Clin Appl Thrombosis/Hemostasis 12(1):111–113, 2006
©2006 Westminster Publications, Inc., Glen Head, NY

Middle Cerebral Arterial Thrombosis in a Patient with
Hypofibrinogenemia, 5 Days After rFVIIa and FFP Infusion
Turkan Patiroglu, MD, PhD, and Musa Karakukcu, MD
Erciyes University Medical School, Department of Pediatric Hematology, Kayseri-Turkey

Summary: A 13-year-old female patient is presented who had hypofibrinogenemia diagnosed as von Willebrand disease at 5 years of
age at another hospital. She was admitted to the department of pediatric hematology with a severe headache, vomiting, and progressive
right flaccid hemiplegia and lethargy. Contrast-enhanced computed
tomography scan showed subdural hematoma in posterior parietal
region of the brain and impending cerebellar herniation. She was
given fresh-frozen plasma (FFP) and then activated factor VII
(rFVIIa), 80 µg/kg was infused for replacement of von Willebrand

factor. The subdural hematoma was emergently drained. The results
of coagulation tests before infusion of FFP and rFVIIa revealed hypofibrinogenemia, and FFP was given every 48 hours. The patient
recovered dramatically in a few days. Five days after rFVIIa infusion,
a magnetic resonance angiography–proven right middle cerebral arterial thrombosis developed. It is an interesting point of discussion
whether the middle cerebral arterial thrombosis was provoked as a
consequence of rFVIIa and FFP infusion.
Key Words: Hypofibrinogenemia—rFVIIa—FFP—Thrombosis.

The two principal ligands known to mediate
platelet adhesion and aggregation are von
Willebrand factor (vWF) and fibrinogen (Fg)
whose importance is underlined by the bleeding
disorders associated with their respective deficiencies, i.e., von Willebrand disease (vWD) and
afibrinogenemia. vWD is the most common inherited bleeding disorder. Congenital afibrinogenemia, described in approximately 150 families, also leads to a bleeding diathesis that can be
fatal in approximately one third of such patients
(1,2).
Another aspect of vWF and Fg are their likely
involvement in thrombosis. Thrombosis in coronary or cerebral arteries is the major cause of
morbidity and mortality worldwide (1).

We report a case of inherited hypofibrinogenemia, with middle cerebral arterial thrombosis 5
days after recombinant activated factor VII
(rFVIIa) and fresh-frozen plasma (FFP) infusion
to stop intracranial hemorrhage.

CASE REPORT
The patient was a 13-year-old girl diagnosed
as having vWD at 5 years of age at a different
hospital. She was born to second-degree consanguineous parent with a family history of vWD.
She had a 6-year-old sister and an 8-year-old
brother, in whom intracranial hemorrhage developed 1 year previously. The patient was admitted to our hospital with a serious headache
and vomiting for 2 days. Physical examination
revealed unconsciousness, right facial paralysis,
and flaccid hemiparesis. Cranial contrast computed tomography (CT) scan showed subdural
hematoma in the posterior parietal region of the
brain and a shift of the intracranial contents (Fig.
1). Blood samples were obtained for prothrom-

Address correspondence and reprint requests to Turkan Patiroglu,
MD, PhD, Erciyes University Medical School, Department
of Pediatric Hematology, 38039, Kayseri-Turkey;
e-mail: turkan66@hotmail.com.

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T. PATIROGLU, M. KARAKUKCU

FIG. 1. Subdural hematoma and a shift of the intracranial
contents on CT (at admission to hospital).

bin time (PT), activated partial thromboplastin
time (aPTT), thrombin time (TT), and vWF antigen before treatment. Then, a subdural tap was
planned. Because of her prolonged bleeding time
(>15 minutes) FFP (10 mL/kg) and rFVIIa were
given at a dosage of 80 µg/kg (total, 3.6 mg) intravenously, as it was available. Because bleeding
time measured 1 hour after infusion was 4 minutes, a successful subdural tap performed on an
emergency basis. She opened her eyes on the
first postoperative day and recovered progressively. Results of coagulation studies including
PT, aPTT, TT, vWF, and fibrinogen concentration
before FFP and rFVIIa infusion were 70 seconds,
120 seconds, 109 seconds, and 120% 0.23 g/L,
respectively. In light of these results, her brother’s and sister’s coagulation test results were determined. It was found that they had prolonged
bleeding time, prolonged PT, prolonged PTT,
prolonged TT, and a decreased concentration of
fibrinogen. One more FFP was infused on the
third postoperative day. On the fifth postoperative day, she became unconscious again. A second CT scan showed a thalamic infarction but
not intracranial hemorrhage. Magnetic resonance angiography (MRA) and Doppler ultrasonography (USG) revealed a thrombus in the
left internal carotid artery (Fig. 2). ATIII, protein C, and protein S were 126%, 119.7%, and
74.5%, respectively.

FIG. 2. Infarction area due to obstruction of the middle
cerebral artery on MRA.

Physical and supportive therapy were advised
for the follow-up period. One year after admission to our hospital, physical examination revealed weakness in the right lower and upper extremities (muscle strength 4/5). Walking and
talking disorders did not recover completely.

DISCUSSION
Afibrinogemia is usually responsible for hemorrhagic diathesis. The prolonged bleeding time
may be obtained in an afibrinogenemic patient
but unexpected ischemic lesions are intriguing
(3–5). A congenital deficiency state known to
predispose to thrombosis was found in 27.2% of
patients. Of these, most were due to deficiencies
of protein C (9.2%), protein S (7.6%), ATIII
(5%), or to increased plasma PAI-1 concentration (3.1%) (3). Lak and colleagues reported that
spontaneous thrombotic episodes developed in
two young patients, and three women had recurrent abortions among 55 patients with inherited afibrinogenemia (6). Dupoy and colleagues
reported ischemic lesions of the feet related to
severe stenosis of the iliac and hypogastric arteries (5). Thrombotic complications are observed
frequently in afibrinogenemic patients following
replacement of fibrinogen. Therefore, we used a
single infusion of fibrinogen at lower doses than

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THROMBOSIS IN HYPOFIBRINOGENEMIA

usually recommended in afibrinogemic patients
(7,8). Our patient was diagnosed as having vWD
at 5 years of age in a different hospital, and had
severe subdural hematoma and a shift of cerebral content on admission to the hospital. She
had a prolonged bleeding time and FFP and
rFVIIa (80 µg/kg) were transfused on an emergent basis for subdural tap before results of other
coagulation tests were available. Then, our patient was diagnosed as having inherited hypofibrinogenemia based on a family history of bleeding and prolonged PT, aPTT, and TT (109 seconds), and decreased fibrinogen concentration
(0.23 g/L). Because the patient lost consciousness again on the fifth postoperative day, it was
thought to be caused by recurrent intracranial
hemorrhage. But, MRA and Doppler ultrasonography (USG) revealed a thrombus in the left internal carotid artery. The values of protein C,
protein S, and ATIII were within normal limits.
Three independent risk factors for arterial
thrombotic disease have been reported; namely,
fibrinogen, coagulation factor VII, and plasminogen activator inhibitor type 1 (9). FVIIa has been
successfully used in patients with hemophilia
with inhibitors to factor VIII or IX. As in the case
of use of rFVIIa, hemostasis is started by the formation of a complex between tissue factor and
activated factor VII following trauma or injury.
In vitro studies have shown that rFVIIa can bind
to the activated platelet surface with low affinity
and induce the thrombin burst for hemostasis. It
has also been used for patients with other congenital or acquired functional platelet disorders
including Bernard-Soulier syndrome, platelet
type vWD, and thrombocytopathies due to uremia or myelodysplastic syndrome (10).
In conclusion, we could not definitively state
the cause of the thrombotic complication in this

113

patient with hypofibrinogenemia; it may have
been caused by multiple infusion of FFP and
rFVIIa.

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