Intracranial hemorrhage in infants due to

acquired prothrombin complex deficiency

PONGSAKDI VISUDHIPHAN,M.D., PARTTRAPORNBHANCHET, M.D.,

CHINTANA LAKANAPICHANCHAT,M.D., ANn SURANG CHIEMCHANYA,M.D.
Department of Pediatrics, Ramathibodi Hospital, Faculty of Medicine, Mahidol
University, Bangkok, Thailand

The authors report eight infants who had acute intracranial bleeding after the
third week of life, in the absence of known trauma. When first seen each was
moribund, pale, and had a tense anterior fontanel; half of the cases had
associated ecchymoses. Spinal and subdural taps yielded large amounts of
bloody fluid. Coagulation studies indicated a severe lack of factors involved in
prothrombin complex formation. The clotting indices were sufficiently low to
account for spontaneous bleeding. Satisfactory clinical and laboratory results
were demonstrated after subdural and spinal taps combined with intravenous
vitamin K and fresh blood transfusion to correct the coagulation defect and
anemia.

KEY WORDS infant intracranial hemorrhage subarachnoid

cerebral swelling prothrombin complex deficiency vitamin K

S
PONTANEOUS intracranial hemorrhage in
early infancy has been rarely reported
in neurosurgical journals. Bleeding
aneurysms, arteriovenous malforma-
tions, ~,7,~.12,a6 and hemophilia ~,~1 are among
the causes mentioned.
Recently, prothrombin complex deficien-
cy occurring beyond the immediate newborn
period has been described. 1,4,5,’~ Ec-
chymoses and neurological abnormalities
are the manifestations usually reported;
there has been only brief reference to the
extent of intracranial bleeding. We are
presenting a detailed report of eight such
cases and their satisfactory neurosurgical
and medical treatment.
cy were seen over a period of 2 years (1970
to 1972) in the Department of Pediatrics,
Ramathibodi Hospital, Mahidol University.
The patients were 3 weeks to 1 year old, and
had definite proof of intracranial bleeding
due to prothrombin complex deficiency. The
deficiency in prothrombin complex was
confirmed by coagulation studies in five
cases. Complete blood counts were done in
all cases. Partial thromboplastin time testing
was done according to the method of
Rodman, et al., TM using the standard com-
mercial preparation of Fibrolet-activated
platelet factor reagent.* Prothrombin time
was performed by Quick’s method 17 using

Material and Method

*Fibrolet-activated platelet factor reagent man-
Eight patients with intracranial hemor- ufactured by BBL Division, Bioquest, Cockeys-
rhage due to prothrombin complex deficien- ville, Maryland 21030.

]4 J. Neurosurg. / Volume 41 / July, 1974

Intracranial hemorrhage in infants

TABLE 1

Clinical data in eight cases of intracranial hemorrhage due to prothrombin complex deficiency

Case Diet
No. Sex Age (Milk) Symptoms Antibiotics

1 M 36 days human upper respiratory infection yes

2 M 50 days human upper respiratory infection --
3 F 34 days human diarrhea, upper
respiratory infection yes
4 M 5 mos formula diarrhea yes
5 M 26 days human upper respiratory infection --
6 F 20 days human upper respiratory infection yes
7 F 7 mos human, food diarrhea yes
8 M 40 days human upper respiratory infection yes

rabbit brain thromboplastin.t T h e thrombin
time test, determined by the m e t h o d of
Schneider ~~ using bovine thrombin,:~ 100
units/ml, was capable of detecting fibrino-
gen concentrations above 80 to 100
rag%.
Results
Clinical Factors
Table 1 summarizes the sex, age of onset,
diet, and symptoms preceding the initial
clinical manifestations of intracranial bleed-
ing. The onset of the first symptoms
occurred between 3 weeks and 2 months in
six patients, and between 5 months and 7
months in two. All patients except one were
breast-fed; some mothers also used the folk
medicine procedure of alcoholic maceration,
which is the extraction by soaking of
alcohol-soluble components of herbs. The
majority of the children were well developed
and nourished. N o n e of them had a history
of bleeding tendency in the family. All had
had upper respiratory tract infection or
diarrhea, and half had taken antibiotics a
few days prior to the onset of the
intracranial bleeding. All were moribund,
showed m o d e r a t e - t o - m a r k e d anemia, tense
anterior fontanels, and grunting breathing at
the time of admission (Table 2).
Blood Studies

tThromboplastin (Simplastin) manufactured by Blood coagulation studies showed pro-

Warner Chilcott Laboratories, Warner-Lambert longed partial thromboplastin time and
Company, Morris Plains, New Jersey 07950.
#Bovine thrombin manufactured by Parke decreased p r o t h r o m b i n time, the range being
Davis & Company, Detroit, Michigan 48232. 0 to 2 4 % of normal activity in all cases.

TABLE 2
Clinical data in eight cases of intracranial hemorrhage due to prothrombin complex deficiency*

Intracranial Bleeding
Case Convul- Outcome
No. Ecchymoses Anemia sion Sub- Sub- Intra-
dural arachnoid cerebral
1 -- mild + - + + recovery
2 face marked + + + + low IQ
3 cheek, knee marked - + + recovery
4 -- moderate + + + + recovery
5 -- mild - + + + hemiparesis
6 buttock, chest mild + - + =~ recovery
7 eyelids mild + q- + + death
8 -- moderate + + + ~- low IQ
*All cases showed a tense fontanel.

J. Neurosurg. / Volume 41 / July, 1974 15

 P. Visudhiphan, et al.
TABLE 3
Results of hemostatic studies before and after treatment*

Case Platelet P.T.T. P.T. T.T. S.G.O.T. S.G.P.T.

No. Time (1000/mm3) (sec) ~o (sec) (S.F.U.) (S.F.U.)
normal -- 287 ~ 55 36--65 60-160 2-12 0--50 0--50
1 before adequate 200+ 0 1.6 -- --
treatment
4 days after vit. -- 35 100 2.0 -- --
K & blood
transfusion
3 before increased 72 18 2 -- --
treatment
6 before 363 98 10 2 14 17
treatment
7 before adequate 108 24 2 87 100
treatment
8 hrs after vit. -- 40 100 2 -- --
K & blood
transfusion
8 before increased 180 10 4.5 64 36
treatment
5 hrs after vit. -- 38 100 2 -- --
K alone
*P.T.T.=partial thromboplastin time; P.T.=prothrombin time; T.T.=thrombin time; S.G.O.T.=serum
glutamic oxaloacetic transaminase; S.G.P.T. = serum glutamic pyruvic transaminase; S.F.U. = Sigma-Frankel
unit.

Thrombin time was normal and a good clot
was obtained in each case, reflecting a
normal fibrinogen level. Blood platelets were
adequate in the blood smear or a direct
count. Red cell morphology showed no
abnormal cells or hemolysis.
Effect o[ Therapy on Blood Studies
At 5 to 8 hours after the administration
of vitamin K1 alone, as in Case 8, or of
vitamin K1 with transfusion of fresh blood,
as in Cases 1 and 7 (Table 3), the low
prothrombin activity was increased to about
75% to 100% normal; this probably
reflected vitamin K deficiency. It should be
noted that studies of liver chemistry were
normal in these cases.
Evidence and Treatment of C N S Bleeding
All patients had massive subarachnoid
hemorrhage. In six, acute subdural hemor-
rhage was also demonstrated, mostly bilat-
erally. Few subdural accumulations needed
additional taps after the coagulation defect
had been controlled by intravenous vitamin
K1, or vitamin K and fresh blood transfu-
sions. One patient required a craniotomy for
the treatment of subdural bleeding. The
clinical diagnosis of intracerebral hemor-
rhage was made in all of the cases.
Outcome
Seven of the eight patients in this series
recovered satisfactorily; one died due to a
delayed diagnosis of cerebral swelling and
herniation. Four of the seven had complete
recoveries, and three had residual neurologi-
cal deficits comprising moderate delayed
psychomotor manifestations (two cases),
and mild hemiparesis (one case). No
patient showed signs of hydrocephalus when
examined 1 to 3 years later, and none had
recurrent bleeding.
Characteristic Case Report
This 7-week-old Thai boy (Case 2) was
admitted to the Department of Pediatrics,
Ramathibodi Hospital, in July, 1970, be-
cause of diarrhea, fever, and vomiting for 3
days and a generalized convulsion on the
day of admission. He had passed loose
stools about 4 to 5 times per day; the stools
contained no blood or mucus. One day
before admission he became lethargic and

]6 J. Neurosurg. / Volume 41 / July, 1974

Intracranial hemorrhage in infants
Pathological bleeding due to prothrombin
refused feedings. The infant, the first child
of the family, was born at home spontane- complex deficiency in older infants and
ously and normally after 33 weeks’ gesta- children is less familiar. In 1946 Rapoport
tion; there had been no known complica- and Dodd TM reported observations made on
tions during pregnancy. The birth weight a group of seven infants 2 to 12 months of
was unknown; he was breast-fed only. age with chronic diarrhea. Each of the
Neither mother nor child had received infants was hypoprothrombinemic, and four
vitamin K. experienced symptomatic bleeding. The
symptoms and abnormal coagulation studies
When first seen the infant was undernour-
ished and weighed 3450 gin. Respiration were effectively corrected with vitamin K.
The significance of prothrombin complex
was irregular and grunting. The patient was
very pale and stuporous. A few small deficiency emphasized in their paper seems
ecchymotic areas were noted on the face. to have attracted little attention for two
The liver edge was 3 cm below the right decades. Recently Goldman and Desposito 5
costal margin. The head circumference was published cases of five infants 2 to 4 months
36 cm and the fontanel very tense. The of age with acute bleeding episodes; three
pupils were small and reacted to light had intracranial hemorrhage which was a
sluggishly. The optic fundi were normal. result of vitamin K deficiency as demonstrat-
There was generalized hypotonia and hy- ed by coagulation studies. Bhanchet, et al., 1
showed that only vitamin-K-dependent fac-
poreflexia of all extremities. The neck was
not stiff, and Kernig’s sign was negative.tors (II, VII, IX, and X) were decreased
Laboratory studies revealed the following:while factors I, V, VIII, and XI were normal
hematocrit 12%, hemoglobin, 3.7 gm%, in this condition.
platelet count adequate, and the Lee White The number of related reports has
clotting time 12 minutes. Liver studies were
increased in the past 5 years. The condition
normal. The partial thromboplastin time has been identified by a variety of terms
was over 200 sec (4 times normal for this such as "hemorrhagic syndrome of early
laboratory), the prothrombin time less than
childhood, ’’1~ "hemorrhagic diathesis and
10% (60% to 160% is normal for this cystic fibrosis, ’’22 or "acquired prothrombin
laboratory). Prolonged bleeding was noted complex deficiency. ’’~ Each of these descrip-
from a venipuncture site. Lumbar puncture tions, however, is characterized by the same
revealed an opening pressure of over 300 basic pathology, namely, vitamin K deficien-
mm H20; the cerebrospinal fluid was bloodycy. These studies indicate that the three
with a hematocrit of 9%, a protein contentfactors commonly associated with vitamin K
of 1900 mg%, and a sugar content of deficiency occurring after birth are 1) low
48 mg%. Subdural taps yielded 10 cc of intake, 2) interference with bacterial syn-
bloody fluid from each subdural space. Thethesis, and 3) intestinal absorption by
patient was given 5 mg of vitamin K diarrhea or bacteriostatic agents. Vitamin K
intravenously followed by a transfusion ofdeficiency usually does not develop from
70 ml of fresh whole blood. Approximately low intake alone, presumably because of
2 hours later, evidence of progressive intestinal bacterial production of vitamin K.
hemorrhage ceased. A repetition of the This is confirmed by the fact that the great
coagulation studies 24 hours later revealed a
majority of infants on a low intake regime
reversal of the previous abnormalities. Indo not bleed. Apparently, significant defi-
the subsequent hospital course, subdural ciency develops only when low intake and
taps were negative. The neurological deficits
low intestinal supply coexist. The combina-
cleared within 2 weeks. Follow-up examina-tion of these factors was common in our
tion at the age of 1 89years revealed no patients. All were breast-fed, and it is
significant sequelae except mild micro- known that mothers’ milk is low in vitamin
cephaly. K. 1~ Our patients also developed upper
respiratory tract infection with or without
Discussion diarrhea a few days preceding the onset of
Hemorrhagic tendencies in newborn in- the intracranial hemorrhage. Half of the
fants have been known for many years. 3,8 patients received antibiotics. In brief, our

J. Neurosurg. / Volume 41 / July, 1974 ]7


TABLE 4
Associated intracranial bleeding due to
prothrombin complex deficiency
Author, No. of Intracranial Hemorrhage
Year Cases No.
Goldman & 5 3
Desposito
(1966)
Lovric & 13 4 30.7
Jones
(1967)
Goldman & 15 4 26.7
Amado
(1969)
Nammacher, 4 2
et al.
(1970)
Waiters & 4 1
Koch
(1972)
findings reinforce the hypothesis concerning
the roles of vitamin K deficiency in this
condition.
The clinical bleeding previously reported
was in most cases from multiple sites
including the skin, eyes, nose, and gastroin-
testinal tract, a,4,5,1~ About 2 5 % to 5 0 % of
the cases showed clinical evidence of
intracranial bleeding (Table 4). Only a few
developed intracranial bleeding without ec-
chymosis or associated bleeding in other
organs. The symptoms and signs were
identical with those of hemorrhage from
other causes.
Our patients were quite different from
those in the previous reports. All of them
had intracranial hemorrhage, and only 5 0 %
had associated ecchymoses in the skin. The
neurological symptoms developed abruptly.
All of our patients showed the signs and
symptoms of acute increased intracranial
pressure due to rapid accumulation of blood
in the intracranial cavity. Bulging of
fontanels, dilated scalp veins, and changes
in vital signs were common. Convulsions
were found in over 50% of the cases; the
seizures were focal, generalized, or a
combination of both. The bleeding was
massive and was often found in the subdural
and subarachnoid spaces and suspected in
the cerebrum.
We believe that it may be difficult to
P. Visudhiphan, et al.
diagnose intracranial hemorrhage due to
prothrombin complex deficiency, especially
in patients with only intracranial bleeding.
The outcome for each patient, particularly
the resolution of neurological deficits, was
% related directly to the severity of the
hemorrhagic manifestations and the prompt-
60 ness of the treatment. Immediate subdural
taps or spinal punctures only transiently
improved the neurological symptoms and
signs. However, correction of the hypopro-
thrombinemic bleeding and anemia with
intravenous vitamin K and fresh blood
transfusion, when combined with the above
50 neurosurgical procedures, should usually be
successful.
25
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Address reprint requests to: Pongsakdi Visu-
dhiphan, M.D., Department of Pediatrics, Faculty
of Medicine, Ramathibodi Hospital, Rama VI
Road, Bangkok 4, Thailand.
19