Original Article

TRANSLATIONAL&PRACTICAL DOI: 10.51271/JTPM-0024

M EDICI NE J Transl Pract Med 2022; 1(3): 85-88

Intracranial hemorrhage in children with hemophilia

Şefika Akyol1, Deniz Koçak Göl1, Ebru Yılmaz1, Zehra Filiz Karaman2, Alper Özcan1,
Ahmet Küçük3, Veysel Gök1, Firdevs Aydın1, Hüseyin Per4, Musa Karakükcü1,
Türkan Patıroğlu1, Mehmet Akif Özdemir1, Ekrem Ünal1,5,6
1Erciyes University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology & Oncology, Kayseri, Turkey
2Erciyes University, Faculty of Medicine, Department of Pediatric Radiology, Kayseri, Turkey
3Erciyes University, Faculty of Medicine, Department of Neurosurgery, Kayseri, Turkey
4Erciyes University, Faculty of Medicine, Department of Pediatric Neurology, Kayseri, Turkey
5Erciyes University, Health Science Institution, Department of Blood Banking and Transfusion Medicine, Kayseri, Turkey.
6Erciyes University, Gevher Nesibe Genom and Stem Cell Institution, Genome and Stem Cell Center (GENKOK), Molecular Biology and
Genetic Department, Kayseri, Turkey

Cite this article as: Akyol Ş, Koçak Göl D, Yılmaz E, et al. Intracranial hemorrhage in children with hemophilia. J Transl Pract Med 2022; 1(3):
85-88.

ABSTRACT
Aim: Hemophilias are inherited bleeding disorders, in which the patients generally present with clinical complaints of
hemarthrosis. Intracranial hemorrhage (ICH) is one of the severe bleeding types with the highest mortality and morbidity
throughout childhood, as well as in patients with a diagnosis of hemophilia. Herein, a single-center experience of intracranial
hemorrhage in children with hemophilia is presented.
Material and Method: The files and hospital records of the patients with the diagnosis of hemophilia who were followed up
by the Pediatric Hematology and Oncology Department of Erciyes University between the years 1993-2022 were evaluated
retrospectively.
Results: A total of 81 patients with hemophilia were evaluated. Among them, 9 patients developed ICH. All patients had severe
disease. The mean age of incidence ICH was 2,6 months (4 days- 8,7 months). All the ICH episodes were observed within the
first year of life. Four patients were diagnosed with the ICH episode initially. None of the patients had primary prophylaxis.
The majority of them were admitted with neurological signs and symptoms. There was no ICH-related mortality in our study
and all of the patients are being followed up in our department.
Conclusion: Intracranial hemorrhage remains important in patients with congenital bleeding disorders, especially in
hemophilia; with difficulties in diagnosis, management, and treatment.
Keywords: Children, Hemophilia, Intracranial hemorrhage

INTRODUCTION The manifestations are related to impaired hemostasis.

Also, the severity of the disease affects the timing and
Hemophilias, both A (factor VIII deficiency) and B
the severity of the clinical manifestations. Patients with
(factor IX deficiency) are X-linked inherited bleeding
severe disease present with the symptoms like easy
disorders, affecting more than 1.2 million individuals
bruising, hemarthrosis, bleeding due to oral injury,
worldwide, most commonly males. Hemophilia A is
or after an invasive procedure, usually in the first year
diagnosed in 1 in 4000 to 1 in 5000 live male births,
of life. Apart from this knowledge which is classically
whereas Hemophilia B is 1 in 15,000 to 1 in 30,000
known, 3-5% of the infants with severe hemophilia
live male births (1,2). Severe disease is identified in
develop subgaleal or intracerebral hemorrhage in the
approximately half to two-thirds of the patients with
perinatal period (7-9).
hemophilia A and one-third to half of patients with
hemophilia B. Also considering heredity, it is worth Intracranial hemorrhage (ICH) is rare when compared
reminding that sporadic cases (which can be named as to other bleeding sites, however, it is life-threatening and
de novo) can be determined. Hemophilia occurs in all also can cause severe morbidity. Patients of all ages can
ethnic groups worldwide (1-6). exhibit ICH either spontaneously or following trauma.

Corresponding Author: Ekrem Unal, [email protected] Received: 16.11.2022  

Accepted: 13.12.2022

This work is licensed under a Creative Commons Attribution 4.0 International License.
Akyol et al. Intracranial hemorrhage in hemophilia J Transl Pract Med 2022; 1(3): 85-88

In children and infants, the severity of hemophilia is the Before the ICH, 3 patients were on-demand treatment,
most important risk factor for ICH, whilst both mild and the remaining 6 had not received treatment before
and moderate forms can develop ICH in adulthood and none of them had primary prophylaxis. In addition,
(9,10). The background of ICH, protective measures, no inhibitor was detected in any of these patients before
appropriate emergency approaches and, long-term the ICH episode.
management complications are still important hot topics
On admission with ICH, 5 patients (55,5%) had
because of long-term behavioral and cognitive outcomes.
neurological signs and symptoms like weakness,
Therefore, in this study, we aimed to share our single-
hemiparesis, hydrocephalus, and associated
center experience with ICH in hemophilia patients.
deterioration in alertness. Three of these patients
developed epilepsy after the ICH period. Apart from
MATERIAL AND METHOD this, 2 patients had neurological sequelae; both
The files and hospital records of 81 patients with the unilateral hemiparesis and weakness in the early
diagnosis of hemophilia who were followed up by the period after the ICH episode. They were supported
Pediatric Hematology and Oncology Department of with physical therapy and rehabilitation in the follow-
Erciyes University between the years 1993-2022 were up. Two patients had only subdural bleeding, one had
assessed retrospectively. Plasma factor levels were intraventricular bleeding and shift, and the remaining
used in determining the disease severity. Besides, the six patients had both parenchymal and subdural
medical records of the patients were evaluated in terms hemorrhage. The radiological image of the patient with
of treatment modalities, inhibitor presence, neurological subdural hematoma was shown in Figure 1.
conditions and, outcomes, both before and after the
ICH. The study protocol was approved by the ethical
committee of Erciyes University Faculty of Medicine
(Decision No: 2019/717).

RESULTS
A total of 81 patients diagnosed with hemophilia were
enrolled. There were 73 patients with the diagnosis
of hemophilia A and 8 patients with hemophilia B. Of
these patients, 39,5% (n:32) had the severe disease in
hemophilia A, whereas 8,6 % (n:7) of the patients with
hemophilia B had severe disease.
Of the 81 patients, 9 (%) patients developed intracranial
hemorrhage. Among them, 8 (89%) had hemophilia A
and only one (11%) had hemophilia B. All the patients
had severe disease, according to plasma factor levels.
The mean age of the patients at the time of ICH was
2,6 months (ranging from 4 days to 8,7 months). All of
these ICH episodes were observed in the first year, and
even one-third of them (n:3) developed in the neonatal Figure 1. Axial T1 weighted MRI. Extra axial effusion compatible
period. Four patients were diagnosed with hemophilia with subacute subdural hematoma is shown (arrow). The right
with initially developing ICH. Bleeding types at the frontal cortex is slightly compressed by hematoma.
initial diagnosis are given in Table 1. Among these 4
In the management of ICH, 3 patients were supported
patients, 3 of them were born by cesarean section and
with packaged red blood cell transfusion. Surgery
one was by spontaneous vaginal delivery. Trauma was
was performed on 4 patients. The mean time between
present in 3 of the patients, and others were non-trauma
the admission and surgery was 2,7 days (minimum
associated. Other risk factors such as medications or
1-maximum 4 days). Anticonvulsant therapy was
hypertension were not present.
implemented in 7 patients. The mean treatment time
Table 1. Bleeding types at diagnosis with factor replacement for the acute period was 14
Bleeding type n days (minimum 10- maximum 21 days). Secondary
Intracranial hemorrhage 4 prophylaxis was initiated for all patients in the follow-
Hemarthrosis 2 up. After the acute period, two patients developed an
Ecchymous /Hematoma 3 inhibitor, and they are now being treated with bypassing

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J Transl Pract Med 2022; 1(3): 85-88 Akyol et al. Intracranial hemorrhage in hemophilia

agents. Recurrence of bleeding was observed in 3 (16,17). Even if there is no index case in the family, it
patients, one of them had two recurrent episodes. All is necessary and recommended to suspect inherited
of the 9 patients are being followed up in our pediatric bleeding disorders, especially hemophilias, in frontline
hematology oncology department. differential diagnosis, while evaluating delivery-related
hematomas of the neonatal period, as seen in many case
DISCUSSION reports and studies in the literature (18,19). Besides the
high suspicion index, the proper evaluation of screening
Among the congenital factor deficiencies, hemophilias tests by primary health care providers is important in
are the most frequently studied group. Besides order to avoid diagnostic delays (20).
considering the treatment modalities, hemophilias have
reached the advanced methods which are successfully In the neonatal period, the mean age of the occurrence
administered such as gene therapy. Today, despite of ICH is 4-5 days (ranging between birth to 28 days),
sophisticated progress in hemophilia, bleeding and however, it should be kept in mind that, there are
bleeding-related morbidities are still ongoing problems. several factors contributing to the risk of bleeding in
hemophilic neonates as well as in the normal neonates,
The most serious bleeding complication in patients such as sepsis, disseminated intravascular coagulation,
with hemophilia is ICH. Among the inherited bleeding vitamin K deficiency and others (16,21). In our study
disorders, each of which may be presented with ICH 3 patients had ICH in neonatal period. No other risk
or may develop ICH in the follow-up, hemophilia A factors increasing the risk of bleeding determined.
is generally the most frequently associated with ICH Another risk factor reported in the literature, catalyzing
(11,12). Despite the increased prophylactic usage of ICH is inhibitor presence (21,22). In our study, no
factor therapies globally, compared to the general patient had an inhibitor before the ICH episode. As well,
population, patients with hemophilia have a greater after the ICH period, the intensification of the therapy
prevalence for ICH which is estimated as 3.5-4%. is recommended, since previous ICH is one of the risk
ICH has still the most devastating outcome in this factors for recurrence (14). In the current study, three
group (13,14). Mortality is still around 20% and even of our patients had recurrent ICH episodes despite they
higher in developing countries, in terms of unknown were on secondary prophylaxis with factor replacement
carrier status of mothers, presence of prematurity, three times a week.
and traumatic birth (12-15). In current study, we
demonstrated an ICH rate of 16%. This is higher The clinical features of ICH vary in different age groups.
compared to the literature. This may be attributed Infants present with clinical signs of anemia such as
to the fact that our patients were not on primary pallor, hypotension, and decreased suction before
prophylaxis before the ICH episode. On the contrary, the neurological signs. After the neonatal period, the
although there were higher rates of ICH, there was no clinical signs of ICH consist of, headache, altered
ICH-related mortality in our study. This is related to level of consciousness, and localized symptoms of the
the rapid implementation of appropriate treatments. neurological system like seizures, hemiparesis, and
hemiplegia (21-23). In our study the most common signs
In the era of prophylactic factor replacement and gene and symptoms on admission were neurological.
therapies, ICH rates have significantly decreased.
Nevertheless, as demonstrated in our study and often The recommended imaging modalities are frequently
noted in the literature, the perinatal period still has a cranial computed tomography and/or magnetic
high risk of ICH (12,14). Moreover, considering that resonance imaging for diagnosis. As well, cranial
hemophilia may manifest de novo, about 30% of cases ultrasonography is also an option in the neonatal period
do not have a family history, and because of this, ICH since it is non-invasive and more accessible. However,
rates may be higher than documented. Since these it may not be able to detect all types of bleedings
patients do not have a family history, they may die successfully. Still, in hemophiliac newborns, routine
without considering hemophilia in the preliminary cranial ultrasonography is recommended even if there
diagnosis. ICH seen in newborns is most commonly are no signs and symptoms and in case of any suspicion
related to delivery (14,16). In the current study, we had of ICH occurrence, factor replacement is recommended
only one patient who was born via vaginal delivery and (24,25). In the current study, cross-sectional imaging
developed ICH within the first 24 hours of life. In the methods were preferred. Also as recommended in the
literature, the risks of ICH after vaginal delivery and literature, the appropriate factor replacement therapy
cesarean section are exhibited to be similar and there is was implemented. The duration of this replacement
no certain answer about the optimal type of delivery for therapy is recommended as 2-3 weeks in literature with
these patients (17). However, the risk was found to be targeted maintenance of plasma factor level around 80-
higher in assisted delivery such as forceps and vacuum 100 IU/dL (24,26).

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Akyol et al. Intracranial hemorrhage in hemophilia J Transl Pract Med 2022; 1(3): 85-88

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