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Valproic acid-associated low fibrinogen
and delayed intracranial hemorrhage:
case report and mini literature review
This article was published in the following Dove Press journal:
Drug Design, Development and Therapy
12 August 2013
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Hai-Fei Chen 1,2
Li-Ping Xu 1
Zhi-Yong Luo 1
Zi-Qiang Yu 2
Zheng-Yang Li 1
Qing-Ya Cui 1
Long-Mei Qin 1
Yong-Ya Ren 1
Hong-Shi Shen 1
Jie-Qing Tang 1
Ling-Juan Jin 1
Jing-Jing Zhu 1
Jing Wang 1
Ke-Yuan Wang 1
Tian-Qin Wu 1
Zhao-Yue Wang 2
Department of Hematology,
100th Hospital of People’s Liberation
Army, 2Jiangsu Institute of Hematology,
First Affiliated Hospital of Soochow
University, Suzhou, People’s
Republic of China
1

Correspondence: Tian-Qin Wu
Department of Hematology,
100th Hospital of People’s Liberation
Army, Suzhou, 215007, People’s
Republic of China
Tel +86 0512 65063541
Email chhf1224@163.com;
Zhao-Yue Wang
Jiangsu Institute of Hematology, First
Affiliated Hospital of Soochow University,
Suzhou, 215006, Jiangsu Province,
People’s Republic of China,
Tel +86 0512 67780460
Email zwang11@sina.com

Abstract: A 41-year-old male had suffered from gradual hearing loss in his right ear for 2 years.
Head computed tomography and magnetic resonance imaging scans showed a neoplasm in the
cerebellopontine angle region, which was confirmed by the diagnosis of acoustic neurilemmoma by
pathological findings after surgery. Following surgery, he routinely received ­valproic acid (VPA) to
prevent seizures. However, the patient presented with hypofibrinogenemia and cerebral hemorrhage
after taking VPA for 12 days. The hypofibrinogenemia recurred when VPA was ­re-administered.
After withdrawal of VPA, his fibrinogen concentration rose to normal within several days. As far as
we are aware, this is the first case of cerebral hemorrhage due to VPA to have been reported. Herein,
as well as reporting on this case, a mini review of the relevant literature is also presented.
Keywords: side effect, hypofibrinogenemia, cerebral hemorrhage, cerebellopontine angle,
neoplasm

Introduction
Valproic acid (VPA) is the main antiepileptic drug broadly administered for all types
of seizures. Its excellent efficiency has been shown over four decades of clinical use.
Acute toxicity is rare, and when it does occur, it usually follows a benign course.1
Fatal hepatic failure is usually seen following chronic use of VPA.2 The most commonly reported adverse effects are anorexia, nausea, and vomiting. Less frequently,
thrombocytopenia; abnormal platelet function; decreased von Willebrand factor
­concentration; abnormal bleeding time; and activated partial thromboplastin time
(APTT) with decreased fibrinogen (Fbg) levels and prolonged prothrombin time
(PT) leading to bruising, petechiae, hematoma, and epistaxis have been reported.3 In
general, the adverse effects in the hemostatic system are mild or found as abnormal
parameters with little clinical significance in laboratory assays.4 Here, we report the
case of a male patient with hypofibrinogenemia and cerebral hemorrhage during
­treatment with oral VPA.

Case presentation
A 41-year-old male had suffered from gradual hearing loss in his right ear for
2 years. Head computed tomography and magnetic resonance imaging scans showed
a ­neoplasm in the cerebellopontine angle region, which was suspected to be acoustic
­neurilemmoma. Preoperative routine coagulation tests of APTT, PT, thrombin time,
Fbg, and ­platelet count (Plt) were within the normal ranges, and he had no history of
bleeding since birth. Clinical ­examination, biochemistry analysis, and kidney function
were normal. The ­echocardiogram showed normal sinus rhythm. The patient had a
767

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http://dx.doi.org/10.2147/DDDT.S47718

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Chen et al

h­ istory of hepatitis B 20 years before; however, liver enzymes
and synthesis function were normal before surgery.
Resection of the neoplasm was successfully performed
and blood loss was not excessive during the operation. The
results of the pathological examination confirmed the diagnosis of acoustic neurilemmoma. VPA was administered at
20 mg/kg/day to prevent seizures after surgery. Twelve days
after surgery, the patient reported headache and examination suggested suspected re-bleeding from the surgical site.
This was confirmed in the second surgery. He was treated by
decompressive craniotomy to relieve the high pressure.
After the second surgery, a drainage tube was inserted in
the incision, since interim bleeding was present (Figure 1). He
received daily transfusions of fresh plasma and cryoprecipitate
to improve coagulation function, but the volume of drainage
from surgical lesions remained about 30 mL/d. His coagulation function was again tested and he was found to have normal PT, APTT, TT, D-dimer, coagulation factors, and Plt, but
a low Fbg level (0.8–1.6 g/L; reference value, 2–4 g/L), high
tissue-type plasminogen activator (t-PA) activity (5,400 U/mL;
reference value, 300–600 U/mL), and high fibrinogen/fibrin
degradation product (FDP) level (60 mg/L; reference value,
,10 mg/L). Meanwhile, his biochemistry results, kidney
function, and liver function remained normal.
The patient was referred to the Department of Hematology for further management on 30 days following his first
surgery. With a supplement of daily Fbg (3 g/d) and use of
antifibrinolytic agents for 5 days, the amount of bleeding from
A

IMAGE 6
−44.1 mm

R
R

10 cm

2011-11-1

W 85 L 46

Figure 1 Image after second surgery. Head CT axial image shows the drainage tube
placed in the lesion.
Abbreviation: CT, computed tomography.

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the drainage tube decreased gradually and the patient felt
his headache relieved without VPA. Coagulation was tested
daily and results showed that the Fbg gradually returned to
normal within 5 days: from 0.8 g/L on the first day to 1.2 g/L
on the second day of treatment, 1.8 g/L on the third day,
2.3 g/L on the fourth day, and 3.5 g/L on the fifth. Coagulation parameters were maintained at normal levels in a week
without Fbg transfusion.
Following this, the patient was referred again to the
Department of Neurosurgery and VPA treatment was
resumed. Amazingly, his Fbg level decreased over time,
reaching the minimum level of 0.53 g/L on the fifth day
of VPA re-administration. Fortunately, the patient had no
bleeding symptoms or manifestation. VPA-associated hypofibrinogenemia was suspected, so the treatment discontinued.
Following this, his Fbg level returned to normal and remained
stable. The drainage tube was removed 61 days after his first
surgery. At follow-up at 6 months, the patient’s hemostatic
parameters including Fbg were normal and no symptoms of
bleeding were found.

Discussion and mini literature
review
The patient presented with hypofibrinogenemia and cerebral
bleeding 12 days after taking the recommended dosage of
VPA. His bleeding was alleviated as plasma Fbg concentration returned to normal after discontinuing VPA. This suggests a causal relationship between the hypofibrinogenemia,
cerebral bleeding, and administration of VPA. Interestingly,
this phenomenon recurred on re-administration of the VPA,
confirmed by this second use and subsequent discontinuance
of the treatment.
VPA was approved by the US Food and Drug ­Administration
in 1978 and is indicated for all seizures ­including complex
partial seizures, simple and ­complex seizures.5,6 Therefore, it
is extensively prescribed as an ­antiepileptic drug to prevent
seizures in patients after neurological ­surgery. Although
­VPA-associated coagulopathies are common, ­significant
clinical bleeding ­complications are rare.4
Fbg, a soluble plasma glycoprotein synthesized by the
liver, is converted by thrombin into fibrin during blood
­coagulation. Congenital deficiency or abnormal function of
Fbg was ruled out in this patient, as he had no personal or
family history of bleeding, and the results of his preoperative
coagulation tests were normal. Therefore, his hypofibrinogenemia during oral VPA administration was acquired. As is well
known, acquired deficiency comprises primary and secondary
fibrinolysis. However, in this case, the latter ­(disseminated

Drug Design, Development and Therapy 2013:7

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VPA-associated hypofibrinogenemia and intracranial hemorrhage

Table 1 Literature on valproic acid (VPA)-associated hypofibrinogenemia
Study

Year

Research type

Hypofibrinogenemia
patients, n/N

VPA dose,
mg/kg/d*

Mean level
of Fbg,
g/L (nadir)

Hypofibrinogenemiaassociated clinical
bleeding

Discontinuation
of therapy

Serdaroglu14
Gerstner4
Anderson15
Tokuda16
Hauser17
Koenig10
Köse12
Eberl18
Topf19

2002
2006
2003
1994
1996
2008
2009
2009
2011

Retrospective
Retrospective
Prospective
Retrospective
Prospective
Prospective
Prospective
Prospective
Comparison study

8/29
5/385
0/75
3/3
NA/50
12/23
2/24
9/40
NA/40

20–30
20–130 mg/mLa
40–100 mg/mLa
59.7 mg/mLa,c
20–27
70–120 mg/mLa
20d
NA
NA

2.40 (1.39)
NA
NA
0.46 (0.22)
1.92 (0.76)
1.51 (NA)
1.89 (0.88)
2.22 (NA)
NAe

No
No
No
No
No
No
No
No
No

No
Nob
No
NA
NA
No
No
No
No

Notes: *Unless otherwise indicated. aSerum level of; bfibrinogen increased after VPA dosage reduction or discontinuation; ccombination of ACTH-Zn (adrenocorticotrophinzinc phosphate) and VPA; dstarted at dose of 10 mg/kg/d (a week later the dose was raised to target dose); epatients in the VPA group had lower hypofibrinogenemia than
those in the control group (P , 0.05).
Abbreviations: Fbg, fibrinogen; NA, not available.

intravascular coagulation) was easily precluded because the
patient had normal Plt count and TT during the course. Thus,
the patient’s low Fbg concentration could have resulted from
acquired/primary fibrinolysis or synthesis deficiency. The
normal liver function during the disease indicated the normal
synthesis function of liver. Therefore, the cause of his low
Fbg level was probably primary fibrinolysis.
Since the 1970s, several studies have documented a VPA
dose-related decrease in Fbg (mean 1.76 g/L; normal, 1.80–
4.00 g/L).7,8 In these studies, patients taking other antiepileptic
drugs had mean Fbg levels of 2.35–2.72 g/L. One patient taking
VPA had their Fbg values decline from 2.10 to 1.25 g/L. After
withdrawal of VPA, Fbg rose to 2.90 g/L in 12 days.9 In three
VPA-treated patients with low Fbg, fibrin degradation products
were normal.8 Koenig et al10 reported that Fbg levels dropped
below the lower limit in 12 out of 23 patients who received
VPA therapy. Blood coagulation disturbances are common in
patients with VPA, but rarely become clinically symptomatic.
Ward et al11 reported similar results. In a prospective study,
Köse et al12 reported that VPA causes decreased factor VII levels, Plt, factor VIII, Protein C, Fbg, and increased lipoprotein
(a) levels. However, no serious bleeding complications were
observed in the studies and no correlation was found between
Fbg concentration and the dose, blood level, or duration of
VPA therapy in the majority of studies (Table 1).
The striking elevation of fibrin degradation products in
our patient suggested his hypofibrinogenemia was a consequence of excessive consumption rather than deficient production. Although most VPA-associated side effects are mild,
we propose that in the case of planned surgery or accidents,
routine screening tests comprising Plt, PT, and APTT may
not be sufficient. Thus, thromboelastography, von Willebrand
factor, and ristocetin cofactor should also be tested to treat
the defects properly.

Drug Design, Development and Therapy 2013:7

To our knowledge, this is the first case of hypofibrinogenemia and cerebral hemorrhage due to VPA treatment that
has been reported. The shorter duration of VPA administration and faster recovery of Fbg level may be why the patient
had no bleeding during the second oral VPA ­administration.
The longer time from the brain surgery to the second onset
of hypofibrinogenemia may also be partially responsible. The
precise mechanisms of VPA-associated low Fbg concentration remain unknown. Recently, Larsson et al13 reported that
VPA induces t-PA expression in cultured endothelial cells
and this is associated with increased histone acetylation at
the t-PA gene promoter. Their results showed that VPA dose­dependently stimulated t-PA mRNA and that protein expression in endothelial cells could reach a two- to fourfold increase
at clinically relevant concentrations and tenfold increase at
maximal concentrations. This could account for the low level
of Fbg in patients who receive VPA treatment.

Disclosure
The authors declare no conflicts of interest in this work.

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