الفهرس 
Hemophilia in pediatricsOnly 14 pages are availabe for public view
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Abstract
Children suffering from hemophilia represent a growing cohort of
our society. Fortunately, we are witnessing great improvements in
management of patients suffering from hemophilia, including early
diagnosis, multimodal therapy and hospital supportive care. These
improvements eventually lead to increasing the survival rate and treatment
outcome of patients suffering of hemophilia. However, hemophilia patients
are at increased risk of facing chronic health problems, some of which
appear early in infancy whereas others manifest years after therapy.
These chronic health problems may limit physical performance, and,
in turn, interfere with functional capacity and participation in work and
social activity, which eventually affect their life quality negatively.
Blood born infections with HCV and HIV, bone fractures in patients
with hemophilic arthropathies and pseudotumor due to inadequately treated
soft tissue bleeds are common complications in patients with hemophilia A.
However, hemophilic arthropathies from repeated musculoskeletal bleeding
and development of inhibitors are the most common and challenging
complications. So it is very important to regularly follow up hemophilia
patients for early detection and management of such conditions.
Hemophilic arthropathy is initially subclinical and unfortunately may
passes unnoticed in regular physical assessment by conventional physical
and routine laboratory and imaging investigations. Also the development of
inhibitors is now considered to be the most problematic and costly
complication of haemophilia treatment. Early detection of hemophilic
arthropathy and development of inhibitors plays a crucial role in
management of the condition before developing a life threatening health
issue. Therefore, it is becoming a priority for hematologist to develop new
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modalities and techniques directed for early detection of subclinical
hemophilic arthropathy and inhibitor developement. Study of serum level
of TNF alpha and its gene polymorphism are giving impressing results
regarding inhibitor development and arthropathy assessment in hemophilia
A patients.
The objective of this study was:
To study the Socio_demographic data of pediatric patients with
hemophilia A in Menoufia university hospitals and to study the clinical
presentation and severity of hemophilia A and their relation to factor level.
In addition to study the association between tumor necrosis alpha level and
genotypes in pediatric patients with hemophilia A and its relation to
inhibitor development and joint status.
This cross-sectional study was applied on 50 pediatric patients with
hemophilia A attending Pediatric Hematology and Oncology Unit,
Pediatric department in Menoufia University hospital and attending for
regular follow up.The age of our patients ranged from 0.83 to 17 years.
Patients were subjected to the followings:
1- Full history taking: age, family history of hemophilia ,symptom at
presentation, annualized bleeding rate (ABR), number of bleeding
episodes, absence from school, quality of life using EQ_5D_5L
instrument, age of initial factor exposure, days of factor exposure
frequency of factor VIII exposure, type of treatment and if receiving
Emicizumab as prophylaxis.
2- Thorough clinical examination with emphasis on:
o Bleeding severity up to time of diagnosis using the International
Society on Thrombosis and Hemostasis (ISTH)/Scientific and
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Standardization Committee (SSC) definitions and bleeding assessment
tool, ISTH-SSC Bleeding Assessment Tool.
o Joint status was assessed using the Hemophilia Joint Health Score
(HJHS).
o Anthropometric measures: Weight, height and calculation of body mass
index. With plotting these figures on Z scores.
3- Investigations:
Tumor necrosis factor alpha level by enzyme linked immune-sorbent
assay (ELISA).
Molecular genetic study: TNFα (rs1800629) gene polymorphism by
real time PCR.
Results showed that:
The age of the studied patients ranged from 10 months to 17 years.
There was positive family history of hemophilia A in 41 patients (82%); 23
patients in patients with severe hemophilia A (85%) and 18 patients in
patients with moderate hemophilia A (78%). Absence from school was
present in 35 patients (70%) of the total studied patients.
Regarding the clinical data, the most common symptom at
presentation was post circumcision bleeding (36%of the total patients).The
mean of the annualized bleeding rate was 45.96 ±18.72 in severe cases
while in moderate cases was only 30.04±16.36 with statistically significant
difference between the severe and moderate cases .The bleeding episodes
were ≥2 times /month in 33.3% of severe cases while in only 8.7% of
moderate cases.
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The range of the HJHS in the studied cases was 0.00 to 27 .The mean
total score of HJHS in severe cases was 9.37±6.41 and 8.39±7.06 in
moderate cases.
In assessing the quality of life in the 5 domains of the EQ_5D_5L
Questionnaire, there was significant difference in the score of mobility
between severe and moderate cases with P value 0.028 and also in the usual
activities with p value 0.022.
Age if initial factor exposure was <12 months in 59.3% of severe
cases and 34.8% in moderate cases.The days of factor VIII exposure among
the studied cases ranged from 2 to 672 days. The frequency of factor
exposure was ≥2 times/month in 55.6% of the severe cases and in 43.5% of
the moderate cases. Most of the studied cases were on on demand therapy
and there was only one case among the severe cases with hemophilia A that
was on factor VIII prophylaxis therapy. Only 9 cases were on Emicizumab
prophylaxis therapy.
The range of Hb% among the studied cases was 6.5 to 14 g/dl. The
minimum MCV was 59 FL in both severe and moderate cases and the
maximum MCV was 87 FL in moderate cases and 78 FL in severe cases.
There were 4 cases with inhibitor to factor VIII (8% of the total cases),
3 cases among the severe group (11.1%) and 1 case among the moderate
group (4.3%).
The mean serum TNF alpha level was 134.56 ± 85.39 ng/L in the
severe group and 66.42 ± 29.10 ng/L in the moderate cases with
statistically significant difference between the two studied groups.
Serum TNF alpha level had a significant diagnostic performance to
discriminate between severe and moderate cases (AUC= 0.899) with P
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value <0.001 .The cut off value was >80 ng/L for severe cases with
sensitivity 88.89% and specificity 82.61 %.
The mean TNF alpha serum level was 123.78 ± 52.81 ng/L in the 9
cases on Emicizumab, and 131.75 ± 75.70 ng/l in the 4 cases with inhibitor
to factor VIII.
G/G homozygosity was identified in 37 patient (74%) of the patients
while G/A heterozygosity was identified in 13 patient (26%). A total of 50
patients, (87%) carry the G allele and (13%) the A allele. There was
significant increase of rs1800629 of TNF alpha mutant G/A genotype and
mutant allele A in cases with severe hemophilia A than in cases with
moderate hemophilia A with p value ≤ 0.05.
Among G/G subjects 1 of 37 had inhibitors (2.7%) compared with 3
of 13G/A patients (23.1%) with significant difference between the two
groups (P value 0.049).
from this study, it is concluded that:
1- The majority of our patients have positive family history of
hemophilia and consanguinity.Most of the studied patients live in rural
areas.Frequent absence from school was abundant phenomenon.
2- The most common clinical presentation of hemophilia is post
circumcision bleeding.
3- Severity of hemophilia A can’t only be assessed by serum level of the
circulating factor but also by history and clinical examination using
ISTH-SSC Bleeding Assessement Tool, HJHS and EQ_5D_5L
instrument.Also by measuring the serum TNF alpha level and TNFα
(rs1800629) gene polymorphism.
4- The serum TNF alpha level was significantly higher in patients with
severe hemophilia A than in those with moderate hemophilia A.
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5- TNFα (rs1800629) gene polymorphism mutant G/A genotype and
mutant allele A were significantly higher in patients with severe
hemophilia A than those with moderate hemophilia A.