Vitamin K Deficiency Bleeding (VKDB) in Early Infancy

Martin J. Shearer PhD, FRCPath

The Centre for Haemostasis and Thrombosis, St Thomas' Hospital, UK

Address for correspondence:

Martin J. Shearer PhD, FRCPath

Centre for Haemostasis & Thrombosis

First Floor North Wing

St Thomas’ Hospital

Westminster Bridge Road

London SE1 7EH

Telephone: +44 (0)207 7188 2801

Fax: +44 (0)207 7401 3125

Email 1. martin.shearer@gstt.nhs.uk

Email 2. martin.shearer@kcl.ac.uk

1
Summary
Vitamin K Deficiency Bleeding (VKDB) is a rare and potentially life-threatening bleeding
disorder of early infancy. Vitamin K stores are low at birth; thereafter breast-fed infants are
at risk because of low concentrations in human milk. Classical VKDB occurs in the first
week of life, is related to delayed or inadequate feeding and is readily prevented by small
doses of vitamin K at birth. Late VKDB peaks at 3-8 weeks, typically presents with
intracranial haemorrhage often due to undiagnosed cholestasis with resultant malabsorption
of vitamin K. Diagnosis can be difficult but PIVKA-II measurements can provide
confirmation even several days post-treatment. Without vitamin K prophylaxis, the incidence
of late VKDB in Europe is 4-7 cases per 105 births; it is higher in SE Asia where in rural,
low-income areas some 0.1% of affected infants may suffer intracranial bleeding. Late
VKDB is largely preventable with parenteral vitamin K providing the best protection. The
efficacy of oral prophylaxis is related to the dose and frequency of administration. Most
multi-dose oral regimens provide protection for all except a small reservoir of infants with
undetected hepatobiliary disease. Targeted surveillance of high-risk groups (e.g. biliary
atresia) offers a novel approach to assess efficacy of prophylaxis.

Key Words
Vitamin K
Phylloquinone
Menaquinones
Vitamin K deficiency bleeding
Bleeding in infancy
Vitamin K prophylaxis

2
A Introduction
The first description of a coagulopathy that had all the attributes of severe vitamin K (VK)
deficiency is accredited to a Boston physician, Charles Townsend who in 1894 described 50
cases of a generalized bleeding tendency in neonates, which he thought sufficiently similar to
classify as a single entity and which he named the Haemorrhagic Disease of the Newborn
(HDN) 1. Townsend noted that HDN could be differentiated from haemophilia by its much
earlier time of presentation (usually on days 2 to 3), lack of family history and by its self-
limiting time course. Commenting on the complete recovery of one particular 9-day old
infant with presumed meningeal haemorrhage, considered by the first physician to be a
‘bleeder’ (haemophiliac) and a hopeless case, Townsend noted “The belief that the disease
was self-limited, with careful artificial and wet nurse feeding, the mother’s supply proving a
failure, was what saved the baby”. Thus Townsend made the first recorded link between the
mother’s capacity to breast-feed and the haemostatic capacity of her newborn infant 1. The
fascinating history of VKDB in infancy has been reviewed by Hathaway 2, a history that is
littered with uncertainties and controversies on the extent of the problem and the role of VK
prophylaxis in public health that still persist to the present day.

The name change from HDN to vitamin K deficiency bleeding (VKDB) was recommended
by the ISTH Pediatric/ Perinatal Subcommittee in 1999 to clarify that the etiological basis
was solely due to VK-deficiency and to include those infants who develop VKDB beyond the
usually defined 4-week neonatal period 3. Finally, the new name avoids any possible
confusion of HDN with haemolytic disease of the newborn. Though VKDB is rare in most
developed countries, the consequences for the few who develop it are potentially catastrophic
with over 50% of infants with late VKDB (post 1-week) presenting with intracranial
haemorrhage (ICH) 4. For this reason nearly all developed countries have introduced
prophylactic measures for its prevention. The inability to identify infants at risk has meant
that prophylaxis is either given to all newborns or to those whose mothers intend to
exclusively breast-feed them. Protection of breast-fed infants is important because VKDB is
strongly associated with breast-feeding and is rare in formula-fed infants. A few countries
such as the UK, Germany and the Netherlands have surveillance schemes in place to monitor
the effectiveness of VK prophylaxis.

The classical role of VK is as an anti-haemorrhagic factor that is needed for the synthesis in
the liver of functional forms of prothrombin (factor II) together with factors VII, IX and X 5.
After secretion into the blood, these four VK-dependent proteins become available to take
part in blood coagulation, the complex series of events that, once initiated, culminates in the
conversion of fibrinogen to fibrin and the formation of a haemostatic plug. The biochemical
role of VK is to act as a cofactor for the conversion of specific peptide-bound glutamate (Glu)
residues to -carboxyglutamate (Gla) residues. Hence VK-dependent proteins are often
known as Gla-proteins. Two other Gla-proteins, proteins C and S, have well-defined roles in
the negative feedback control of coagulation. Put simply, a deficiency of VK is a failure to
synthesize -carboxyglutamic acid. The consequences of VK-deficiency for haemostasis are
an inability to synthesize functional molecules of factors II, VII, IX and X resulting in a
hypocoagulable state. The haemostatic system has a considerable capacity to function
adequately at low factor concentrations but as deficiency progresses a point will be reached
when the procoagulatory mechanisms fail and bleeding occurs. This point is highly
individual and unpredictable.

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A Nutrition and physiology of vitamin K in the healthy infant
Naturally occurring compounds with VK activity have a common 2-methyl-1, 4-
naphthoquinone nucleus and a variable alkyl substituent at the 3 position. The VK found in
the plant kingdom is phylloquinone (vitamin K1) whereas the multiple forms of VK
synthesized by bacteria are menaquinones (vitamins K2). Phylloquinone has a phytyl side
chain whereas menaquinones have multi-prenyl side chains, the number of prenyl units being
indicated by a suffix (i.e. menaquinone-n, abbreviated MK-n). In the pharmaceutical and
pharmacological literature, synonyms for phylloquinone are ‘Phytomenadione’ (Europe) and
‘Phytonadione’ (USA). In Japan the major product used for VK prophylaxis in infants are
oral preparations of menaquinone-4 (MK-4) with the trade name ‘Menatetrenone’. The
synthetic compound 2-methyl-1, 4-naphthoquinone (trivial name menadione) lacks biological
activity per se but the body is able to add on a geranylgeranyl side chain to produce MK-4; in
this sense menadione may be regarded as a provitamin K. Water-soluble salt forms of
menadione such as Synkavit(e) were abandoned for prophylaxis of VKDB in the 1960s
because of toxicity issues but are still used for this purpose in some developing countries.

B Vitamin K contents of breast and formula milks

Based on the early link made by paediatricians such as Salomonsen in the 1930s between
breast feeding and VKDB, and the protection offered by cows’ milk 6, the Danish Biochemist
and discoverer of VK, Henrik Dam employed a chick curative bioassay to measure the VK
content of human and cows’ milks. The values he obtained of 15 g/litre for breast milk and
60 g/litre for cows’ milk 7 came to be widely cited in the literature. In fact this cows’ milk
concentration of 60 g/litre formed the basis for the fortification level of infant formulas
recommended in 1971 by the American Academy of Pediatrics 8, a level which remains
substantially unaltered to the present day. Later values obtained using physiochemical
techniques showed that the bioassay overestimated VK contents 9. The highest
concentrations of VK in breast milk are provided by phylloquinone, the next highest by MK-
4 and there are trace concentrations of some higher menaquinones (MKs 6 to 8) 10, 11. With
standardized sampling techniques, average concentrations of phylloquinone in colostrum and
mature human milk are now known to be about 2 g/litre and 1 g/litre respectively 12.

The presence of MK-4 in breast milk at concentrations that are about half those of
phylloquinone 11 is of interest with respect to its origin because MK-4 is neither a common
bacterial form nor a major dietary form. However, recent evidence suggests that MK-4 in
breast milk is derived by synthesis in the body from dietary phylloquinone, either synthesized
in the mammary gland or selectively taken up 11.

As shown in Table 1, there is a huge disparity in the measured daily intakes of about 1 g/d
of phylloquinone in infants who are exclusively breast-fed compared to infants fed a typical
formula milk (supplemented to 55 g/litre) in whom intakes average about 50 g/d 13.

B Assessment of vitamin K status

Traditional screening tests for VK deficiency are based on global coagulation assays such as
the prothrombin time (PT) and the activated partial thromboplastin time (APTT). These are
simple to perform but a lengthening of the PT is not specific to VK deficiency and needs to
be confirmed by demonstrating that two or more of the four VK-dependent procoagulants are
specifically reduced. The most useful confirmatory test is to show that the PT (and individual
factors) can be restored by VK administration. Inherent to the PT is its insensitivity,
becoming prolonged only when the prothrombin concentration drops below about 50% of

4
normal 14. Thus while the PT is appropriate for diagnosis of overt VK deficiency, it is not
useful for picking up subclinical deficiency.

When the supply of VK is insufficient, abnormal, functionally defective molecules of VK-

coagulation factors are released into the bloodstream. These abnormal molecules comprise a
heterogeneous spectrum of undercarboxylated or partially carboxylated molecules. The
historical collective abbreviation for these undercarboxylated species is PIVKA (Proteins
Induced by Vitamin K Absence or Antagonism). The development of assays to detect
undercarboxylated prothrombin (PIVKA-II) has proved to be extremely useful as a functional
marker of subclinical VK deficiency in infants 14, 15. The most sensitive assays are enzyme
immunoassays (EIA) using antibodies that recognize PIVKA-II but do not cross-react with
native factor II 16, 17.

The major circulating form of VK is phylloquinone and its measurement in serum is a useful
status indicator. Reference values in healthy adults range from 0.2-1.0 g/litre with a median
of around 0.5 g/litre. The common hepatic forms MKs 9 to 13 have not been detected in
plasma although there is evidence that MK-7 and perhaps MK-8 are present at lower
concentrations than phylloquinone. Dietary restriction of VK leads, within a few days, to a
rapid decline in plasma levels of phylloquinone 18.

B Vitamin K status of the normal breast-fed infant

C Coagulation factor concentrations
The first detailed studies of developmental changes during infancy by the late Maureen
Andrews in Canada indicated that the plasma concentrations of the VK-dependent
coagulation factors in healthy, full-term infants are about half of normal adult values although
there is a 3 to 6 fold range 19. After birth the plasma concentrations rise gradually and attain
adult values by about 6 months 19. Since all the infants in these Canadian studies had
received VK prophylaxis by intramuscular (IM) injection (1 mg at birth) the low factor
concentrations reflect a reduced synthesis of the core proteins rather than a failure of VK-
dependent -carboxylation. However, it has long been appreciated that if VK is not given at
birth, VK-dependent factors may fall during the first week of life. Aballi and de Lamerens 20
collated early-published work on the natural course of prothrombin activity in breast-fed
infants who had not been given VK at birth. Their meta-analysis showed that prothrombin
activity follows a U-shaped curve falling rapidly after birth to a trough by the second or third
day before recovering again to initial concentrations by six days 20. It is likely that this trough
reflects an early nutritional deficit of VK.

C Abnormal or Undercarboxylated Coagulation Factors (PIVKA)

The use of several methodologies for PIVKA-II with different sensitivities often makes their
interpretation difficult. In the past, the failure to detect PIVKA-II in cord blood using
relatively insensitive methods led to false assumptions that the VK status of newborns was
adequate and that VK prophylaxis was unnecessary 21. Using sensitive EIA methodologies,
PIVKA-II is often found to be raised in cord blood; for example a similar prevalence of
detectable PIVKA-II of around 20% was reported in full-term babies in Japan 16 and in pre-
term babies in England 17. In babies not given VK at birth, the time course of PIVKA-II in
infants confirms that many have a temporary dip in VK status in the first week of life as
suggested by Aballi and de Lamerans 20 from coagulation data. Thus, even using a relatively
insensitive electrophoretic assay, PIVKA-II was readily detectable on the fifth day of life in
about 70% of breast-fed infants 22. PIVKA-II measurements by sensitive EIA reveal that
some infants still have suboptimal VK status at 1-2 months and that a higher prevalence of

5
PIVKA-II is related to both exclusive breast-feeding and lack of VK prophylaxis 23, 24. After
administration of VK to correct VKDB, PIVKA-II is cleared from the circulation at a similar
rate to native carboxylated prothrombin (half-life of about 60 h). This means that PIVKA-II
can be used to detect VK deficiency retrospectively even after VK has been administered.

C Plasma concentrations and tissue stores of vitamin K

Concentrations of VK in cord blood are extremely low compared to those in adults 25. There
is no accepted reference range, but best estimates suggest that cord concentrations are
generally <0.05 g/litre. Estimates of the maternal/fetal concentration gradient lie between
20:1 and 40:1 and show that VK has by far the highest placental blood gradient of any of the
fat-soluble vitamins 25. Plasma phylloquinone concentrations begin to be measurable in
breast-fed infants at around 12-24 hours after delivery and by 3-4 days their plasma
concentrations are within the same range as adults 25. The large disparity in dietary intakes
between breast- and formula-fed infants is reflected in plasma concentrations that may be an
order of magnitude higher in infants who are exclusively fed with supplemented formulas
(Table 1).

C Liver reserves
The needs of the human fetus and neonate are largely met by phylloquinone 25. This is
reflected in the findings that whereas the long-chain MKs (mainly MKs 7 to 13) make up the
majority of adult reserves (~90%) they are absent, or very low, at birth and build up slowly
over several weeks 25. This means that total liver stores of VK at birth are very low compared
to adults. This slow build up of hepatic MKs would be consistent with the colonization of the
neonatal gut by MK-producing bacteria although some dietary contribution cannot be ruled
out. The implication that low hepatic reserves of MKs may be a major contributory factor to
the brittleness of neonatal VK status is enticing but presently lacks hard evidence. In fact the
larger question of the relative importance of MKs to human nutrition still remains
unanswered. In reviewing the evidence, Suttie 26 concluded that although MKs may partially
satisfy the human requirement for VK, their contribution is probably much less than
previously thought.

A Classification and etiology of VKDB

In 1985 Lane and Hathaway 27 gave a detailed description of three patterns of VKDB (Table
2 ), which is still widely accepted and recognized by the Pediatric/Perinatal subcommittee of
the International Society on Thrombosis and Haemostasis (ISTH) 3. It has been customary to
differentiate between idiopathic and secondary VKDB. In secondary VKDB there is an
underlying cause, usually an undiagnosed disease such as a hereditary
hepatobiliary/malabsorptive disease (e.g. biliary atresia, -1-antitrypsin deficiency, cystic
fibrosis) or the effects of drugs that have been given to the mother or infant 27. Exclusive
breast-feeding is a common risk factor for both secondary and idiopathic VKDB 27.

B Early VKDB
Early VKDB is defined as bleeding attributable to VK deficiency in the first 24 hours of life.
It is rare and is typically seen in infants whose mothers have been prescribed drugs that
interfere with VK metabolism, by mechanisms that are known (oral anticoagulants such as
warfarin) or uncertain (anticonvulsants e.g. phenytoin; antituberculous drugs e.g. rifampicin,
isoniazid).

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B Classical VKDB
Defined as VKDB between days 2 and 7, classical VKDB is often regarded as idiopathic but
a known cause, largely hidden, is inadequate feeding. Maternal drugs taken during
pregnancy may also contribute. The typical window of presentation between days 2 and 3
noted by Townsend 1 corresponds to the already mentioned natural dip in prothrombin
activity seen in early coagulation studies 20. The importance to VK status of the successful
establishment of breast-feeding is supported by several coagulation studies, some of which
have employed PIVKA-II as a sensitive functional marker of VK status. Von Kries and
coworkers 22 showed that VK status is strongly related to the cumulative intake of human
milk in the first week of life. Thus, fully breast-fed infants who had a raised PIVKA-II (by
immunoelectrophoresis) and factor II activities of <25% of normal on day 5 were shown to
have received <100 ml milk/d over the first 4 days. In contrast, infants who had factor II
levels >25% on day 5 had increased their average breast milk intakes to >100 ml/d by days 3
and 4. Motohara et al. 28 obtained essentially similar findings using a more sensitive PIVKA-
II assay (by EIA) to show that a total intake of 500 ml of breast milk taken during the first 3
days was sufficient to ensure complete -carboxylation of prothrombin.

B Late VKDB
The term late VKDB is now used to denote bleeding due to VK deficiency that presents
between day 8 and 6 months 3. It has a peak incidence between 3 and 8 weeks 4, 29, 30. A major
distinguishing feature of late VKDB from the classical syndrome is the much higher
prevalence of ICH, often as the first presenting sign.

Although late VKDB had been reported in Thailand 30 as early as 1966, it went unnoticed in
developed countries until there was a flurry of case reports in the early 1980s. One of these
publications from the UK was entitled “Haemorrhagic disease of the newborn returns” 31.
The authors suggested that the likely reason for its reappearance in the UK was the
progressive rise in exclusive breast-feeding ensuing from an increased awareness of
intolerance to cows’ milk protein. This had led to a decrease in supplementary feeds with
formula milk which, in the absence of widespread VK prophylaxis, had presumably been a
protective influence owing to their high VK concentrations.

Late onset VKDB, which nearly always occurs in exclusively breast-fed infants, occurs at a
time when lactation is fully established, and the mothers of affected infants seem to have
normal concentrations of VK in their milk 32. Breast-feeding apart, the only other consistent
factor is the growing evidence of an association of late VKDB with hepatobiliary
dysfunction, which leads to an impaired secretion of bile salts and malabsorption of VK.
Such is the high dependence of the intestinal absorption of VK on bile salts that any reduction
in their production and/or luminal secretion will result in a degree of VK malabsorption 25. In
many nationwide surveys, especially in the Far East 29, 30, the majority of cases have been
reported as idiopathic. In the second Japanese survey, liver function tests in infants with
idiopathic VKDB were often abnormal but not sufficiently so to cause noticeable jaundice 29.
In European surveys the proportion of cases deemed idiopathic declines with increasing
thoroughness of investigation with as many as 60% having undiagnosed hepatobiliary disease
3
. The apparently increasing proportion of infants with late VKDB with liver disease
probably relates to the increased coverage and efficacy of current multi-dose oral regimens
for protecting healthy babies but which exposes an underlying reservoir of infants with
cholestasis who are not being protected. Evidence for this has come from the German survey
from 1995-98 in which cholestasis was found to be present in 20/23 of infants with late

7
VKDB despite all having received 3 oral doses of 2 mg of phylloquinone 33. An important
point is that this cholestasis may be mild, and its course transient and self-correcting 32.

A Clinical aspects of VKDB

B Clinical presentation
Early VKDB is rare but frequently life threatening. Common sites/bleed types are the head
(cephalhaematoma, intracranial, or at site of scalp electrodes), intrathoracic, intra-abdominal,
or gastrointestinal tract 27. The severity may relate to maternal drugs that inhibit VK
metabolism. Idiopathic cases are rarer and sometimes the separation of early and classical
VKDB as separate entities seems unwarranted. In a hospital-based Ethiopian survey of
VKDB during the first week of life, the mean age of onset among the 20% classified as
having the early syndrome was 20 hours and the clinical features were no different from
classical VKDB 34. Thus it might be more appropriate to classify early VKDB caused by
maternal drugs as a separate category from idiopathic forms.

In classical VKDB, bleeding typically occurs from the gastrointestinal tract, umbilicus, skin,
nose or after circumcision 27, 35. In the Ethiopian study described above the most common
bleeding sites among 127 cases of early/classical VKDB were the gastrointestinal tract (53%)
and umbilicus (23%) 34. Only one infant in this Ethiopian series was suspected of having bled
into the central nervous system, in addition to having presented with gastrointestinal and
umbilical bleeding. The mortality rate from classical VKDB in the developed world is
extremely low but in the Ethiopian study 26% of infants died after hospital admission; this
high death rate is salutary and reflected the scarcity of resources and long delay before proper
treatment could be instigated 34.

As already mentioned, the majority of cases of late VKDB recorded in the literature have
presented with ICH. A pooled data analysis of 131 published cases of late VKDB throughout
the world up to the end of 1992 showed that 63% had presented with severe ICH and 14%
had died 4. Of the 67 surviving infants in whom follow-up data were available, some 40%
had long-term neurological handicaps. Of special note is that about one third of the infants
had had previous minor ‘warning bleeds’ that had not been acted upon before the serious
bleeding episode 4. As would be expected, the fatality and sequelae rates are higher in low-
income countries. Of 691 cases of late VKDB in Thailand from 1963 to 1995, the prevalence
of ICH was 82%, the fatality rate was 24% and about 50% of the survivors suffered
permanent neurological deficits 30 (Table 3). It may be predicted that many more die in low-
income countries before reaching hospital. Another consistent finding from population
surveys is that late VKDB is about twice as likely to occur in males as in females 29, 30.

B Diagnosis of Vitamin K Deficiency Bleeding

Several participating countries with surveillance programmes for VKDB have agreed upon a
uniform case definition to allow meaningful cross-country comparisons 36. Accordingly, a
confirmed case of VKDB should fulfill the diagnostic criteria of having a PT that is ≥4 the
control value and display at least one of the following:
(1) Normal or raised platelet count, normal fibrinogen and absent fibrin degradation products.
(2) PT returning to normal after VK administration.
(3) PIVKA (usually that of factor II) level exceeding normal controls.
A probable cases of VKDB is defined as one in which the PT and APTT are abnormal for age
and one of the three extra criteria listed above is present 36.

8
For reporting purposes, the British Paediatric Surveillance Unit (BPSU) for their current
survey (October 2006-08) have the simplified definition: ‘Any infant under 6 months of age
with spontaneous bruising/bleeding or ICH associated with prolonged clotting times (PT at
least twice control value) and normal or raised platelet count, NOT due to an inherited
coagulopathy or disseminated intravascular coagulation’. As seen from the data from two
recent British surveys, the majority of cases are clear cut with very high PT values (or INRs)
but a number of cases are listed as probable because the clotting times were less than the
criteria demanded for confirmation and supporting tests were lacking 37. It is reasonable to
surmise that the reliance on PT (and APTT) alone could easily give rise to both false
inclusions and false exclusions. There are several reasons for this view not least of which
being the rapid developmental changes in coagulation that occur during the first few weeks of
life 19, 38. As stated by Andrew 19, for the proper diagnosis of VK deficiency “the coagulation
tests must be compared with values from age-matched, healthy, non-VK deficient infants to
distinguish physiologic and pathological deficiencies”. This is especially important for the
PT and PT-influencing factors that change rapidly even during the first week of life 19, 38, 39.
Ideally, coagulation results should be compared to ‘in-house’ age-matched reference ranges
but this is only really feasible in some large centres, and poses the difficult ethical question of
taking blood from healthy infants. As recently highlighted by Monagle 38, superimposed on
the developmental haemostatic changes is the problem that reference ranges will vary
according to the coagulation analyser and reagents used. Another problem is the lack of
standardization and the widespread practice of reporting PT and INR values interchangeably
as seen in data from recent BPSU surveys 37. The UK task force for haemostasis and
thrombosis discourages the practice of reporting INR values in patients not taking VK
antagonists and encourages the practice of reporting the PT value either in seconds or as the
prothrombin ratio (PTR), in both cases with a 95% reference range for comparison 40. In
conclusion, in the absence of local age-related reference ranges, the literature ranges
established by Andrew 19 and Monagle 38 are the most comprehensive but it is important to
realize that there are significant differences between them and that absolute values of
coagulation assays are strongly dependent on the reagent/analyser combination 38.

The real answer for accurate diagnosis of VKDB is to make wider use of the supportive tests
that lend specificity to the diagnosis. Chief among these is the PT response to VK and the
measurement of PIVKA-II. Serum VK measurements are only feasible if sufficient plasma
can be obtained prior to VK treatment. As outlined later, the PT response to VK is rapid but
in the emergency situation it may not be possible to obtain a second sample to test this
response because of the need to administer blood products. The advantage of PIVKA-II is
that it can provide confirmation of VKDB even on a post-treatment clotted sample 41. In our
Centre we have shown that the long half-life of clearance of PIVKA-II enables retrospective
diagnosis of VKDB to be made days, and sometimes weeks, after the original bleeding event.
This makes PIVKA-II the single most useful of the specific tests.

The accurate diagnosis of VKDB is also important in the medico-legal context to exclude
VKDB in cases of suspected non-accidental injury (NAI). There are several presentational
features of NAI that may also occur in VKDB. One of these is retinal haemorrhage which is
usually considered to be a signature of NAI but was also found in two recent and well-
documented fatal cases of late VKDB 41, 42. In both these cases a highly raised PIVKA of
factor II and/or of factor X was of major diagnostic value in confirming VKDB.

9
B Treatment of Vitamin K Deficiency Bleeding
With its rarity, sudden onset, and varying degrees of severity, there are few evidence-based
studies of how best to treat infants with VKDB. Infants who present with a non-life
threatening bleed should only need to be treated with phylloquinone (vitamin K1;
phytomenadione; phytonadione) given slowly by intravenous or subcutaneous injection. The
“BNF for Children” recommends a single intravenous dose of 250-300 g/kg body weight 43.
The dose range of 1 to 2 mg is more than sufficient to fully correct VK deficiency in infants
aged up to 6 months. Higher doses of VK are often given to young infants with VKDB but
offer no advantage in efficacy or speed of reversal of even a severe coagulopathy due to a
nutritional VK deficiency (as opposed to the higher doses that may be needed to reverse the
coagulation defect caused by VK antagonists such as warfarin).

It is not commonly appreciated how quickly VK acts to reverse the coagulopathy and stop the
bleeding due to even the most severest forms of VKDB. Sutor and Künzer 44 reported on the
time interval between VK administration and effective haemostasis in four infants with
severe VKDB from various sites (none, however, with intracerebral bleeding) and in whom
the PT at presentation ranged from <1 to 4% of normal. In all infants, the PT was restored to
30 to 50% of normal within one hour of receiving intravenous VK (1-3 mg phylloquinone)
with demonstrable reduced bleeding being seen as early as 20 minutes. Significant increases
in all four VK-dependent factors are seen as early as 30 minutes after intravenous VK and by
2 hours they are usually within or near the lower limit of the neonatal range 44, 45. With its
short half-life of about 6 hours, factor VII levels usually show the greatest early increases 44,
45
. However, the initial rate of appearance in plasma of active carboxylated forms of the
individual VK-dependent factors in response to VK is more rapid than that predicted from the
de novo synthesis rates of these proteins under steady state conditions. In VK-replete
individuals, the synthesis rate of VK-factors would normally mirror the rate of metabolic
removal for which the half-lives are approximately 6, 20, 40, and 60 hours for factors VII,
IX, X and II respectively 46. The initial rapid burst in the synthesis of VK-factors in infants
with VKDB can be explained by the presence of precursor, undercarboxylated (des--
carboxy), molecules that build up in the liver microsomes in VK deficiency. These
undercarboxylated forms serve as an immediately available substrate for the VK-dependent -
carboxylase enzyme to produce active forms of factors II, VII, IX and X that can be released
into the circulation as their fully active, carboxylated forms without the need for de novo
protein synthesis. Precursor substrates for the VK-dependent -carboxylase are readily
demonstrable in microsomes from VK-deficient 47, 48 or warfarin-treated 49 rats. These
microsomal precursors are distinct from those undercarboxylated forms (PIVKAs) that are
present in the circulation. Once released into plasma, PIVKAs cannot serve as substrates for
the -carboxylase 48, presumably because they lack the propeptide that serves as the
recognition site 50. The observation that a greater rate of carboxylation is seen in microsomes
taken from VK-deficient rats compared to VK-replete rats 47, 48 suggests that the -carboxylase
enzyme is up-regulated in states of VK deficiency; this may also help to explain the rapid
response to VK in infants with VKDB.

For severe bleeding episodes it may be necessary to give blood products such as fresh frozen
plasma (FFP), or a prothrombin complex concentrate (PCC). FFP should be administered at
a dose of 10-15 ml/kg 51. For infants with life-threatening bleeding and needing extensive
factor replacement, a PCC containing all four VK-dependent factors offers a better option
because it provides a more rapid reversal of a VK-dependent coagulopathy with a much
lower volumetric load. As yet there is no data to guide dosage for the use of PCC in VKDB 52
but extrapolation from adult studies suggests a dose of 50 units/kg 51. If there is any

10
suspicion whatsoever that a bleeding event in an infant may be due to VKDB, an intravenous
injection of VK should also be administered while waiting for the blood product to be
prepared and before the laboratory results have confirmed the diagnosis 3, 51, 53. This is
justified by the rapid effect of VK, as outlined above, and its lack of toxicity. If venous
access cannot be established, then VK can be given subcutaneously but should not be given
by the IM route in the presence of an existing coagulopathy 3, 51.

Two recent publications have reported the first use of recombinant factor VIIa (rFVIIa) for
the treatment of severe ICH in three infants with VKDB who required immediate surgical
intervention 45, 54. The first report describes two North American infants with late VKDB,
neither of whom had received any VK prophylaxis and who both developed ICH at 5 weeks
of age 54. In one of these infants the administration of rVIIa at 100 g/kg was reported to
have allowed the surgeon to begin a left parietal craniotomy only 20 min later with minimal
blood loss; a second dose of rFVIIa (100 g/kg) was given during the operation 2 h after the
initial dose 54. In the second infant, a dose of 90 g/kg enabled the emergency placement of a
ventriculostomy catheter 54. Although in the original article 54 the authors had not mentioned
whether VK had been given, subsequent correspondence 55 established that both infants had
received 1 mg phytonadione by intravenous injection on emergency admission 55. Both
infants also received FFP but only after surgery had been initiated. Although rFVIIa
appeared to be an effective therapeutic strategy in these two cases, it is not possible to
separate out its effect from that of VK and the rarity of VKDB means that the potential extra
value and/or unwanted side effects of rFVIIa are unlikely to be tested in any trial.

A Incidence and prevention of VKDB

B Incidence of classical VKDB
There is little accurate national data on the incidence of classical VKDB, even in
industrialized countries. In a two-year prospective survey in the British Isles 56 during 1988-
90 the incidence rate of 5.4 per 105 births for classical VKDB 57 was similar to that of 4.4 per
105 births for late VKDB 57. Earlier studies had suggested a higher incidence for classical
VKDB with Salomonsen 6 reporting that the incidence of classical VKDB in Oslo during
1934-39 was 0.8%. The later important and influential studies in the 1960s by a group in
Cincinnati showed that the incidence of moderate or severe bleeding in an urban population
was 1.7% among breast-fed infants who had not received VK 35. This data from Cincinnati
would not have been representative of the national incidence of VKDB in the USA since the
hospital served a mainly black disadvantaged population. Also, a minority of the bleeds
could not be attributed to VK deficiency and the high frequency of bleeds after circumcision
gave an upwards bias to the incidence. The studies by the Cincinnati group are important
because they reaffirmed the connection between breast-feeding and classical VKDB 35 and
the link between coagulation status and feeding practices and/or VK prophylaxis 58.

If economic deprivation predisposes to classical VKDB, it might be expected that there

would be a greater incidence in underdeveloped countries but this has been difficult to
document. A retrospective study of 14,110 admissions in the first week of life in a children's
hospital in Addis Ababa, Ethiopia from 1982 to 1991 showed that 0.9% had early or classical
VKDB of whom 80% had the classical syndrome 34. Most of the affected infants came from
families with a very low income and poor educational background. High incidence rates of
classical VKDB have also been reported in SE Asia. A recent review of the history of VKDB
in Thailand cites incidence rates of 89 and 54 per 105 births for two longitudinal field studies
in Ayutthaya Province, which were carried out before Thailand brought in widespread VK
prophylaxis 30. In a 2-year regional, hospital-based survey in Malaysia from 1987-88, the

11
incidence of classical VKDB in Kelantan was estimated to be 25 per 105 births 59. This is a
rural state on the East Coast of the Malaysian peninsula with about 40,000 live births per
year, the majority (77%) at home. This Malaysian incidence appears somewhat lower than in
Thailand but being a hospital-based survey may have missed infants with mild bleeding
symptoms who were not referred to hospital and perhaps some who died before reaching
hospital.

B Incidence of late VKDB

The first attempts to document the incidence of late VKDB in a large population were made
in Japan in a series of nationwide surveys spanning the years from 1980-90. The extent of
the problem can be gauged by the results of the second Japanese nationwide survey (1981-
85), which reported some 484 cases of late VKDB 29. Of these 484 cases, 427 were classified
as ‘idiopathic’ and 57 cases, in which there was an identifiable cause, as ‘secondary’ late
VKDB 29.

In order to make valid comparisons of incidence rates between different populations when
VK prophylaxis had not been given, The Scientific and Standardization Committee of the
ISTH have clarified the criteria necessary for inclusion as a case (the numerator), and defined
the denominator as the proportion of the population given no prophylaxis 57. Table 4 shows
comparisons of incidence rates of late VKDB in several countries. As can be judged from the
relatively wide 95% confidence intervals the ability to determine accurate incidence rates is
limited by the comparative rarity of late VKDB. However the average incidence rates in four
Western European countries ranged from 4 to 7 cases per 105 births with an even higher
incidence in Japan.

Table 4 also shows data from Thailand taken from the review by Chuansumrit et al. 30 which
suggests that before the widespread introduction of VK prophylaxis, there had been a very
high prevalence of late VKDB. The figure of 72 cases per 105 births was collected from a
regional field study in central Thailand (Ayutthaya Province) conducted during 1981-84.
Although this figure lacks confidence intervals, it is consistent with an even higher incidence
from a previous survey in the same region and with the many case reports in the Thai
literature during this period. In 1983, a Thai nationwide hospital-based study reported an
incidence of late VKDB of 35 cases per 105 births 60. This lower figure probably reflects the
underestimation of hospital-based studies compared to studies in the field 30. This
underestimation in hospital-based surveys might have been a factor in the Malaysian survey
that reported 13 cases of late VKDB per 105 births 59.

The high incidence of late VKDB in Thailand compared to Japan during the 1980s suggests
that emerging countries in SE Asia have much higher rates than industrialized countries in the
same region. This is supported by recent data from Hanoi province, Vietnam which, based on
cases of ICH in infants aged 1-13 weeks, suggests that the incidence of late VKDB in infants
who received no prophylaxis was 142 and 81 per 105 births in rural and urban areas
respectively 61.

B Effect of vitamin K prophylaxis on incidence rates

In 1961 the American Academy of Pediatrics recommended phylloquinone (phytonadione) as
the compound of choice for VK prophylaxis and concluded: “a single parenteral dose of 0.5
mg to 1.0 mg or oral dose of 1.0 to 2.0 mg is probably adequate for prophylaxis” 62. In
practice parenteral injections became the common route of administration in the USA.

12
The IM injection of a single dose of phylloquinone has long been regarded the gold standard
against which other prophylactic regimens should be judged. A literature search carried out
for a review published in 1988 found only 4 cases of VKDB in which VK had been given by
IM injection, and none from the USA where large numbers of infants had been exposed to
this route of administration 32. Since this time there have been other sporadic reports of
VKDB in infants said to have received IM VK at birth 37, 45 including one 5-month old infant
from the USA 45.

The implementation of surveillance programs in different countries has greatly improved our
knowledge of how VK supplementation protects against late VKDB 57, 63. The data shown in
Table 4 shows some of the first results from these surveys at a time when most countries
(Japan is the exception) were giving single doses of phylloquinone by IM injection or by
mouth. The figures from the British Isles, Sweden, Switzerland and Germany confirm that
the IM injection of 1 mg of phylloquinone gives almost complete protection but that the oral
route is less effective than the parenteral route when equivalent (or even greater) amounts of
phylloquinone are given as a single bolus.

In Thailand, the Ayutthaya Province field study of 1981-84 indicated a very high incidence
rate of late VKDB of about 72 cases per 105 births when VK prophylaxis extended to less
than 20% of the population. However, based on nationwide hospital surveys from 1988 to
1995 the incidence was reduced by at least tenfold by the administration of a single dose of
phylloquinone given IM or by mouth 30. It is unclear from this publication 30 what proportion
of the newborn population of Thailand had received each regimen but by 1995 the coverage
of VK prophylaxis had extended to nearly the entire population.

Japan differs from other countries in that most infants are given a member of the
menaquinone series (MK-4) rather than phylloquinone 64. The introduction of oral
prophylaxis in Japan with one to three oral doses of a syrup formulation of MK-4 (2 mg)
reduced late VKDB substantially and by 1990 the incidence (2.8 per 105 births) was similar to
that seen in Europe after one oral dose of phylloquinone (Table 4). Moreover, no cases of
late VKDB were reported in the one third of infants who had received three oral doses 64.
This suggested that this 3-dose oral regime with MK-4 was similar in efficacy to parenteral
prophylaxis, although there are still occasional reports of failure.

With the shift towards oral prophylaxis after the vitamin K and cancer scare (see later),
paediatricians in four countries with an active surveillance program for VKDB instigated a
joint assessment of the efficacy of the oral prophylactic regimens being used in their
respective countries 36, 63. A summary of their findings, together with data from Denmark, is
given in Table 5. Two countries, Germany and Australia originally followed a 3-dose oral
regimen with 1 mg of phylloquinone (Konakion Cremophor). Although the occurrence of
late VKDB in infants who had received this regimen was low (~2 per 105 births) it was still
higher than that seen after IM prophylaxis. In Germany, an increase of the dose from 1 mg to
2 mg in a 3-dose regimen significantly reduced but did not eliminate VKDB 33. The strength
of this German data for the 3-dose (2 mg) regimen 33 lies in the large population of 3.2
million infants exposed to prophylaxis and the resulting close confidence intervals of the
incidence data (Table 5). Although based on much smaller population sizes, the figures from
Denmark and Switzerland indicate the importance of dose and frequency of administration.
In Denmark the incidence after a single oral dose of 1 mg at birth was similar to that seen in
Europe without any prophylaxis 63, 65, while in Switzerland a 2-dose (2 mg) regimen did not
prevent all cases 36, 63. However, when Denmark changed to a regimen of a 2-mg dose at birth

13
followed by a 1-mg dose given at weekly intervals for 3 months, no case was reported over a
7.5-year observation interval 65, 66. The Netherlands have adopted yet another approach by
giving a single dose of 1 mg phylloquinone at birth followed by a daily 25 g dose for 3
months to breast-fed infants 36. This daily dose is >20-fold higher than the estimated daily
phylloquinone intake provided by mature human milk during exclusive breast-feeding and
about half of the intake provided by milk formulas.

The UK differs from most other European countries in that there is no uniformity of practice.
Prophylactic regimens range from the IM route to oral regimens using different products and
dosages as well differences in the frequency and number of doses given. Because of this
heterogeneity, it is difficult to obtain efficacy data for individual oral regimens and so the
recently published data 37 from Great Britain and Ireland for the BPSU surveys, 1993-94 and
2001-02 are not shown in Table 5. Overall, however, the data showed that the incidence of
VKDB and associated morbidity/mortality fell significantly between 1994 and 2002 and the
authors suggested this trend was related to the increased uptake of prophylaxis in general and
increased proportion being given IM prophylaxis 37. With this survey data was an
accompanying survey on current practices, which described VK prophylaxis in the UK as
chaotic 67. IM prophylaxis was the most efficacious route when administered but was not
superior on an intention-to-treat basis 67. The likely reason was that parenteral refusal was
more common in units recommending IM prophylaxis 37, 67.

B The Dutch low daily oral dose experience revisited: targeted surveillance
Initially, the introduction in the Netherlands of a daily 25 g dose regimen appeared to
provide effective prophylaxis and in a nationwide 2-year surveillance carried out by the
Dutch Paediatric Surveillance Unit from 1992-94 no case of VKDB was reported in any
infant who had been given this regimen 36. However, subsequent reports in the Dutch
literature of some prophylaxis failures in infants with liver disease were worrying and led to a
new 1-year survey during 2005 which revealed six cases of late VKDB including one fatal
idiopathic intracranial bleed and five others who had underlying cholestatic liver disease 68.
Since four of the six infants in this Dutch survey had biliary atresia 68, van Hasselt and
colleagues recently set out to determine the efficacy of the Dutch low daily dose regimen in
this high-risk group 69. To do this, they extracted data on the incidence of VKDB from the
Dutch national biliary atresia registry for 1991-2003 and compared the VKDB data to that
from the equivalent Danish registry for 1994-2005. In Denmark from June 2000 there had
been a change in prophylaxis from weekly oral prophylaxis (outlined in the previous section)
to a single IM dose of 2 mg of phylloquinone; this policy change had followed the
withdrawal from the market of the Konakion Cremophor preparation and the introduction of
Konakion MM. In the Netherlands VKDB had been recorded in the notes of 25/30 of breast-
fed infants with biliary atresia, while in Denmark VKDB the equivalent figures were 1/13
(after weekly oral prophylaxis) and 1/10 (after IM injection). For formula-fed infants, the
pooled data from both countries showed only one recorded case of VKDB among 98 infants.
This important and innovative study has provided incontrovertible evidence that the Dutch
regimen does not protect breast-fed infants with biliary atresia. This contrasts to Denmark
where the weekly oral and IM regimens were of equal high efficacy in preventing VKDB in
biliary atresia.

By targeting a single disease at high risk of VKDB this Dutch-Danish collaboration offers an
alternative approach to detect prophylactic failures and to compare the efficacy of different
prophylactic regimens 69. Such methodology allows nationwide prophylaxis to be tailored to
protect those individuals that are at the highest risk of developing VKDB, namely those with

14
diseases associated with cholestasis 69. Importantly it provides a check for nationwide
schemes, which are known to be subject to an underreporting bias.

B Why do oral regimens fail? The cholestasis problem

The Dutch data are just the latest in a line of evidence showing that while the great majority
of infants can be protected by oral prophylaxis, a few are not and the main reason for this lies
with latent cholestasis causing malabsorption of VK. This seems to be true both for the daily
low-dose regimen used in the Netherlands 68, 69 and the three dose (2 mg) oral regimen
common in many other European countries 33. Some issues with oral prophylaxis have been
considered recently 70. In brief, the only oral regimen to date that seems to give almost
complete protection in infants affected by liver disease is the weekly 1 mg regimen used in
Denmark (see earlier) up until June 2000 when Konakion (Cremophor) was withdrawn from
the market. With the introduction of the re-formulated (3-dose recommended) mixed
micellar preparation (Konakion MM), there had been an expectation that this new preparation
might be better absorbed in infants with cholestasis. This appears not to be the case as
demonstrated by direct absorption studies showing an erratic, and generally impaired,
intestinal absorption of Konakion MM in cholestatic infants 71 and by the German
Surveillance data 72 from 1997-2000. This German survey showed that Konakion MM did
not reduce the incidence of late VKDB compared to the Cremophor preparation, and that
there was a similarly high proportion of infants with VKDB associated with cholestasis for
both preparations 72.
Given the evidence that the 25 g Dutch regimen is not effective there is an impetus
to increase the daily dose. One suggestion 68 is that dose should be doubled to 50 g, the
rationale being that this would be comparable to the intake from typical infant formulas
known to provide almost complete protection against VKDB 69. However, it cannot be
assumed that a 50 g drop preparation given in isolation, often on an empty stomach, would
be as well absorbed as the same dose contained in a formula feed. Being fat-soluble, the
absorption of VK is likely to be very poor unless taken with a feed that has bile-salt
stimulating properties 5, 25, 70. Another problem in setting the dose for a daily oral regimen is
that there is a paucity of data on compliance even in countries where this has been practised
70
. True confidence in any daily oral regimen requires that the twin issues of bioavailability
and compliance have been appropriately addressed.

A The vitamin K and childhood cancer story

The events that led to the ‘vitamin K and childhood cancer’ scare are a typically British story.
On August 2nd 1990 the Guardian newspaper reported on an epidemiological study of Jean
Golding and colleagues into factors associated with childhood cancer and particularly on an
unexpected association with VK, which in the investigators words, ‘fitted no prior
hypothesis’ 73. The Guardian was the only paper to give this report any prominence; the
article itself being a fair synopsis of Golding’s peer-reviewed paper 73. Then on May 7th 1992
the Daily Mail ran a front-page banner headline “Vitamin link to child cancer” and the next
day the quality papers also devoted several column inches to this story. However, this time it
turned out that the story had somehow leaked out from a closed paediatric meeting where
Golding had presented, in preliminary form, the follow-up data of a new and larger study to
test the VK and cancer link. The seriousness of the headlines prompted the Department of
Health to join with the then British Paediatric Association to convene a meeting of experts.
Within 3 months Golding’s findings had been peer reviewed and published 74. In essence
they reported an approximate doubling of the risk of leukaemia in children who had been
given intramuscular VK at birth but no increased risk when given by the oral route 74. In an
accompanying editorial Sir David Hull had warned that “the risk of haemorrhagic disease is

15
certain; that of cancer is not” and that “before we change our practice we must be confident
that any programme of oral administration will be as effective as injected vitamin K” 75. The
publication had two major consequences. Firstly in the UK it led to a dramatic increase in the
use of oral prophylaxis; in 1993 the year after the Golding publication 74, about 60% of units
were giving oral prophylaxis compared to only about 30% in 1998 67. Secondly, it spawned a
series of studies across several countries to test the validity of this association. Of nine
further epidemiological studies published in major journals up until 1998, only one found a
positive cancer link; this study in the north of England suggested that intramuscular VK
increases the risk of acute lymphoblastic leukaemia but only when diagnosed between 1 and
6 y of age 76. All of these studies were considered by a working group of the WHO
International Agency for Research on Cancer (IARC) which in 1999 concluded that there was
“inadequate evidence in humans and experimental animals for the carcinogenicity of vitamin
K substances” 77. Two later studies, the first comprising a pooled analysis of the six major
case-control studies 78 and the second being the most comprehensive study yet reported 79,
both concluded that there was no convincing evidence that VK given by any route influences
cancer risk in children. Ten years after the original Golding paper, the fears of the cancer link
seem to have greatly subsided. In a UK survey of maternity units in 2003, some 60%
recommended IM prophylaxis and 25% recommended oral prophylaxis, the remainder
making no recommendation about route 67.

The lack of cohesion of any nationally agreed policy in the UK is not typical of most other
countries. In the USA, a position paper on the validity of the epidemiological data concluded
that the confirmed benefits of VK far outweigh the hypothetical association with childhood
cancer 80. The American Academy of Pediatrics also issued a policy statement discounting
any association with cancer and reaffirmed that 0.5 or 1 mg of phylloquinone should be given
as a single IM injection 81.

A Global perspectives of VKDB

While VKDB and its prevention is still a significant concern in industrialized countries, it is a
bigger problem in emerging countries. In many low-income countries the problem is unseen
or overshadowed by more common and more visible deprivation and disease. One reason for
the lack of information from developing countries is that bleeding in infancy can have
different causes and VKDB can only be properly diagnosed by laboratory tests or, failing this,
by showing that bleeding responds to VK. Perhaps another is that the bleeding in late VKDB
is often sudden in onset and the infant may die before reaching hospital. The differences in
mortality rates for developed and developing countries reflects differences in access of their
respective populations to intensive care facilities.

Victora and van Haecke 82 have made a detailed analysis of the public health issues and
global implications of VK prophylaxis including cost effectiveness and feasibility. With the
high rate of mortality and long-term disabilities in survivors they conclude that the costs of
VK prophylaxis in industrialized and middle-income countries (where most births take place
in hospitals) are considerably smaller than the economic consequences of the disease 82. For
low-income countries, the introduction of a prophylactic program needs to be made on a
national basis, after considering mortality levels and causes, health resources, budgets and
feasibility. Based on the World Bank model of disability-adjusted life years (DALYs) and an
intermediate incidence rate of 28 cases of VKDB per 105 births it was calculated that late
VKDB had much less impact on lost DALYs than iodine or vitamin A deficiency 82. On the
other hand the more recently-published data from Hanoi province suggests that incidence
rates in some low-income countries in the Far East exceed 100 cases per 105 births 61. Using

16
the same World Bank model, the authors of the Vietnamese study calculated that routine VK
prophylaxis would be highly cost effective and below the figure the World Bank regards as
indicating a high priority for implementation 61. Although breast-feeding is a risk factor for
VKDB, concern to prevent the syndrome should not affect the promotion of breast-feeding in
the developing world 82.

With respect to the efficacy of different VK compounds, the preparation used in most
countries is phylloquinone and this is clearly effective when an appropriate protocol is
followed. The Japanese experience also shows MK-4 to be an effective alternative to
phylloquinone. In some emerging countries, such as India, the only widely available VK
preparation is menadione sodium bisulphite 83. Although effective in the short-term against
classical VKDB, nothing is known of the ability of menadione salts to protect against late
VKDB, which depends on its in vivo conversion to MK-4. Another major concern is that
menadione, unlike phylloquinone, has an unsubstituted 3-position which makes it highly
reactive with thiol groups of both small molecules and macromolecules making it cytotoxic
77
. This reactivity is responsible for the well-known haemolytic toxicity of menadione, which
may lead to severe haemolysis in infants with a congenital deficiency of glucose 6-phosphate
dehydrogenase 62, 77. Of even greater concern is recent evidence that menadione is also
mutagenic causing DNA damage and chromosomal aberrations in cultured mammalian cells
77
. Although cheap, menadione and its derivatives should be avoided for prophylaxis.

VK deficiency in infancy differs from many other micronutrient deficiencies in that

substantial protection against the devastating consequences of VKDB can be prevented by
minimal supplementation. In the population context, even one oral dose at birth gives
considerable protection. Thailand is a good example of how an initially very high incidence
of VKDB can be reduced by the integration of VK prophylaxis into the national healthcare
program so that by 1994 Thailand achieved almost complete coverage of the population 30.
Even in Thailand, however, the incidence in 1995 30 was still similar to the baseline incidence
seen in Europe 57 before the widespread introduction of prophylaxis.

Practice points
 Late VKDB that presents as intracranial bleeding is often preceded by warning bleeds
or bruising that should always be investigated by appropriate laboratory tests.
 Accurate diagnosis of VKDB requires that gestational and/or postnatal age be taken
into consideration when interpreting coagulation results (developmental haemostasis).
 In cases of suspected VKDB confidence in diagnosis is greatly increased by use of
specific tests of VK status (e.g. PIVKA-II) even post-VK or factor replacement.
 Assess VK status in any baby who has jaundice persisting after 2-3 weeks or has other
indications of cholestasis.
 Intravenous injection of VK in the treatment of VKDB results in significant reversal
of the haemostatic defect within minutes and its prompt use may obviate the need to
administer plasma products.

Research agenda
 Determine the bioavailability of low-dose oral drop regimens when taken with and
without feeds.

17
  Make further use of local and national registries of diseases associated with
cholestasis (e.g. biliary atresia and -1-antitrypsin deficiency, cystic fibrosis) to assess
prophylactic efficacy of different oral VK regimens.
 Incidence, causes, and prevention of VKDB in developing countries.
 Metabolism and dietary requirements of VK in infants during the first six months of
life.
 Significance of gut microfloral menaquinones to infant VK requirements in breast-fed
and formula-fed infants.

Conflict of interest statement

The author has previously received funding from F. Hoffmann-La-Roche, Ltd, Basel,
Switzerland for analytical work connected with the licensing of Konakion MM and a grant
for the development of a PIVKA-II assay.

Acknowledgments
I would like to thank Dr Paul Clarke, Norfolk and Norwich University Hospital for his
thoughtful and incisive comments.

18
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