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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 Summary & conclusion 134 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 Summary & conclusion 135 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. Summary & conclusion 136 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 Summary & conclusion 137 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. Summary & conclusion 138 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. |