Download PDF
Thromb Haemost 1999; 81(03): 456-461
DOI: 10.1055/s-0037-1614494
Scientific and Standardization Committee Communications
Schattauer GmbH

Vitamin K Deficiency Bleeding (VKDB) in Infancy[*]

On behalf of the ISTH Pediatric/Perinatal Subcommittee
Anton H. Sutor
1   From the Universitäts-Kinderklinik, Freiburg, Germany
,
Rüdiger von Kries
2   Institut für Soziale Pädiatrie und Jugendmedizin, München, Germany
,
Marlies E. A. Cornelissen
3   University Children’s Hospital, Nijmegen, The Netherlands
,
Andrew W. McNinch
4   Department of Child Health, Royal Devon and Exeter Hospital, Exeter, United Kingdom
,
Maureen Andrew
5   Hamilton Civic Hospital Research Centre, Henderson General Division, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

    Permissions and Reprints

Summary

Terminology. Replace the term “Hemorrhagic Disease of the Newborn” (HDN) by “Vitamin K Deficiency Bleeding” (VKDB), as neonatal bleeding is often not due to VK-deficiency and VKDB may occur after the 4-week neonatal period. Definition. VKDB is bleeding due to inadequate activity of VK-dependent coagulation factors (II, VII, IX, X), correctable by VK replacement. Diagnosis. In a bleeding infant a prolonged PT together with a normal fibrinogen level and platelet count is almost diagnostic of VKDB; rapid correction of the PT and/or cessation of bleeding after VK administration are confirmative. Warning signs. The incidence of intracranial VKDB can be reduced by early recognition of the signs of predisposing conditions (prolonged jaundice, failure to thrive) and by prompt investigation of “warning bleeds”. Classification. VKDB can be classified by age of onset into early (<24 h), classical (days 1-7) and late (>1 week <6 months), and by etiology into idiopathic and secondary. In secondary VKDB, in addition to breast feeding, other predisposing factors are apparent, such as poor in-take or absorption of VK. VK-Prophylaxis: Benefits. Oral and intramuscular VK (one dose of 1 mg) protect equally well against classical VKDB but intramuscular VK is more effective in preventing late VKDB. The efficacy of oral prophylaxis is increased with a triple rather than single dose and by using doses of 2 mg vitamin K rather than 1 mg. Protection from oral doses repeated daily or weekly may be as high as from i.m. VK. VK-Prophylaxis: Risks. VK is involved in carboxylation of both the coagulation proteins and a variety of other proteins. Because of potential risks associated with extremely high levels of VK and the possibility of injection injury, intramuscular VK has been questioned as the routine prophylaxis of choice. Protection against bleeding should be achievable with lower peak VK levels by using repeated (daily or weekly) small oral doses rather than by using one i.m. dose. Breast feeding mothers taking coumarins. Breast feeding should not be denied. Supervision by pediatrician is prudent. Weekly oral supplement of 1 mg VK to the infant and occasional monitoring of PT are advisable. Conclusion. VKDB as defined is a rare but serious bleeding disorder (high incidence of intracranial bleeding) which can be prevented by either one i.m. or multiple oral VK doses.

* Before completion this report was sent to all members of the ISTH Pediatric/Perinatal Subcommittee. We are very grateful for the expert help, particularly of Corrigan JJ, Dreyfus M, Hagstrom N, Hathaway WmE, Lazerson J, Manco-Johnson MJ, Matthew P, Melnikow AP, Schlegel N.


 

  • References

  • 1 American Academy of Pediatrics. Committee on Nutrition. Vitamin K compounds and water soluble analogues: use in therapy and prophylaxis in pediatrics. Pediatrics 1961; 28: 501-7.
    PubMedGoogle Scholar
  • 2 Andrew M.. The relevance of developmental hemostasis to hemorrhagic disorders of newborns. Sem Perinat 1997; 21: 70-85.
    PubMedGoogle Scholar
  • 3 Ansell P, Bull D, Roman E.. Childhood leukemia and intramuscular vitamin K: findings from a case control study. Brit med J 1996; 313: 204-5.
    CrossrefPubMedGoogle Scholar
  • 4 Auerswald G, Sutor AH.. Thirteen cases of Alpha-1-Antitrypsin deficiency presenting as a bleeding diathesis with intracranial hemorrhage in the newborn. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds. >Stuttgart, New York: Schattauer; 1995: 217-23.
    Google Scholar
  • 5 Chaou W-T, Chou M-L, Eitzman DV.. Intracranial hemorrhage and vitamin K deficiency in early infancy. J Pediatr 1984; 105: 880-4.
    CrossrefPubMedGoogle Scholar
  • 6 Cornelissen EAM, Smeets D, Merkx G, de Abreu RA, Kollee L, Monnens LAH.. Analysis of chromosome aberrations and sister chromatid exchanges in peripheral blood lymphocytes of newborns after vitamin K prophylaxis at birth. Pediatr Res 1991; 30: 550-3.
    CrossrefPubMedGoogle Scholar
  • 7 Cornelissen EAM, Kollée LA, de Abreu RA, Motohara K, Monnens LAH.. Prevention of vitamin K deficiency in infancy by weekly administration of vitamin K. Acta Paediatr 1993; 82: 656-9.
    CrossrefPubMedGoogle Scholar
  • 8 Cornelissen EAM, Steeger S-T, heunissen R, Kollée LA, Eskes T, Vogel S-M, entink G, Motohara K, De Abreu R, Monnens LA.. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993; 168: 923-8.
    CrossrefPubMedGoogle Scholar
  • 9 Cornelissen EAM, SteegerS-Theunissen R, Kollée LA, Eskes T, Motohara K, Monnens LA.. Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol 1993; 168: 884-8.
    CrossrefPubMedGoogle Scholar
  • 10 Cornelissen EAM, Kollée LAA, van Lith TGPJ, Motohara K, Monnens LAH.. Evaluation of a daily dose of 25 μg Vitamin K 1 to prevent vitamin K deficiency in breast-fed infants. J Pediatr Gastroenterol Nutr 1993; 16: 301-5.
    CrossrefPubMedGoogle Scholar
  • 11 Cornelissen EAM, Hirasing R.. Epidemiological studies on the efficacy of vitamin K prophylaxis in the Netherlands. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995. a 149-52.
    Google Scholar
  • 12 Cornelissen EAM, Kollée L, De Abreu R, Monnens L, Widdershoven J.. Influence of vitamin K prophylaxis on vitamin K and PIVKA II plasma concentrations in breast-fed infants. Oral vs. parenteral application. Single vs. multiple small doses of oral vitamin K. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995. b 153-7.
    Google Scholar
  • 13 Cornelissen EAM, von Kries R, Loughnan P, Schubiger G.. Prevention of vitamin K deficiency-bleeding: efficacy of different multiple oral dose schedules of vitamin K. Eur J Pediatr 1997; 156: 126-30.
    CrossrefPubMedGoogle Scholar
  • 14 Deblay MF, Vert P, Andre M, Marchal F.. Transplacental vitamin K prevents haemorrhagic disease of infant of epileptic mother. Lancet 1982; I: 1242.
    PubMedGoogle Scholar
  • 15 Draper GJ, Passmore SJ.. Current UK studies on the possible association between vitamin K and childhood cancer. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 321-5.
    Google Scholar
  • 16 Eberl W.. Vitamin K deficiency despite intramuscular prophylaxis in a soyfed infant. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 241-3.
    Google Scholar
  • 17 Ekelund H, Finnström O, Källen B, Larsson Y.. Administration of vitamin K to newborn infants and childhood cancer. Brit med J 1993; 307: 89-91.
    CrossrefPubMedGoogle Scholar
  • 18 Ekelund H.. Vitamin K prophylaxis and vitamin K deficiency (VKD) bleeding in Sweden. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 173-4.
    Google Scholar
  • 19 Fondevila CG, Meschengiener S, Blanco A, Penalva L, Lazzari MA.. Effect of acenocoumarine on the breast-fed infant. Thromb Research 1989; 56: 29-36.
    CrossrefPubMedGoogle Scholar
  • 20 Golding J, Greenwood R.. Intramuscular vitamin K and childhood cancer: Two British studies. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 283-9.
    Google Scholar
  • 21 Hanawa Y, Maki M, Matsuyama E, Tada H, Urayama T, Yamada K, Mori H, Nagao T, Terao T, Mikami S, Shiraki K, Onishi S, Shirahata A, Tsuji V, Motohara K, Tsukimoto I, Sawada K.. The third nationwide survey in Japan of Vitamin K deficiency in infancy. Acta Paediatr Jpn 1990; 32: 51-9.
    CrossrefPubMedGoogle Scholar
  • 22 Hanawa Y.. Vitamin K deficiency in infancy: The Japanese experience. Acta Paediatr Jpn 1992; 34: 107-16.
    CrossrefPubMedGoogle Scholar
  • 23 Hansen KN, Ebbesen F.. Neonatal vitamin K prophylaxis in Denmark: three year’ experience with oral administration during the first three months of life compared with one oral administration at birth. Acta Paediatr 1996; 85: 1137-9.
    PubMedGoogle Scholar
  • 24 Hathaway WE.. Efficacy of vitamin K prophylaxis in the USA. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 161-3.
    Google Scholar
  • 25 Isarangkura PB, Mahadandana C, Panstienkul B, Nakayama K, Tsukimoto I, Yamamoto Y, Yonekubo A.. Vitamin K level in maternal breast milk of infants with acquired prothrombin complex deficiency syndrome. S East Asian J Tropical Med and Public Health 1983; 14: 275-6.
    PubMedGoogle Scholar
  • 26 Isarangkura P, Shearer MJ, Pintadit P, Grüter J, Sanmanoj T, Chuansumrit A, Sasanakul W, Hanck A, Hathirat P.. Oral vitamin K for the prevention of hemorrhagic disease of the newborn and idiopathic vitamin K deficiency in infants. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 349-53.
    Google Scholar
  • 27 Israels LG, Friesen E, Jansen AH, Israels ED.. Vitamin K1 increases sister chromatid exchange in vitro in human leukocytes and in vivo in fetal sheep cells: a possible role for “vitamin K deficiency” in the fetus. Pediatric Research 1987; 22: 405-8.
    CrossrefPubMedGoogle Scholar
  • 28 Israels LG, Israels ED.. Vitamin K deficiency in the fetus and newborn. Has nature made a mistake? In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 261-72.
    Google Scholar
  • 29 Klebanoff MA, Read JS, Mills JL, Shiono PH.. The risk of childhood cancer after neonatal exposure to vitamin K. N Engl J Med 1993; 329: 905-8.
    CrossrefPubMedGoogle Scholar
  • 30 von Kries R.. Vitamin K prophylaxis – a useful public health measure?. J Paediatric and Perinatal Epidemiology 1992; 6: 7-13.
    PubMedGoogle Scholar
  • 31 von Kries R, Funda J, Shearer M, Göbel U.. Late hemorrhagic disease of newborn: a case with increased vitamin K requirement. Acta Paediatr 1992; 81: 728-30.
    CrossrefPubMedGoogle Scholar
  • 32 von Kries R, Göbel U.. Vitamin K prophylaxis and late hemorrhagic disease of the newborn. Acta Paediatr Scand 1992; 81: 655-7.
    CrossrefPubMedGoogle Scholar
  • 33 von Kries R, Hanawa Y.. Neonatal vitamin K prophylaxis. Report of scientific and standardization subcommittee on perinatal hemostasis. Thromb Haemost 1993; 69: 293-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 von Kries R, Nöcker D, Schmitz-Kummer E, de Vries JX.. Transfer of phen procoumon in mother’s milk: Is an oral anticoagulant with phenprocoumon a contraindication for breast-feeding?. Mschr Kinderheilk 1993; a 141: 505-7.
    PubMedGoogle Scholar
  • 35 von Kries R, Göbel U.. Oral vitamin K prophylaxis and late haemorrhagic disease of the newborn. Lancet 1994; 343: 352.
    PubMedGoogle Scholar
  • 36 von Kries R, Hachmeister A, Göbel U.. Repeated oral vitamin K prophylax is in Germany: Acceptance and Efficacy. Brit med J 1995; 310: 1097-8.
    CrossrefPubMedGoogle Scholar
  • 37 von Kries R, Göbel U, Hachmeister A, Kaletsch U, Michaelis J.. Vitamin K and childhood cancer: a population based case-control study in lower Saxony, Germany. Brit med J 1996; 313: 199-203.
    CrossrefPubMedGoogle Scholar
  • 38 von Kries R.. Neonatal vitamin K prophylaxis: the Gordian knot still awaits untying. Editorial. Brit Med J 1998; 316: 161-2.
    CrossrefPubMedGoogle Scholar
  • 39 Loughnan P, McDougall PM.. The duration of vitamin K1 efficacy: Is intramuscular vitamin K1 acting as a depot preparation? In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 225-34.
    Google Scholar
  • 40 Mountain KR, Hirsh J, Gallus AS.. Neonatal coagulation defect due to anti-convulsant drug treatment in pregnancy. Lancet 1970; I: 265-8.
    PubMedGoogle Scholar
  • 40a McKinney PA, Juszczak E, Findlay E, Smith K.. Case-control study of childhood leukaemia and cancer in Scotland: findings for neonatal intramuscular vitamin K. BMJ 1998; 316: 173-7.
    CrossrefPubMedGoogle Scholar
  • 41 McNinch AW, Upton C, Samuels M, Shearer MJ, McCarthy P, Tripp JH, Orme L'ER.. Plasma concentrations after oral or intramuscular vitamin K1 in neonates. Arch Dis Child 1985; 60: 814-8.
    CrossrefPubMedGoogle Scholar
  • 42 McNinch AW, Tripp JH.. Haemorrhagic disease of the newborn in the British Isles: two year prospective study. Brit Med J 1991; 303: 1105-9
    CrossrefPubMedGoogle Scholar
  • 43 McNinch AW, Barton J, Tripp JH.. Vitamin K deficiency bleeding in the British Isles and the changing pattern of vitamin K prophylaxis. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 165-70.
    Google Scholar
  • 44 Olsen JH, Hertz H, Blinkenberg K, Verder H.. Vitamin K regimens and incidence of childhood cancer in Denmark. Brit Med J 1994; 308: 895-6.
    CrossrefPubMedGoogle Scholar
  • 45 Orme ML'E, Lewis PJ, Swiet de M, Serlin MJ, Sibeon R, Baty JD, Breckenridge AM.. May mothers given warfarin breast-feed their infants?. Br Med J 1977; 114: 1564-5.
    PubMedGoogle Scholar
  • 45a Parker L, Cole M, Craft AW, Hey EN.. Neonatal vitamin K administration and childhood cancer in the north of England. BMJ 1998; 316: 189-93.
    CrossrefPubMedGoogle Scholar
  • 46 Passmore SJ, Draper G, Brownbill P, Kroll M.. Case-control studies of relation between childhood cancer and neonatal vitamin K administration. Brit Med J 1998; 316: 178-84.
    CrossrefPubMedGoogle Scholar
  • 47 Passmore SJ, Draper G, Brownbill P, Kroll M.. Ecological studies of relation between hospital policies on neonatal vitamin K administration and subsequent occurrence of childhood cancer. Brit Med J 1998; 316: 184-9.
    CrossrefPubMedGoogle Scholar
  • 48 Sann L, Leclercq M, Guillaumont M.. Vitamin K in infancy. Eur J Pediatr 1988; 147: 177.
    PubMedGoogle Scholar
  • 49 Schubiger G, Tönz O, Grüter J, Shearer MJ.. Vitamin K and PIVKA II con centrations in breast-fed infants after prophylaxis with different preparations of Vitamin K. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 339-45.
    Google Scholar
  • 50 Shearer M.. Vitamin K metabolism and nutriture. Blood Reviews 1992; 6: 92-104.
    CrossrefPubMedGoogle Scholar
  • 51 Shearer MJ.. Chemistry, sources and metabolism of vitamin K with special reference to the newborn. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 21-32.
    Google Scholar
  • 52 Sutherland JM, Glueck I H, Gleser G.. Hemorrhagic disease of the newborn. Breast feeding as a necessary factor in the pathogenesis. Am J Dis Child 1967; 113: 524-33.
    CrossrefPubMedGoogle Scholar
  • 53 Sutor AH, Künzer W.. Time interval between Vitamin K administration and effective hemostasis. In: Perinatal Thrombosis and Haemostasis. Suzuki S, Hathaway WmE, Bonnar J, Sutor AH. eds Berlin, Heidelberg, New York, London, Tokyo, Hong Kong: Springer; 1991: 257-62.
    Google Scholar
  • 54 Sutor AH, Dagres N, Niederhoff H.. Vitamin-K-Mangelblutungen bei äuglingen unter besonderer Berücksichtigung der Spätform. Hämo staseologie 1992; 12: 116-26.
    PubMedGoogle Scholar
  • 55 Sutor AH.. Vitamin K deficiency bleeding in infants and children. A status report. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 3-18.
    Google Scholar
  • 56 Sutor AH, Dagres N, Niederhoff H.. Late form of vitamin K deficiency bleeding in Germany. Klin Pädiatr 1995; 207: 89-97.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Suzuki S, Maki M, Shirakawa K, Terao T.. Can perinatal vitamin K deficiency be prevented? In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 207-16.
    Google Scholar
  • 58 Thorp JA, Parriot J, Ferrette-Smith D, Meyer BA, Cohen GR, Johnson J.. Antepartum vitamin K and phenobarbital for preventing intraventricular hemorrhage in the premature newborn: a randomized, double blind, placebo-controlled study. Obstet Gynec 1994; 83: 70-6.
    PubMedGoogle Scholar
  • 59 Tönz O, Schubiger G.. Neonatale Vitamin-K-Prophylaxe und Vitamin-K-Mangelblutungen in der Schweiz 1986-1988. Schweiz med Wschr 1988; 118: 1747-52.
    PubMedGoogle Scholar
  • 60 Townsend CW.. The haemorrhagic disease of the newborn. Arch Paediatr 1894; 11: 559-65.
    PubMedGoogle Scholar
  • 61 Tripp JH, Al Khanan M, Shearer MJ, McNinch AW, Grüter J.. Low-dose vitamin K (Konakion MM) in newborns: Plasma vitamin K1, PIVKA II and International Normalized Ratio at four weeks of age. In: Vitamin K in Infancy. Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 355-60.
    Google Scholar
  • 62 Tripp JH, Cornelissen M, Loughnan P, McNinch A, Schubiger G, von Kries R.. Suggested protocol for the reporting of prospective studies of vitamin K deficiency bleeding (Previously called Hemorrhagic Disease of the Newborn). In Sutor AH, Hathaway WE. eds Stuttgart, New York: Schattauer; 1995: 395-9.
    Google Scholar
  • 63 Warkany J.. A warfarin embryopathy?. Am J Dis Child 1975; 129: 287-8.
    PubMedGoogle Scholar
  • 64 Widdershoven J, Lambert W, Motohara K. et al. Plasma concentrations of vitamin K and PIVKA-II in bottle-fed and breast-fed infants with and without vitamin K prophylaxis at birth. Eur J Pediatr 1988; 19: 354-7.
    PubMedGoogle Scholar
  • 65 Zipursky A.. Vitamin K at birth. Editorial. Brit med J 1996; 313: 179-80.
    CrossrefPubMedGoogle Scholar