الفهرس 
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Abstract
There is ample evidence showing that the clinical phenotype of severe hemophilia may vary markedly among patients. A limited number of recent studies have suggested that prothrombotic factors may modulate the severity of severe hemophilia A.
The aim of this work was to study the incidence of the most common prothrombotic risk factors (Factor V Leiden (G1691A), prothrombin G20210A ,MTHFR (C677T) and MTHFR (A1298C) gene polymorphisms) among Egyptian patients with hemophilia and their impact on the clinical phenotype; annual bleeding frequency and severity of hemophilic arthropathy.
The current study was carried out on 101 patients diagnosed as having hemophilia A. Patients were collected among the patients referred to the outpatient hematology clinics of El Shabraweshy Hospital and Abo El Reesh Pediatric Hospital of Faculty of Medicine Cairo University, in the period between March 2011 and January 2012. Local ethical committee approval as well as informed consents was undertaken from the patients or their parents prior to participation in the study.
Patients were subjected to: Full history taking, Clinical examination, routine laboratory investigations including: Platelet count, Bleeding time, PT and a PTT.
Patients were diagnosed by FVIII & FIX activity assays. Genotyping for factor V Leiden (G1691A), prothrombin G20210A, MTHFR C677T and MTHFR A1298C mutations was done using real-time PCR assay based on allele-specific fluorescent oligonucleotides that contain a 3’ minor groove binding (MGB) group.
Patients were classified clinically according to: age of first presentation, frequency of bleeding episodes, frequency of replacement therapy and number of affected joints.
According to the above score, 39 patients (38.6%) were classified as mild, 52 patients (51.5%) were classified as moderate and 9 patients (8.9%) were classified as severe. Out of the 101 hemophilia patients 25 patients showed mild clinical phenotype inspite of severe or moderate laboratory F VIII activity.
Our results revealed 3%, 14%, 41.5% and 58.4% patients showing Prothrombin G20210A, factor V leiden (G1691A), , MTHFR (C677T) and MTHFR (A1298C) mutations respectively.
Results of gene polymorphism in the patients classified according to clinical severity revealed that, inspite of non significant statistical analysis of each gene separately the 3 cases detected as being heterozygous prothrombin G20210A variants were mild while all moderate and severe cases showed normal alleles. As regards F V leiden we detected 13 heterozygous cases, 8 of them showed mild and 5 showed moderate severity, while all the severe cases showed the normal wild type allele. These results showed that the presence of heterozygous cases of P G20210A or F V leiden is always associated with mild or moderate clinical presentation of hemphilia and never with severe presentation. These findings supports the hypothesis of the protective effect of the prothrombotic genes ( P G20210A & Factor V leiden) on the clinical presentation of hemophilia patients.
Statistical analysis revealed that the lowest bleeding frequency among the studied patients (< once/ month) was encountered among the patients with two heterozygous variants irrespective to the involved genes. In addition, our finding that the incidence of hemarthrosis was significantly higher among patients with wild genotype of prothrombin gene and factor V Leiden and that the average number of affected joints was significantly higher among patients with wild prothrombin gene than heterozygous patients, all these data collectively strongly points to the cumulative effect of these prothrombotic polymorphisms in amelioration of the severity of bleeding in hemophilic. The most prominent effect is that of prothrombin G20210A ,followed by that of factor V leiden. . Findings of MTHFR C677A and A1298C gene polymorphisms are less conclusive and large scale multicenter or meta-analysis studies are needed to have accurate final conclusions.