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review

Wien Med Wochenschr (2008) 158/1314: 385395


DOI 10.1007/s10354-008-0538-7
 Springer-Verlag 2008
Printed in Austria

The neonatal coagulation system and the vitamin K


deciency bleeding a mini review
Ewald Pichler2 and Ludwig Pichler1
1
2

Department Toxicology/Pharmacology, Octapharma PPGmbH, Oberlaaer Strae, Vienna, Austria


Department of Paediatrics, Landeskrankenhaus Klagenfurt, St. Veiterstrae, Klagenfurt, Austria

Received August 9, 2007, accepted (after revision) February 20, 2008

Das neonatale Gerinnungssystem und die


Vitamin K Mangelblutung eine kurze bersicht
Zusammenfassung. Die vorliegende bersicht versucht einen
Bogen zu spannen von der Blutgerinnung und den Gerinnungsfaktoren des Neugeborenen ber 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 berschreiten nicht die Plazentabarriere, sondern werden vom Fetus gebildet. Bei der Geburt sind
die Faktoren des Vitamin K-abhangigen 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 ahnlicher Konzentration wie beim Erwachsenen vor. Die antikoagulatorischen Proteine wie Antithrombin, Protein C und Protein S sind signikant
erniedrigt. Plasminogen ist um etwa 50 % erniedrigt. Die Plattchen
liegen im Erwachsenen-Normalbereich, sind jedoch hyporeaktiv.
Die Konzentration des von Willebrand Faktors, der groe Multimere aufweist, ist erhht. 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: frhe Form, klassische Form und spate Form. Fr die
Vitamin K Prophylaxe wird ein kurzer historischer Rckblick
gegeben, anschlieend werden die Vitamin K Plasmaspiegel nach
gebrauchlichen Dosierungen beschrieben und schlielich wird
die fr sterreich empfohlene Prophylaxe wiedergegeben. Die fr
andere Lander gltigen Empfehlungen sind in einer Tabelle
zusammengefat. Den Schlu stellt eine kurze Darstellung der
Therapie der Vitamin K Mangelblutung dar.
,,

Schlsselwrter: Plazentabarriere, Gerinnungssystem des


Neugeborenen, Vitamin K Mangelblutung, Vitamin K Prophylaxe

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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The placenta forms an effective barrier and does


not allow macromolecules (e.g. proteins) to cross from
maternal to fetal circulation. The major exception is
the immunoglobulins (IgGs) [1]. Interestingly enough,
only Igs of the G class are transported across the
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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.)

The neonatal coagulation system


Plasma concentrations of the coagulation proteins
responsible for generating thrombin are different in
386

Pichler and Pichler The neonatal coagulation system

children and adults. At birth, concentrations of the


vitamin K dependent factors II, VII, IX, and X (serine
proteases, zymogens, synthesized in the liver) and the
contact factors XI and XII are reduced to about 50% of
normal adult values and are further reduced in preterm
infants (Table 1). Regarding the factors II, VII, IX, and X,
however, Lane and Hathaway [9] point out that the
coagulant activities are decreased, whereas the corresponding antigens are in the normal range. The concentrations of the factors V, VIII, XIII, and brinogen are
similar to adult values at birth. However, according to
the results of the group of Andrew [12, 68, 69] levels of
factor V and factor XIII are signicantly lower in fullterm infants than in adults. According to Muntean et al.
[10] factor VIII levels are elevated (activity, day 1: 156%;
antigen, day 2: 190%).
Plasma concentrations of the naturally occurring
anticoagulant proteins (antithrombin, protein C, protein S) are signicantly lower at birth than during the
adult years (Table 1). The activity of protein S, however,
is high because of very low levels of C4b-binding protein
[11]. (Protein C and S are also synthesized in the liver
depending on vitamin K.)
The activated partial thromboplastin time is significantly prolonged in healthy full-term infants, whereas
the prothrombin time is in the physiological range of
adults [12]. There is a discrepancy concerning thrombin
generation in neonates: according to Schmidt et al. [13]
and Andrew et al. [14] only 30 to 50% of peak adult
thrombin activity can be produced in neonatal plasma.
Muntean et al. [15], on the contrary, emphasized that in
neonates thrombin generation in a capillary wound
starts fast and is at least as strong as in adults and this
is exemplied by low levels of tissue factor pathway
inhibitor together with low levels of antithrombin [16].
The discrepancy mentioned is elucidated by technical
reasons: thrombin generation in neonates is only impaired when strong activators are used to start clotting
and this difference between neonates and adults cannot
be shown when small amounts of tissue factor are used
as activator [15]. The bleeding time (measured in vitro
using a Thrombostat 4000 device) is short in neonates,
even shorter than in their mothers [17]. In summary,
neonates have an excellent hemostasis, despite the
apparent functional immaturity, resulting in relatively
few clinical coagulation problems for the healthy term
infant.
All components of brinolysis are present at
birth. Plasminogen, however, one of the most important proteins of brinolysis, is reduced by approximately 50%, resulting in a relatively hypobrinolytic state (Table 1).
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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

Reference values (means)


In healthy fetuses/infants (day 1); % of adult values
Premature (weeks gestation)
1923 (27; C)

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

Reference values (means)


In healthy fetuses/infants (day 1); % of adult values
Premature (weeks gestation)
1923 (27; C)

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

Ag: not given


Act: not given

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

von Willebrand Factor

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.

Platelet counts are within the normal adult range


both in term and preterm infants [8]. Studies on platelet
functions, however, underscore that neonatal platelets
are hyporeactive compared with adult platelets [18, 19].
This hyporeactivity seems to be a developmental phenomenon and is obviously not due to pre-activation
of the clotting system, which takes place physiologically
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Pichler and Pichler The neonatal coagulation system

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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Tab. 2: Regimens of vitamin K prophylaxis in different countries


Country

Targeted population

Dosage and route


i.m.

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

2 mg (3: at birth, day


310, week 46)

[57, 70]

or

1mg

according to [24]

plus

1 mg weekly up to 1 month
1 mg monthly up to 6 months

well babies

1 mg at birth plus 25 mg daily


from week 1 to week 13 (breast-fed)
1 mg

plus

all breast-fed babies

formula-fed neonates

2 mg at birth; 2 mg before
discharge (day 27)

[74]

breast-fed infants

2 mg at birth; 2 mg before discharge


(day 27); 2 mg weekly or
25 mg/day (duration not given)

1 mg

0.51 mg
(or i.v.)

plus

antenatal (mothers treated


with drugs inhibiting
vitamin K activity)

Australia
New Zealand

25 mg daily (breast-fed;
duration not stated)
[55]

neonates at risk

USA (Canada)

[56]

2 mg at birth and 1 mg weekly


during the rst 3 months of life

infants at increased risk


France

[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

Doses should be repeated,


particularly in premature infants,
by a route of administration
decided for each dose accordingly
to the clinical state of the infant.
1020 mg/day for 1530 days
before delivery

all newborns

0.51 mg

[32]

newborns < 1,000 g

0.3 mg/kg

[71]

healthy infants

1 mg

unwell infants; unable to


take oral vitamin K; whose
mothers have taken
medications that interfere
with vitamin K metabolism

1 mg
(infants < 1,500 g:
0.5 mg)

Japan

all full-term newborns

Thailand

not stated

or

1 mg

2 mg (3: at birth,
days 35, week 4)

[72]

2 mg (3: day of birth, upon


discharge from the maternity
hospital, and at one month of age)

[75]

[73]

Where not otherwise stated, all doses refer to vitamin K1 given at birth.

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however, do not reach adult levels until early or late


childhood. These differences must be accepted as physiologic [23].

Vitamin K and vitamin K deciency


bleeding (VKDB)
In the past, the term haemorrhagic disease of the
newborn was used to describe bleeding in the newborn
(see [24]), which was not due to traumatic birth or to
hemophilia. Today the term vitamin K deciency
bleeding (VKDB) has been adopted [25], since not all
bleeding episodes in the newborn are due to vitamin K
deciency and bleeding due to this cause is not conned
to the newborn.
Vitamin K is a fat-soluble vitamin. There are two
naturally occurring forms, which have a common 2methyl-1,4-naphtoquinone nucleus but differ in the
structures of a side chain at the 3-position. Plants synthesize phylloquinone, also known as vitamin K1 (dietary
intake), which has a phytyl side chain. Gut bacteria
synthesize a range of vitamin K forms, designated as
menaquinones, also referred to as vitamin K2, which
have side chains based on repeating unsaturated 5carbaon (prenyl) units [26]. However, the intestinal bacteria predominating in breast-fed infants (lactobacillus)
do not synthesize menaquinones. Thus, the primary
source of vitamin K for infants is the small amounts of
vitamin K1 present in human milk. There is strong
evidence that vitamin K1 is absorbed across the intestinal
mucosa by an energy-dependent transport (see [9]).
Vitamin K is essential as a coenzyme of a carboxylase that catalyzes the gammacarboxylation of glutamic acid (Gla) residues in the proteins of the so-called
prothrombin complex (FII, FVII, FIX, FX, protein C,
protein S and protein Z). The gamma-carboxyl group
allows the coagulation factors to bind to calcium, which
permits localization on negatively charged phospholipid surfaces. This carboxylation occurs in the rough
endoplasmic reticulum of the hepatocyte. Under-carboxylated forms (called PIVKAs Protein Induced in
Vitamin K Absence) are unable to participate in the
normal coagulation cascade.
(Besides the prothrombin complex extra-hepatic
Gla proteins were described: osteocalcin and matrix Gla
protein. Impairment of the function of these proteins
owing to incomplete carboxylation results in an increased risk for developing osteoporosis and vascular
calcication, respectively; see [27].)
The daily need of vitamin K, dened by the AI
(adequate intake), is 2 mg/day for 0 to 6-month-old
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Pichler and Pichler The neonatal coagulation system

babies assuming an average vitamin K concentration


of 2.5 mg/l in human milk with an average milk intake of
0.78 l/day [28]. The AI for babies between 7 months and
12 months is given with 2.5 mg/day.
At birth, plasma levels (cord) of vitamin K are often
below the detection limit of 0.02 ng/ml in healthy newborns [29] because vitamin K1 does not readily cross the
placental barrier from mother to child [30]. Measurable
values are usually found about 12 hours after birth and
adult levels of 0.4 ng/ml by day 4 in breast-fed babies
given no vitamin K supplement [29], i.e. the sub-clinical
vitamin K deciency in the rst 23 days of life is selflimiting.
VKDB can be classied by age of onset (see
below) and by etiology into idiopathic and secondary
[25]. In idiopathic VKDB no cause other than breastfeeding can be demonstrated. In secondary VKDB
additional factors are diagnosed, such as poor intake
of milk, malabsorption of vitamin K because of liver
(hepatobiliary disease, predominantly cholestasis) or
bowel disease or antagonism of vitamin K by drugs
[25]. Even though it is rare, the congenital deciency
of vitamin K dependent factors caused by genetic
mutations should be mentioned here. Thirteen families have been represented so far. The phenotype
varies considerably with respect to bleeding tendency and response to vitamin K substitution. The cause
of the phenotype is unknown in nine families, and
is due to a defect in the gamma-carboxylase enzyme
in one family or due to a defect in a protein of the
vitamin K 2,3-epoxide reductase complex in three
families [31].
The traditional classication of vitamin K deciency bleeding according to age of onset distinguishes
between an early VKDB, the classical form and the late
VKDB. Today, the early and the classical form seem to
be pooled as the early VKDB, dened as an unexpected bleeding (0.251.7% incidence) during the rst
week of life in previously healthy-appearing neonates
[32]. This reclassication is based obviously on the
paper of Hey [33], who queried the traditional early
form as a distinct entity.
In the present review, however, the old classication will be retained for the sake of clearness.

The early VKDB


The early VKDB occurs within the rst 24 h of
life. It is rare and is conned to infants of mothers who
have received medications interfering with the vitamin
K metabolism (anticonvulsants: phenytoin, barbiturates, carbamazepam; antitubercular drugs: rifampicin,
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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.

The classical VKDB


The classical VKDB, occurring between 1 and 7
days after birth, is more common in infants who are
unwell at birth or who have delayed onset of feeding.
The incidence reported in the literature is variable going
up to 1.5%. Bleeding is usually from the umbilicus, the
gastrointestinal tract (melena neonatorum), the skin,
the nose, from surgical sites (circumcision) and uncommonly in the brain. (In a clinical trial of Sutherland
intracranial hemorrhage occurred in only 0.5% of all
infants who bled, and 4% of those with moderate and
severe bleeding; see [43].)

The late VKDB


The late VKDB, an apparently new condition,
emerged in Europe in the early 1980s. This form occurs
from 8 days to 6 months after birth, most presenting at 2
to 3 months. It is almost completely conned to fully
breast-fed infants. These babies are at an increased risk
of vitamin K deciency for the following reasons: i)
human milk is relatively low in vitamin K compared to
formula milk (see below), ii) the newborns intestines
are not yet colonized with bacteria that synthesize
vitamin K2, and iii) the vitamin K epoxide cycle may
not be fully functional in newborn, especially premature
infants [34]. (This cycle allows a small amount of vitamin
K to function in the gamma-carboxylation of proteins
many times, decreasing the dietary requirement.)
Koppe et al. [35] discuss the possibility that
polychlorinated biphenyls, polychlorinated dibenzop-dioxines, and polychlorinated dibenzofuranes preswmw

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ent in breast milk in industrial countries promote this


disease. It is plausible that these strong chemical
enzyme inducers interfere with quinone metabolism.
(Both forms of the vitamin [K1 and K2] are quinones).
In a human infant with a low vitamin K intake in breast
milk, an increased quinone metabolism may lead to a
vitamin K deciency with the hemorrhagic diathesis
mentioned.
The vitamin K1 content of mature human milk
ranges between 1 and 4 mg/l, with average concentrations near the lower end of this range [26, 36]. There is
considerable intra- and inter-subject variation, and
levels are higher in colostral milk than in mature milk
[26, 36]. Vitamin K2 concentrations in human milk
appear to be much lower than those of vitamin K1. The
concentrations of vitamin K1 in infant formula milk
range from 3 to 16 mg/l in unsupplemented formulas
[26, 36] and up to 100 mg/l in fortied formulas. Currently most formulas are fortied with a typical vitamin
K1 concentration of about 50 mg/l [26].
In infants who receive no prophylaxis at birth, late
onset VKDB has been reported. This is more commonly
seen in Asian countries and in warmer climates; boys
are more often affected than girls. The estimated incidence was <0.005% (<5 per 100,000 births) in the UK
[37], 0.0071% in Germany [38], 0.02% in Japan [39],
0.035% in Thailand [40], and 0.116% (116 per 100,000)
in Vietnam [41]. The latter percentage is only based on
cases presenting with intracranial hemorrhage. The real
incidence of late VKDB, therefore, might even be higher.
Interestingly, no gures on the incidence of late VKDB in
the US were found to be related to the fact that in this
country the parenteral vitamin K prophylaxis is routine
since 1961 [42].
About half of the infants have underlying cholestatic liver disease (biliary atresia, alpha1 antirypsin
deciency) or occasionally other malabsorptive states.
(Bile salts are essential for the intestinal absorption of
the fat-soluble vitamin K by micellar solubilisation.)
More than 60% of the infants present with
an acute intracranial hemorrhage [43]. The mortality
is 1015%, and at least 40% of the survivors have longterm neurological sequelae. Other sites of bleeding
are skin, gastrointestinal tract, umbilicus or surgical
sites.

The vitamin K prophylaxis


History
In the 1950s, vitamin K prophylaxis started on a
broad basis. Most maternity units treated infants
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Vitamin K prophylaxis and resulting


plasma levels
The vitamin K1 plasma concentration is 0.4 ng/ml
(range 0.170.68) in adults, as mentioned above.
McNinch et al. [50] determined the plasma levels after
1 mg vitamin K1 given orally or intramuscularly to
babies at birth. After oral application the peak concen-tration (73 ng/ml) was reached at 4 h; by 24 h the
concentration had fallen to 23 ng/ml. Intramuscular
administration gave a peak with 1781 ng/ml at 12 h; at
24 h the concentration was 444 ng/ml. Schubinger et al.
[51] tested Konakion MM in healthy, fully breast-fed,
newborn babies at single doses of either 1.5 mg i.m. or
3 mg p.o. Plasma levels were (i.m.) 146 ng/ml at 25 h,
34 ng/ml at 4 days, and 1.05 ng/ml at 24 days; the
corresponding values after p.o. administration were
89 , 51, and 0.44 ng/ml. The intravenous administration
of Konakion MM was evaluated by Raith et al. [52]: a
single dose of 0.3  0.1 mg/kg was given to 14 preterm
and 4 sick newborns. After 22.9  18.4 hours the plasma
level was 191.3  102.6 ng/ml, after 111.8  49.1 h it was
98.7  75.2 ng/ml (n 10).
392

Pichler and Pichler The neonatal coagulation system

The results with single doses of 3 mg p.o., which is


above the recommended dose of 2 mg (given 3 times,
see below), and 0.3 mg/kg i.v., which is the recommended dose, are most interesting : i) initially plasma levels
are measured which are several hundred times above
the physiological values, ii) the effect is long lasting, up
to 24 days in the case of oral treatment, and this is in
excellent agreement with a median terminal half-life of
76 h as postulated by Stoeckel et al. [53] for vitamin K1 in
neonates.
Excessively high serum levels of vitamin K were
measured in preterm infants treated with 0.5 and 1 mg
vitamin K, which received additional vitamin K via total
parenteral nutrition [54]. However, there are no toxic
effects of vitamin K reported in these infants. In general,
there is no clinical syndrome attributable to hypervitaminosis of vitamin K1.

The vitamin K prophylaxis today


There was (and still is) a broad discussion on the
right vitamin K prophylaxis: what is the right dose,
what is the right dose regimen, what is the right application route, what is the most appropriate formulation
[5557]? There is, however, consensus that one single
dose of vitamin K can prevent late VKDB if given i.m. or
s.c., but not if given orally. Repeated oral doses might be
as effective as the parenteral dose but the optimal dose
regimen remains to be established [56].
For Austria, the GKJ (sterreichische Gesellschaft
fr Kinder- und Jugendheilkunde) edited the following recommendations, the preparation mentioned is
Konakion ,,Roche Mischmizellenlsung-Ampullen
(Roche Austria GesmbH, 1210 Vienna, Austria) [58]:
1. Healthy full-term babies and orally fed preterm babies should receive 3 times 2 mg vitamin K per os:
after birth, at days 46, and at an age of 46 weeks.
2. Small preterm babies and sick full-term babies
should be treated after birth with 0.3 mg/kg vitamin
K (maximum 1 mg ) i.m. or i.v. The daily vitamin K
supply should be 510 mg/kg. All babies should be
treated orally with 2 mg vitamin K at the age of 4
weeks (or at discharge from the hospital, if earlier).
3. Mothers who take medications, which interfere with
the vitamin K metabolism, should receive 1020 mg
vitamin K per day on the last 1530 days of
pregnancy.
The last point is still under debate, although
prenatal administration of vitamin K to pregnant mothers is effective in raising vitamin K levels in the cord
blood: cord blood concentrations of vitamin K were
raised by nearly 60 times when mothers received 20 mg/
,,

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.

1314/2008

wmw

review

day orally for at least 3 days before delivery [59]. On the


basis of their results, Cornelissen et al. [60] also recommend vitamin K1 supplementation during the last days
of pregnancy in mothers on a regimen of enzymeinductive anticonvulsant medication to prevent vitamin
K deciency in their neonates. The Schweizerische
Gesellschaft fr Padiatrie on the other hand made the
following statement [61]: pregnant women who take an
enzymeinducing medication (phenobarbital, phenytoin, carbamazepine, primidone, rifampicin, INH) on a
regular basis, normally do not need an antenatal vitamin K substitution. Exceptions stated are i) planned
delivery before week 37 of pregnancy, ii) therapy with a
combination of the drugs mentioned above, and iii)
hepatic disease of the mother.
The situation in babies of breast-feeding mothers
taking oral anticoagulants is not covered by the GKJ
recommendations. Although the transfer of these substances into the milk is minimal [62], even trace
amounts of anticoagulants in breast milk might precipitate a VKDB in babies whose vitamin K status is already
critical. A weekly oral supplement of 1 mg vitamin K to
the infant is recommended [25].
The prophylactic regimens of some other countries are summarized in Table 2. Of special interest are
the low daily doses as recommended in The Netherlands. The UK recommendations are not included in
Table 2, because several prophylactic regimens are
described as equally effective by the corresponding
guideline [63].

According to a recommendation of the British


Committee for Standards in Haematology [64] children
born after 1 January 1996 should receive only pathogenreduced plasma. There are two methods of inactivating
pathogens in plasma for clinical use: treatment with
methylene blue and light (MBFFP) and solvent/detergent (SDFFP). MBFFP is available in small packs. SDFFP
has been used in neonates and infants and no shortterm toxicity has been reported. The recommended
dose is 1020 ml/kg [64].
No direct data are available for the use of prothrombin complex preparations (e.g. Octaplex, Beriplex, Prothromplex-T) in the neonate. Extrapolation of
adult studies would suggest a dose of 50 IU/kg [63].
Recombinant factor VIIa (rVIIa) might be an option in acute intracranial bleeding, but there is only
limited experience with rVIIa in neonates. Dempe
et al. [65] summarize 28 bleeding episodes in 27 neonates (nine different papers), the publications of Brady
et al. and Hnseler et al., however, are not included.
Brady et al. [66] treated nine infants (two thereof
with vitamin K deciency and intracranial bleeding),
Hnseler et al.[67] three cases. In summary, there is
preliminary evidence that rFVIIa (at 90200 mg/kg) is
not only effective, but also well tolerated by patients.
Intensive care unit-actions like ventilatory support
or operation of hematomas etc. are not covered by this
review.

Therapy of the VDKB

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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
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