A case of intracranial hemorrhage in a neonate with congenital factor VII deficiency.
ABSTRACT Congenital factor VII deficiency is a rare autosomal-recessive bleeding disorder. Bleeding manifestations and clinical findings vary widely, ranging from asymptomatic subjects to patients with hemorrhages that may cause significant handicaps. Treatment has traditionally involved factor VII(FVII) replacement therapy using fresh frozen plasma, prothrombin complex concentrates or plasma-derived FVII concentrates. Recombinant activated FVII (NovoSeven®) is currently considered the first-line treatment for replacement therapy of FVII deficiency. Here we present a case of severe intracerebral and intraventricular hemorrhage in a neonate with congenital FVII deficiency.
Korean J Pediatr 2010;53(10):913-916
A case of intracranial hemorrhage in a neonate with
congenital factor VII deficiency
Congenital factor VII deficiency is a rare autosomal-recessive bleeding
disorder. Bleeding manifestations and clinical findings vary widely,
ranging from asymptomatic subjects to patients with hemorrhages
that may cause significant handicaps. Treatment has traditionally
involved factor VII(FVII) replacement therapy using fresh frozen
plasma, prothrombin complex concentrates or plasma-derived
FVII concentrates. Recombinant activated FVII (NovoSeven®) is
currently considered the first-line treatment for replacement therapy
of FVII deficiency. Here we present a case of severe intracerebral
and intraventricular hemorrhage in a neonate with congenital FVII
Key words: Congenital factor VII deficiency, Intracranial hemorrhage,
Won Seok Lee, M.D., and Young Sil Park,
Department of Pediatrics, Kyung Hee University School
of Medicine, Seoul, Korea
Received: 13 August 2010, Revised: 13 September, 2010
Accepted: 30 September 2010
Corresponding author: Young Sil Park, M.D.
Department of Pediatrics, Kyung Hee University School of
Medicine, East-West Neo-medical Center, 149 Sangil-dong,
Kangdong-gu, Seoul, 134-727, Korea
Tel: +82.2-440-7173, Fax: +82.2-440-7175
Copyright © 2010 by The Korean Pediatric Society
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Factor VII (FVII) is a vitamin K-dependent clotting factor
that is part of the extrinsic pathway of blood coagulation1). The
complex formed between the naturally occurring procoagulant
serine protease, activated FVII (FVIIa), and the integral membrane
protein tissue factor (TF), exposed on the vascular lumen upon
injury, is known to be the trigger for blood clotting. In the
blood stream, FVIIa is the active portion of the FVII mass and is
detectable at normal concentrations as low as 5-10 ng, i.e., 1-2% of
the zymogen; in contrast to FVII zymogen, FVIIa has a very high
affinity for TF1, 2).
Congenital FVII deficiency is a rare bleeding disorder. In patients
with congenital FVII deficiency, bleeding manifestations and
clinical findings vary widely, ranging from asymptomatic subjects
to life threatening bleeding1, 3). However, severe and life-threatening
hemorrhaging is rare in general (about 5% of the bleeds) and occurs
most frequently during the first six months of life. The correlation
between FVII coagulation activity (FVII:C) and bleeding tendency
appears to be poor4, 5). Treatment has traditionally involved FVII
replacement therapy using fresh frozen plasma, prothrombin
complex concentrates (PCCs) or plasma FVII concentrates2, 3).
Intravenous administration of recombinant FVIIa (NovoSeven®,
NovoNordisk, Bagsvaerd, Denmark) is now widely used for the
treatment of FVII deficiency. Here we present a case of severe
intracerebral and intraventricular hemorrhage in a neonate with
congenital FVII deficiency.
A 28-day-old male neonate was referred with fever for five
days and sudden progress of anemia, suggestive of an intracranial
hemorrhage (ICH). He was born to a 35-year-old gravida 1, para
1 mother at 39+6 weeks of gestation via cesarean delivery without
WS Lee, and YS Park • A case of intracranial hemorrhage in a neonate with congenital factor VII deficiency
any perinatal problems. His birth weight was 3,000 g. There was
no significant family history about any bleeding disorder. At the
time of transfer, the pulse rate was 150 beats/min, respiratory
rate was 42 breaths/min, blood pressure was 80/50 mmHg and
body temperature was 37.3℃. Physical examination revealed
pallor, anemic conjunctivae, and a minimal systolic murmur. The
head circumference was 38 cm (50-75 percentile) and there were
no abnormalities on the neurological examination. Laboratory
findings were as follows: hemoglobin of 6.5 g/dL; white blood cell
(WBC) count of 17,500/mm3; and a platelet count of 387,000/
mm3. CRP was 1.03 mg/dL (normal range: 0.0-0.5). The blood
coagulation test revealed a prothrombin time 34.8 seconds (INR
3.65) and activated partial thromboplastin time of 34.2 seconds.
The FVII assay was 2%. Brain computed tomography (CT)
demonstrated an intraventricular hemorrhage in both lateral
ventricles with hydrocephalus and an intracerebral hemorrhage
in the right parietotemporal lobe and corpus callosum (Fig. 1).
On admission, recombinant activated FVII (Novoseven®, Novo
Nordisk, Bagsvaerd, Denmark) was administrated at a dose of
20 μ g/kg every 4 hours. To treat the hydrocephalus, external
ventricular drainage was considered; however, the risk of bleeding
was a concern. Therefore, periodic lumbar puncture and drainage
were performed and mannitol was administered. First lumbar
puncture was done at hospital day 3 and performed every 3-4 days
after Novoseven® was administrated. Results of CSF study were as
follows: Red blood cell count of 23,000/mm3, WBC count of 77/
mm3; glucose of 18 mg/dL, protein of 223.0 mg/dL. The FVII
level was checked 1 hr after administration of the Novoseven®
and was confirmed to be 125%. The interval between dosing with
Novoseven® was increased to seven days after admission. The
fever persisted until seven days after admission, and then, finally
subsided. Blood, urine, CSF, and stool culture were unremarkable.
The patient was treated with a third generation cephalosporin. The
brain CT at seven days after admission revealed decreased IVH
in both lateral ventricles and slight resolution of the ICH with
perilesional edema. Administration of the FVII was continued
Fig. 1. Brain CT on admission showed an IVH in both lateral ventricles with hydrocephalus
and ICH with perilesional edema in the right parietotemporal lobe and corpus callosum.
Fig. 2. A follow-up brain CT scan 1 month later revealed a resolving ICH, decreased IVH
and slightly improved hydrocephalus.
Korean J Pediatr 2010;53(10):913-916 • DOI: 10.3345/kjp.2010.53.10.916
for 20 days during the hospitalization. The patient was discharged
21 days after admission. A follow-up CT of the brain at 1 month
showed a resolving ICH, decreased IVH and slightly improved
hydrocephalus (Fig. 2). At present, the patient is on no medication
and is followed in the outpatient clinic regularly. The development
currently is within normal limits. A follow-up CT scan of the brain
and developmental testing are planned.
Congenital FVII deficiency is a rare autosomal recessive bleeding
disorder that has an estimated incidence of 1/500,000 among the
general population6). There are 20 known patients with congenital
FVII deficiency in Korea7). And, neonate with FVII deficiency
and ICH has not been reported yet. FVII plays a pivotal role in the
initiation of hemostasis and coagulation. Binding of FVII to TF
in the damaged vascular bed results in rapid conversion of FVII to
FVIIa through the action of proteases1, 8). In turn, FVII plays a key
role in the early phases of the intrinsic and extrinsic coagulation
pathways through activation of factor IX (FIX) and factor X (FX).
Nosebleeds are a common symptom. This disorder is not gender-
related. Other very common symptoms are postoperative, skin
and gum bleeding1, 2). A female gender is more common among
bleeders: this is mainly attributable to menorrhagia. Severe and
life-threatening hemorrhages are rare in general (about 5% of the
bleeds) and occur most frequently during the first six months of
life. According to some reports, central nervous system (CNS)
bleeding has been identified in 4.4-8%. Severe bleeding, CNS and
gastrointestinal bleeding have been reported mainly in babies and
infants1, 3, 5).
In patients with hemophilia A and B, a reliable classification
of severity can be obtained by plasma factor VIII or IX activity
levels. Depending on the concentration of FVIII or FIX coagulant
activity in the blood, the disorders may be classified as severe (<1%
of normal activity). In patients with FVIII or IX concentrations
in plasma <1% of normal, joint bleeding episodes may occur as
frequently as 20-30 times/year, and life-threatening bleeding such
as intracranial hemorrhage may occur9). However, in a study on
FVII deficiency, it was reported that patients with FVII:C levels
below 2% were either asymptomatic or had a very mild phenotype;
by contrast, patients with FVII:C levels above 5%, most had
severe symptoms. Even when FVII:C levels are statistically lower
in bleeders, it is generally agreed that they do not predict bleeding
tendency in an individual patient5, 10).
Treatment of congenital FVII deficiency consists of replacement
therapy with fresh frozen plasma (FFP), PCCs, FVII concentrates
and/or recombinant FVIIa (NovoSeven®)4, 11). As FFP, PCCs and
FVII concentrates are plasma-derived products, the use of these
products is associated with the risk of transmission of pathogens12).
In addition, the use of PCCs results in an unwanted increase in
other vitamin-K-dependent factors and is associated with both
arterial and venous thrombosis. Recombinant FVIIa has been
available on a compassionate and emergency use basis since 1988
for patients with hemophilia with inhibitors to FVIII or FIX,
and patients with congenital FVII deficiency4, 12). Intravenous
administration of recombinant FVIIa (NovoSeven®) is now widely
used for the treatment of FVII deficiency; however, there are no
recommended guidelines for the dose and treatment schedule.
According to recent reports, the median dose per injection (22 μ g/
kg) was within the dose range recommended in the protocols for
FVII-deficient patients (15-30 μg/kg every 4-6 h until hemostasis
was achieved). For more severe bleeding (e.g. central nervous system
and internal bleeding episodes) the patients were treated for a
longer period of time. Treatment with recombinant FVIIa for CNS
bleeding was rated as effective in 11/14 cases4, 11). Cases of ICH with
FVII deficiency treated by FFP have been reported13, 14). In the case
reported here, recombinant FVIIa was administrated at dose of 20
μ g/kg for 20 days, and it was effective.
Review of the medical literature revealed that as many as one-
third of episodes recorded in the neonatal period had a delayed
diagnosis and/or treatment10, 15, 16). Pediatricians should be advised
of the need for hemostasis control in newborns with ICH.
This should facilitate the early diagnosis of possible hemophilia
and appropriate treatment. The frequency and significance of
neonatal ICH underscores the importance of the early diagnosis
of hemophilia. Moreover, children should be closely followed for
several days as symptoms of ICH may be delayed for up to six days
in the case of severe hemophilia, and longer for mild hemophilia.
For the case reported here, there were no specific signs of an ICH,
e.g. persistent vomiting, change of mental status, seizure; the patient
had the nonspecific findings of fever and poor feeding. The initial
administration of factor replacement was started five days after the
Prophylactic therapy with factor concentrates is currently the
most effective intervention available for the prevention of bleeding
episodes in patients with hemophilia. In congenital FVII deficiency,
prophylaxis has been a debated issue, especially because of the very
brief maintenance of infused FVII in the blood stream17, 18). One
report suggests that prophylactic treatment with recombinant
FVIIa in patients with FVII deficiency with dosage of 20-30 μ g/kg
once to twice weekly may be beneficial in preventing hemorrhagic
complications in spite of the short plasma half life17). However, this
WS Lee, and YS Park • A case of intracranial hemorrhage in a neonate with congenital factor VII deficiency
remains a controversial issue.
In summary, congenital FVII deficiency is a rare inherited
bleed ing disorder. Clinical heterogeneity is the hallmark of this
hemorrhagic disorder; the severity ranges from lethal to mild, and
there are asymptomatic forms. Here, a case of FVII deficiency and
severe ICH with successful management using recombinant FVIIa
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