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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 brinogen are similar to adult values.
Plasma concentrations of the naturally occurring anticoagulant
proteins (antithrombin, protein C, and protein S) are signicantly
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 deciency bleeding
(VKDB), the classical nomenclature is used: early (presenting
within the rst 24 h of life), classical (day 17 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 sterreichische Gesellschaft fr
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
1530 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 freshfrozen plasma, prothrombin complex preparations, and recombinant factor VIIa is discussed.
Key words: Placental barrier, neonatal coagulation system,
vitamin K deciency bleeding, vitamin K prophylaxis
Introduction
Summary. Coagulation factors do not cross the placental
barrier but are synthesized independently by the conceptus. At
Corresponding author: Ludwig Pichler, DVM, Prof, Department Toxicology/Pharmacology, Octapharma PPGmbH, Oberlaaer Strae 235,
1100 Vienna, Austria.
Fax: 43-1-61032-9249, E-mail: ludwig.pichler@octapharma.com
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placenta. The results of Avrech et al. [2] support the effectiveness of the human placenta barrier for IgA, IgD,
IgE, and IgM.
There are only few reports on hemostasis in the
newborn and the role of placental barrier. Szirmai [3, 4]
summarized the literature on this topic, which was
controversial at that time, and published his experiments in 1951. In 100 cases, the prothrombin content
of the mother, the neonate and the cord blood was
investigated (macromethod according to Quick, micromethod according to Soulier). A typical reaction pattern
was obtained in 92 cases: the prothrombin levels were
the same in the blood of the mother and in the cord
blood, but less in the blood of the neonates. According
to these results, Szirmai assumed that coagulation factors are able to cross the placental barrier. The reduced
concentration of coagulation factors in the neonates
was explained by the very high afnity of some fetal
tissues (liver?) to coagulation factors (which might
have been removed by this mechanism from the fetal
circulation).
Cade et al. [5] collected cord blood for coagulation
studies from 66 term and 35 premature neonates of
between 25-week and 37-week gestation. Neonatalmaternal comparisons were made on blood taken from
10 normal infants and their mothers. Remarkable and
signicant differences were found between neonatal
and maternal values especially regarding the factors
VII and X. There were, on the contrary, no signicant
differences in coagulation tests performed on umbilical,
venous and arterial blood samples. Authors reported
an almost complete placental barrier to coagulation
factors.
Reverdiau-Moalic et al. [6] are cited in recent
papers (e.g. [7]) as reference for an existing placental
barrier. Analysing coagulation factor levels in fetuses of
different age, full-term newborns, and adults, these
authors came to the conclusion that fetal hemostasis
is a dynamic system that evolves gradually toward the
neonatal state and then toward the adult state.
Male et al. [8] state that plasma coagulation
proteins do not cross the placental barrier but are
synthesized independently by the fetus, without presenting any experimental evidence or references. (Primarily these authors investigated coagulation factor
levels of fetuses at different weeks of gestation and of
infants during the rst 6 months of life.)
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Tab. 1: Factors of the hemostatic and brinolytic system which are different between fetuses/neonates
and adults (including FVIII; see text)
Parameter
Authors
2429 (D)
In adults
Full-term
3036 (38; D)
2831 (C)
F II
44.4
FV
41.7
11.1
28.7
41.7
44.4
1.08 U/ml
17.1
20.2
28.3
44.1
98.7%
67.9
1.06 U/ml
A
83.0
38.7
61.3
83.0
67.9
1.06 U/ml
32.1
36.8
48.9
89.9
99.8%
62.9
1.05 U/ml
A
63.8
26.7
35.2
63.8
62.9
1.05 U/ml
27.0
33.4
45.3
51.8
101.3%
101.0
112.1
79.8
112.1
101.0
34.5
35.5
50.1
94.3
101.8%
48.6
1.09 U/ml
A
32.1
0.99 U/ml
1.09 U/ml
9.2
16.5
32.1
48.6
1.09 U/ml
9.6
9.4
11.7
30.3
104.8%
37.7
1.06 U/ml
A
38.7
1.06 U/ml
19.8
33.9
38.7
37.7
1.06 U/ml
20.7
25.1
28.2
39.9
99.2%
39.2
0.97 U/ml
A
B
30.9
C
D
F XII
0.99 U/ml
39.4
F XI
0.99 U/ml
FX
1.05 U/ml
F IX
1.06 U/ml
F VIII
1.08 U/ml
F VII
1.08 U/ml
13.2
23.7
30.9
39.2
0.97 U/ml
12.1
14.8
37.1
100.2%
49.1
1.08 U/ml
A
B
0.97 U/ml
35.2
1.08 U/ml
(Continued)
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Tab. 1: (Continued)
Parameter
Authors
2429 (D)
In adults
Full-term
3036 (38; D)
2831 (C)
F XIII subcomponent A
subcomponent B
Antithrombin
20.4
23.1
35.2
49.1
1.08 U/ml
14.7
22.4
25.4
68.8
101.4%
75.2
78.4
1.05 U/ml
0.97 U/ml
A
B
66.7
83.5
66.7
83.5
A
B
Protein C
60.0
1.05 U/ml
1.05 U/ml
22.9
26.7
36.2
60.0
1.05 U/ml
20.2
30.1
37.2
59.5
99.8%
36.5
0.96 U/ml
A
29.2
11.5
Ag: 9.4
Act: 9.7
29.2
Ag: 12.0
Act: 10.5
Ag: 15.8
Act: 14.3
36.5
Ag: 32.2
Act: 28.5
28.3
total: 15.2
free: 21.9
total: 17.5
free: 28.3
total: 21.1
free: 27.5
Ag: 22.7
Act: 73.6
153.3
147.8
3.36 U/ml
3.36 U/ml
147.8
69.6
0.92 U/ml
total: 99.6%
free: 98.7%
166.3
Ag: 100.8%
Act: 98.8%
total: 38.7
free: 49.9
50.6
0.96 U/ml
0.92 U/ml
58.0
0.96 U/ml
39.1
1.05 U/ml
0.97 U/ml
Plasminogen
75.2
78.4
36.2
Protein S
1.05 U/ml
0.97 U/ml
0.92 U/ml
0.92 U/ml
166.3
0.92 U/ml
A [12], B [68], C [69], D [6], E [11]; Ag Antigen, Act Activity. Values given refer to activity measurements regarding the factors II, VII, IX,
X, XI, XII, protein C and S (where indicated), and plasminogen. Immunological methods were used for determination of antithrombin, protein C,
protein S, and von Willebrand factor.
during delivery [20]. The concentration of von Willebrand factor, containing large multimers [21], is increased (Table 1), contributing to the efcient von
Willebrand factor-platelet binding in neonates [22].
In summary, plasma concentrations of many coagulation proteins reach adult ranges by 6 month of
age; some individual coagulation proteins or inhibitors,
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Targeted population
Switzerland
2 mg (3: at 4 h after
birth, day 4, week 4)
0.5 mg
(also i.v.)
Germany
healthy babies
Czech Republic
not at risk
1 mg
pre-term, high-risk
1 mg
The Netherlands
plus
[57, 70]
or
1mg
according to [24]
plus
1 mg weekly up to 1 month
1 mg monthly up to 6 months
well babies
plus
formula-fed neonates
2 mg at birth; 2 mg before
discharge (day 27)
[74]
breast-fed infants
1 mg
0.51 mg
(or i.v.)
plus
Australia
New Zealand
25 mg daily (breast-fed;
duration not stated)
[55]
neonates at risk
USA (Canada)
[56]
[61]
2 mg at week 4
breast-fed
unwell babies
Denmark
oral
healthy newborns
sick newborns; preterm
newborns with i.v.-access;
infants unable to take
oral vitamin K
Reference
all newborns
0.51 mg
[32]
0.3 mg/kg
[71]
healthy infants
1 mg
1 mg
(infants < 1,500 g:
0.5 mg)
Japan
Thailand
not stated
or
1 mg
2 mg (3: at birth,
days 35, week 4)
[72]
[75]
[73]
Where not otherwise stated, all doses refer to vitamin K1 given at birth.
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isoniacid; vitamin K antagonists: warfarin, phenprocoumarin). The reported incidence (without vitamin K
supplementation during pregnancy) is 612%. Common bleeding sites are cephalohematoma, intracranial,
intrathoracic, and intra-abdominal. Hemorrhages are
often life threatening and usually not prevented by
vitamin K prophylaxis at birth.
As mentioned above, Hey [33] does not believe
that there is a distinct, early form of neonatal vitamin K
deciency that is different from, and more dangerous
than, the classical form of the disease. According to the
authors opinion, it would be more apt to say that such
babies are at greater risk of severe bleeding if they
sustain serious trauma during delivery, and they are
also more likely to develop classic symptoms later in the
rst week of life, unless given prophylactic vitamin K at
birth.
1314/2008
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immediately after birth orally with a synthetic, watersoluble analogue (prodrug), menadione (Synkavit). As
this was not effective in some babies, higher and higher
doses, up to 30 mg and more, were given. Under these
high doses, however, cases of hemolytic anemia leading
to severe jaundice and even death from kernicterus
were observed in premature babies [44, 45]. Doses were
reduced and menadione was replaced by the fat- soluble phytomenadione (phylloquinone, vitamin K1,
Konakion). The prophylaxis with intramuscular injection of 1 mg became routine (see [46]). Golding
et al. [47, 48] attempted to show an association between intramuscular (not oral!) vitamin K administration in newborns and an increased incidence in
childhood cancer (leukemia). After careful evaluation
of all upcoming reports the American Academy of
Pediatrics, Committee on Fetus and Newborn [32],
reiterated by [49], however, came to the conclusion
that a possible causal association has not been substantiated. In the mean time, a new water-soluble
preparation of Konakion was developed (introduced in Switzerland 1995). In this preparation
(Konakion MM paediatric, provided in ampoules),
vitamin K1 is solubilised by means of a colloid system
of bile acid-lecithin micelles (mixed-micelle system).
The product is suitable for oral, intramuscular and
intravenous administration.
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[1] Cohen SG. The placental transmission of antibodies and serum gglobulins. J Infect Dis, 87: 291298, 1950.
[2] Avrech OM, Samra Z, Lazarovich Z, Caspi E, Jacobovich A, Sompolinski D. Efcacy of the placental barrier for immunoglobulins:
correlation between maternal and fetal immunoglobulin levels. Int
Arch Allergy Immunol, 103: 160165, 1994.
[3] Szirmai E. Der plazentare bergang der Koagulationsfaktoren und
die Hypoprothrombinamie der Neugeborenen. Zentrbl Gynakol, 74:
10511056, 1952.
[4] Szirmai, E. Der plazentare bergang der Gerinnungsfaktoren und die
Koagulationsbeziehungen zwischen Mutter und Frucht. Folia Haematol Int Mag Klin Morphol Blutforsch, 74: 207220, 1956.
[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: 281283, 1969.
[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: 900906, 1996.
[7] Chalmers EA. Haemophilia and the newborn. Blood Rev, 18: 8592,
2004.
[8] Male Ch, Johnston M, Sparling C, Brooker LA, Andrew M, Massicotte
P. The inuence of developmental haemostasis on the laboratory
diagnosis and management of haemostatic disorders during infancy
and childhood. Clin Lab Med, 19: 3969, 1999.
[9] Lane PA, Hathaway WE. Vitamin K in infancy. J Pediatr, 106: 351359,
1985.
[10] Muntean W, Belohradksky BH, Klose HJ, Riegel K. Faktor-VIIIAktivitat und Faktor-VIII-assoziiertes Antigen bei Neugeborenen.
Klin P
adiat, 189: 412416, 1977.
[11] Schwarz HP, Muntean W, Watzke H, Richter B, Grifn JH. Low total
protein S antigen but high protein S activity due to decreased C4bbinding protein in neonates. Blood, 71: 562565, 1988.
Babies often show warning bleeds before presenting with VKDB. Bleeding, even in an apparently well
baby, requires urgent investigation. Bleeding from the
gut, nose bleeds, spontaneous bruises, and persistent
oozing from the umbilicus or after Guthrie testing must
not be ignored [37].
Intravenous vitamin K (1 mg; [63]) should be given
even before laboratory conrmation of the diagnosis
since vitamin K deciency bleeding carries always the
risk of intracranial bleeding. Intramuscular administration should be avoided (bleeding!); the intravenous
administration is impeded because of the theoretical
risk of anaphylaxis. The coagulopathy is usually corrected within a few hours after parenteral administration
because noncarboxylated procoagulants are readily
carboxylated in the presence of vitamin K [9]. In severe
bleeding, additional therapy with whole blood, fresh
frozen plasma or prothrombin complex preparations
may be indicated [25].
wmw
1314/2008
References
393
review
394
[37] McNinch AW, Tripp JH. Haemorrhagic disease of the newborn in the
British isles: two year prospective study. Brit Med J, 303: 11051109,
1991.
[38] Kries R von. Vitamin K prophylaxis a useful public health measure?
Paediatr Perinat Epidemiol, 6: 713, 1992.
[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 deciency in infancy. Eur J
Pediatr, 147: 472477, 1988.
[40] Ungchusak K, Tishyadhigama S, Choprapawon C, Sawadiwutipong
W, Varintarawat S. Incidence of idiopathic vitamin K deciency in
infants: a national, hospital based, survey in Thailand, 1983. J Med,
Assoc Thai, 71: 417421, 1988.
[41] Danielsson N, Hoa DP, Thang NV, Vos T, Loughnan PM. Intracranial
haemorrhage due to late onset vitamin K deciency bleeding in Hanoi
province, Vietnam. Arch Dis Child Fetal Neonatal Ed, 89: F546F550,
2004.
[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: 501506, 1961.
[43] Loughnan PM, McDougall PN. Epidemiology of late onset haemorrhagic disease: a pooled data analysis. J Paediatr Child Health, 29:
177181, 1993.
[44] Allison AC. Danger of vitamin K to newborn. Lancet, i: 669, 1955.
[45] Meyer TC, Angus J. The effect of large doses of Synkavit in the
newborn. Arch Dis Child, 31: 212215, 1956.
[46] Hey E. Vitamin K what, why, and when. Arch Dis Child Fetal
Neonatal Ed, 88: F80F83, 2003.
[47] Golding J, Paterson M, Kinlen LJ. Factors associated with childhood
cancer in a national cohort study. Brit J Cancer, 62: 304308, 1990.
[48] Golding J, Greenwood R, Birminham K, Mott M. Childhood cancer,
intramuscular vitamin K, and pethidine given during labour. Brit Med
J, 305: 341346, 1992.
[49] American Academy of Pediatrics. AAP publications reafrmed, May
2006. Pediatrics, 118: 1266, 2006.
[50] McNinch AW, Upton C, Samuels M, Shearer MJ, McCarthy P, Tripp
JH, Le Orme R. Plasma concentrations after oral or intramuscular
vitamin K1 in neonates. Arch Dis Child, 60: 814818, 1985.
[51] Schubiger G, Tonz O, Grter 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: 435439, 1993.
[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: 467472, 2000.
[53] Stoeckel K, Joubert PH, Grter 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: 421423, 1996.
[54] Costakos DT, Porte M. Did Controversies concerning vitamin K and
the newborn cover all the controversies? Pediatrics, 113: 1466-1467,
2004.
[55] Hansen KN, Ebbesen F. Neonatal vitamin K prophylaxis in Denmark:
three years experience with oral administration during the rst three
month of life with one oral administration at birth. Acta Paediatr, 85:
1137-1139, 1996.
[56] Cornelissen M, Kries R von, Loughan P, Schbinger G. Prevention of
vitamin K deciency bleeding: efcacy of different multiple oral dose
schedules of vitamin K. Eur J Pediatr, 156: 126130, 1997.
[57] Kries R von, Hachmeister A, Gbel U. Oral mixed micellar vitamin K
for prevention of late vitamin K deciency bleeding. Arch Dis Child
Fetal Neonatal Ed, 88: F109F112, 2003.
[58] Zwiauer K. Vorschlag zur Vitamin K-Prophylaxe bei Neugeborenen.
Mschr Kinderheilk, 151: 563564, 2003.
[59] Mandelbrot L, Guillaumont M, Leclercq M, Lefrere JJ, Gozin D, Daffos
F, Forestier F. Placental transfer of vitamin K1 and its implication in
fetal hemostasis. Thromb Haemost, 60: 3943, 1988.
[60] Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Motohara K,
Monnens L. Supplementation of vitamin K in pregnant woman
receiving anticonvulsant therapy prevents neonatal vitamin K deciency. Am J Obstet Gynecol, 168: 884888, 1993.
[61] Schubiger G, Laubscher B, Banziger O. Vitamin K-Prophylaxe bei
Neugeborenen: neue Empfehlungen. Available at: http://www.swisspaediatrics.org/paediatrica/vol13/n6/vitk_ge.html. 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: 15641565, 1977.
1314/2008
wmw
review
[63] Williams MD, Chalmers EA, Gibson BE. The investigation and management of neonatal haemostasis and thrombosis. Br J Haematol,
119: 295309, 2002.
[64] OShaugnessy 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: 1128, 2004.
[65] Dempe 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 padiatrischen Erkrankungen. Empfehlungen einer Expertengruppe. Med Klin, 102: 7081, 2007.
[66] Brady KM, Easley RB, Tobias JD. Recombinant activated factor VII
(rFVIIa) treatment in infants with hemorrhage. Pediatr Anesth, 16:
10421046, 2006.
[67] Hnseler C, Kribs A, Einger 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: 706713,
2006.
[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: 16511657, 1988.
wmw
1314/2008
395