar 

  • 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, 2000

    Article  PubMed  CAS  Google Scholar 

  • 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, 1996

    Article  PubMed  CAS  Google Scholar 

  • Costakos DT, Porte M. Did "Controversies concerning vitamin K and the newborn" cover all the controversies? Pediatrics, 113: 1466–1467, 2004

    Article  PubMed  Google Scholar 

  • 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, 1996

    Article  PubMed  CAS  Google Scholar 

  • 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, 1997

    Article  PubMed  CAS  Google Scholar 

  • 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, 2003

    Article  PubMed  CAS  Google Scholar 

  • Zwiauer K. Vorschlag zur Vitamin K-Prophylaxe bei Neugeborenen. Mschr Kinderheilk, 151: 563–564, 2003

    Google Scholar 

  • 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, 1988

    PubMed  CAS  Google Scholar 

  • 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, 1993

    PubMed  CAS  Google Scholar 

  • Schubiger G, Laubscher B, Bänziger O. Vitamin K-Prophylaxe bei Neugeborenen: neue Empfehlungen. Available at: http://www.swiss-paediatrics.org/paediatrica/vol13/n6/vitk_ge.html. Accessed June 16, 2006

  • 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, 1977

    PubMed  CAS  Google Scholar 

  • Williams MD, Chalmers EA, Gibson BE. The investigation and management of neonatal haemostasis and thrombosis. Br J Haematol, 119: 295–309, 2002

    Article  PubMed  Google Scholar 

  • 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, 2004

    Article  Google Scholar 

  • 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, 2007

    Article  CAS  Google Scholar 

  • Brady KM, Easley RB, Tobias JD. Recombinant activated factor VII (rFVIIa) treatment in infants with hemorrhage. Pediatr Anesth, 16: 1042–1046, 2006

    Article  Google Scholar 

  • 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, 2006

    Article  PubMed  Google Scholar 

  • 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, 1988

    PubMed  CAS  Google Scholar 

  • 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, 1990

    Article  PubMed  CAS  Google Scholar 

  • 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, 1999

    Article  PubMed  CAS  Google Scholar 

  • 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, 1998

    Google Scholar 

  • 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, 2000

  • Mahasandana C, Isarangkura P. Vitamin K prophylaxis: its role in reducing infant morbidity and mortality. Haemophilia, 10(Suppl 3): 92, 2004

    Google Scholar 

  • Autret-Leca E, Jonville-Béra A-P. Vitamin K in neonates. How to administer, when and to whom. Paediatr Drugs, 3: 1–8, 2001

    Article  PubMed  CAS  Google Scholar 

  • 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, 2007

    Article  PubMed  CAS  Google Scholar 

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  1. Department Toxicology/Pharmacology, Octapharma PPGmbH, Vienna, Austria

    Ludwig Pichler

  2. Department of Paediatrics, Landeskrankenhaus Klagenfurt, Klagenfurt, Austria

    Ewald Pichler

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Pichler, E., Pichler, L. The neonatal coagulation system and the vitamin K deficiency bleeding – a mini review. Wien Med Wochenschr 158, 385–395 (2008). https://doi.org/10.1007/s10354-008-0538-7

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