HEMORRHAGIC DISEASE

OF NEWBORN
MIHAI CRAIU MD PhD

TERMINOLOGY
The more appropriate term for hemorrhagic
disease of newborn is VITAMIN K
DEFICIENCY BLEEDING (VKDB).
Historically, all bleeding disorders in the
newborn were grouped together under the
diagnosis of hemorrhagic disease of the
newborn (HDN).
With methods available today for the
accurate diagnosis of other factor deficiency
states and immune thrombocytopenias, VKDB
can be excluded very easy.

VITAMINS
The name vitamin is derived from the
Latin words vita (meaning life) and
amine (an organic chemical nitrogen
containing molecule).
This name was used for the first time
by Kasimir Funk in 1910.

VITAMIN K
Vitamin K is a fatsoluble vitamin that
can be absorbed
from the GI tract in
the presence of bile
salts.

3 FORMS OF VITAMIN K ARE :

K1: PHYLLOQUINONE, found
in dairy products, green
vegetables, and vegetable oils,
is an aqueous, colloidal solution
of vitamin K1.
K2: MENAQUINONE, which is
synthesized by gut flora.
K3: MENADIONE is a
synthetic, water soluble form
that is no longer used
medically because of its ability
to produce hemolytic anemia.

VITAMIN K - FUNCTION
Vitamin K is required for the production of
coagulation factors II, VII, IX, and X in the
liver.

DEFICIENCY OF VIT K
Because of the short half-life of these
factors, and the small amounts of vitamin K
that can be stored in the body, inadequate
intake of vitamin K can result in deficiency in
a short period of time.
PIVKA, inactive precursor proteins induced in
vitamin K's absence, are measurable and can
be used as an indicator of vitamin K
deficiency.

DEFICIENCY OF VIT K
Newborns are relatively vitamin K
deficient for a variety of reasons.
Factors that can contribute to this
deficiency include

low vitamin K stores at birth,

poor placental transfer of vitamin K,
low levels of vitamin K in breast milk,
sterility of the gut.

DEFICIENCY OF VIT K
Because standard commercial infant
formulas contain supplemental vitamin K,
VKDB is almost exclusively a problem of
breastfed infants.
Infants with inadequate intake are at
higher risk.

FINDINGS
The most common sites of bleeding are

the umbilicus,
mucous membranes,
GI tract,
circumcision, and
venipunctures.

Intracranial bleeding can occur and is

the main cause of mortality and longterm morbidity.

FREQUENCY
In the United States, routine intramuscular
administration of vitamin K immediately after
birth has made VKDB an uncommon
occurrence.
The frequency of VKDB is variably reported,
from 0.25-1.7% in the first week of life.
The frequency in a given US population
depends upon the frequency of breastfeeding.
Late VKDB (2-12 wk) appears to be prevented
with parenteral administration of vitamin K, as
well.

Mortality/Morbidity
Intracranial hemorrhage (ICH) is
uncommon in classic VKDB but can be
observed in more than 50% of infants
with late-onset VKDB.
ICH is responsible for nearly all
mortality and all long-term sequelae
resulting from VKDB.

TIME FRAMES 1
Early onset, at less than 24 hours after birth,
rarely occurs and is almost always associated
with maternal medications that interfere with
vitamin K, such as anticonvulsants,
anticoagulants, and antibiotics.
Postnatal administration of vitamin K has no
effect in preventing early-onset disease.
Maternal vitamin K supplementation that is
administered prenatally may prevent this
form of VKDB.

TIME FRAMES 2
The classic onset of VKDB is 2-7 days
after birth in breastfed infants.
Late-onset VKDB occurs after 2 weeks
of life. Late-onset VKDB tends to be
more severe than early-onset or classic
disease and has a high frequency of
ICH.

LATE-ONSET VKDB
In addition to breastfeeding, risk
factors include

diarrhea,
hepatitis,
cystic fibrosis (CF),
celiac disease,
alpha1-antitrypin deficiency or
absence of prophylaxis in otherwise healthy
infants.

CAUSES
Maternal medications that interfere
with vitamin K stores or function:

carbamazepine,
phenytoin,
barbiturates,
some cephalosporins,
rifampin,
isoniazid,
warfarin

DIFFERENTIALS
Consumption Coagulopathy
Von Willebrand Disease
Other Problems to Be Considered

Maternal isoimmune thrombocytopenia

Alloimmune thrombocytopenia
Hepatobiliary disease
Uncommon coagulopathies

LAB 1
prothrombin time (PT), activated partial
thromboplastin time (aPTT), fibrinogen
levels, and a platelet count in the initial
workup for bleeding in a newborn.
A thrombin clotting time (TCT) is
optional.
A prolonged PT usually is the first
laboratory test result to be abnormal in
VKDB;

LAB 2
Vitamin K direct assay is not useful because
levels normally are low in newborns.
Levels of protein induced by vitamin K
antagonism (PIVKA) II are increased in VKDB,
but this test generally is not available outside
of research laboratories.
Infants with VKDB typically have a prolonged
PT with reference range platelet counts and
fibrinogen levels.
Thrombocytopenia or a prolonged aPTT should
prompt workup for other causes of bleeding.

LAB 3
No laboratory test can confirm the
diagnosis of VKDB.
The diagnosis of VKDB is confirmed if
administration of vitamin K brings a halt
to the bleeding and reduces the PT
value.

IMAGING
Intracranial bleeding is
rare and usually
associated with other
causes of bleeding,
particularly the
thrombocytopenias;
ICH has been reported
in VKDB and can be
fatal.
Investigate any
neurologic symptoms
with a CT scan.

PREVENTION 1
Prevention of VKDB with intramuscular
vitamin K is of primary importance in medical
care.
A single dose of intramuscular vitamin K after
birth effectively prevents classic VKDB.
Oral vitamin K prophylaxis improves
coagulation tests at 1-7 days, it has not been
tested in randomized trials for its effect on
either classic or late VKDB.

PREVENTION 2
In the early 1990s, an association between
parenteral vitamin K and the later occurrence
of childhood cancer was reported
however, a large cohort study and a large
retrospective analysis of a database in the
United States could not confirm this
association.
Because this association is weak at best,
routine vitamin K prophylaxis is recommended
and supported by the American Academy of
Pediatrics.

TREATMENT 1
Immediately administer vitamin K
subcutaneously for any infant in whom
VKDB is suggested or who has any sort
of bleeding until a diagnosis is
established.
IM administration can result in a hematoma
because of the coagulopathy.
IV administration of vitamin K has been
associated with anaphylactoid reactions.

TREATMENT 2
Fresh frozen plasma may be considered for
moderate-to-severe bleeding.
Life-threatening bleeding may also be treated
with prothrombin complex concentrates (PCC).
Because the bleeding in classic VKDB usually is
not life threatening, a single dose of
parenteral vitamin K is sufficient to stop the
bleeding and return PT values to the
reference range.

VITAMIN K
Aqueous (for injection): 2 mg/mL and 10
mg/mL diluted in 5-10 mL D5W or NS;
maximum concentration 10 mg/mL; infuse over
15-30 min; maximum rate of infusion 1 mg/min
Prophylaxis:
0.5 SC/IM in small premature neonates (eg <1000
g)
1 mg SC/IM in neonates >1000 g

Treatment: 1 mg SC or 1-10 mg IV
Note: Use IM or IV administration routes only
when SC is not feasible, and the infant's
condition justifies the risk of anaphylaxis

COMPLICATIONS
ICH is the primary serious complication
of VKDB.
Complications of treatment
anaphylactoid reactions to IV vitamin K,
hyperbilirubinemia or hemolytic anemia
after high-dose vitamin K,
hematomas at the site of injection if
administered IM.

FOLLOW-UP
Follow-up interval after discharge
depends on the nature and severity of
bleeding, hematocrit at discharge, and
any neurologic complications.
Mild VKDB that has been treated
successfully can be monitored at routine
newborn visits.

VITAMIN K SOURCES