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We evaluated the correlation between thrombin generation (TG) parameters with bleeding symptoms and disease severity in patients with hemophilia. In this cross-sectional study, 59 patients with hemophilia without inhibitors and regardless of their severity were randomly selected from southern Iran and TG assays were conducted. Bleeding score (BS) was calculated by performing a clinical evaluation using Tosetto questionnaire. Only lag time showed a statistically significant correlation with BS (rs = .316, P = .016). All TG parameters except peak showed association with disease severity (P < .05). Endogenous thrombin potential showed a significant correlation with factor activity level (rs = .459, P < .001). Both lag time and start tail showed significant negative correlations with factor activity level (rs = −0.488, P < .001 and rs = − .289, P < .026, respectively). Although most of the TG parameters evaluated were not significantly correlated with the BS of patients with hemophilia, the majority of TG parameters were significantly associated with factor activity level and disease severity. [ABSTRACT FROM AUTHOR]

Objective: Pre-natal diagnosis is the most effected way to prevent genetic diseases in a society. The aim of this research was to show the prevention level of the birth of the children with major thalassemia disorder and the demographic condition of the people referring to the Shahid Dastgheib Genetic Center in Shiraz for the pre natal diagnosis. Materials and methods: The present research was a cross- sectional (descriptive, analytical) one. In this study, the amount of sampling was done by census in a way that all the case (372 cases) related to the year 2010. The questionnaire was prepared based on the information present in the files. In order to compare the quantitative and qualitative variables, two sample t - test and K sample t- test were used. Results: Out of 372 fetuses tested, 25.5% had major thalassemia, 48.7% minor thalassemia, 0.8% intermediate, 1.3% sickle cell, and 23.7% were healthy. All the cases diagnosed with thalassemia were introduced for abortion, and abortion was carried out. Major thalassemia was more prevalent in Lore tribes (32.9%), which was more in comparison to the members of others tribes. Conclusion: In order to prevent major thalassemia, it is important to identify the gene carriers and prevent their marriage. Nevertheless, in many places in the country, especially in the villages and rural areas, the couples do the experiment after they have already gotten emotionally involved and made the arrangements to get married; therefore they're unwilling to stop the marriage. As a result, post-nuptial CVS during pregnancy is crucial. [ABSTRACT FROM AUTHOR]

Normal hemostasis requires balanced regulation of prothrombotic and antithrombotic factors. Inherited alteration of factor V and prothrombin gene, the G20210A mutation, increases the resistance of factor V to degradation and booster production of prothrombin respectively. These alterations can increase hypercoagulability leading to thrombotic consequences. We aimed to assess the frequencies of these mutations in a group of the population of southern Iran. In total, 198 healthy volunteers with the age range of 1-64 years were selected and screened for factor V Leiden and prothrombin mutations using polymerase chain reaction and restriction fragment length polymorphism techniques. The carrier frequencies for factor V Leiden and prothrombin mutation in the studied cohort were 4.1% and 3.07%, respectively. In the studied area, the allele frequency of factor V is higher than the prothrombin G20210A mutation (0.0204 v 0.0153). According to the data and Hardy-Weinberger equation, the total risk of thrombosis caused by homozygosity and heterozygosity of factor V Leiden, prothrombin G20210A mutation and compound heterozygosity of these mutations are about 1 in 500 individuals. [ABSTRACT FROM AUTHOR]

Background: Chorionic Villous Sampling (CVS) is a diagnostic method for determining genetic disorders. The present study aimed to determine the negative predictive value of the CVS in the diagnosis of major thalassemia in genetic laboratory of Dastgheib Hospital, Shiraz, Iran. Methods: The present research was an evaluation diagnostic test conducted on 372 records of embryos examined through CVS in the genetic lab in 2010 and definitely diagnosed by electrophoresis after birth in 2012. The sensitivity and positive predictive value of the test were assessed for minor thalassemia. The negative predictive value and the specificity of this test were determined, as well. Results: A total of 3 embryos (0.8%) were aborted due to testing. In this study, the sensitivity and specificity were 94.8% and 80.4%, respectively. Also, the negative predictive values for diagnosis of major and minor thalassemia were 100% and 89.2%, respectively. No relationships were found between the gestational age and the test results. Conclusion: The results of this study showed that CVS genetic testing in genetic laboratory of Dastgheib Hospital was valid and had a high diagnostic value. Thus, minor couples can undergo this test with relative safety in order to prevent major thalassemia. [ABSTRACT FROM AUTHOR]

The inherited deficiency of ADAMTS13 is usually associated with severe forms of thrombotic thrombocytopenic purpura. Among the mutations identified in the ADAMTS13 gene, none have been described on the TSP1-6 repeat domain. We investigated an Iranian family with a history of chronic recurrent thrombotic thrombocytopenic purpura, severe ADAMTS13 deficiency and a heterogeneous pattern of clinical symptoms among affected members. Genetic analysis revealed a homozygous deletion of nucleotides 2930-2935 (GTGCCC) in exon 23 of ADAMTS13, leading to the replacement of Cys977 by a Trp and the deletion of Ala978 and Arg979 in the TSP1-6 repeat domain. To explore the mechanism of ADAMTS13 deficiency, in vitro expression studies were performed. Western blotting, pulse-chase labeling and immunofluorescence studies demonstrated a secretion pathway defect of the mutant protein, with no intracellular accumulation. This finding is consistent with the severe ADAMTS13 deficiency but does not explain the heterogeneous clinical picture of the 3 siblings carrying the same mutation.

Background: Factor V deficiency is a rare autosomal recessive hemorrhagic disorder, associated with bleeding manifestations of variable severity. In the present study, we investigated the molecular basis of factor V deficiency in three patients, and performed a comprehensive analysis of the factor V gene (F5) splicing pattern., Design and Methods: Mutational screening was performed by DNA sequencing. Wild-type and mutant F5 mRNA were expressed by transient transfection in COS-1 cells, followed by reverse-transcriptase polymerase chain reaction and sequencing. Real-time reverse-transcriptase polymerase chain reaction was used to evaluate degradation of mRNA carrying premature termination codons., Results: Mutational screening identified three hitherto unknown splicing mutations (IVS8+6T>C, IVS21+1G>A, and IVS24+1&#95;+4delGTAG). Production of mutant transcripts in COS-1 cells demonstrated that both IVS21+1G>A and IVS24+1&#95;+4delGTAG cause the activation of cryptic donor splice sites, whereas IVS8+6T>C causes exon-8 skipping (F5-Delta 8-mRNA). Interestingly, F5-Delta 8-mRNA was also detected in wild-type transfected samples, human liver, platelets, and HepG2 cells, demonstrating that F5 exon-8 skipping takes place physiologically. Since F5-Delta 8-mRNA bears a premature termination codons, we investigated whether this transcript is subjected to nonsense-mediated mRNA decay degradation. The results confirmed the involvement of nonsense-mediated mRNA decay in the degradation of F5 PTC(+) mRNA. Moreover, a comprehensive analysis of the F5 splicing pattern led to the identification of two in-frame splicing variants resulting from skipping of exons 3 and 5-6., Conclusions: The functional consequences of three splicing mutations leading to FV deficiency were elucidated. Furthermore, we report the identification of three alternatively spliced F5 transcripts.

Factor X deficiency is a severe rare hemorrhagic condition inherited as an autosomal recessive trait. It is one of the most severe recessive inherited coagulation disorders. We analyzed the clinical manifestations, laboratory phenotype and genotype in 10 patients with severe Factor X deficiency and in their heterozygous relatives. The most frequent bleeding episodes were hematomas (70%) and gum bleeding (60%). Fifty percent of the homozygous patients required blood transfusion and one-third of heterozygotes required treatment after surgery or delivery. The genetic characterization revealed six different missense mutations, two of which were novel: p.Glu69Lys and p.Asp103His. Haplotype analysis, performed with intra- and extra- FX gene polymorphic markers in Indian, Iranian and Italian patients with the same mutations failed to establish identity by descent, despite the same Caucasian origin. In conclusion, factor X deficiency was confirmed to be one of the most serious among rare bleeding disorders and genetically heterogeneous in different populations.

Background: beta-thalassemia is the most common inherited single gene disorder worldwide, and glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme deficiency. The goal of this study was to compare the frequency of beta-thalassemia trait and G6PD among the Moslem and Jewish populations in Shiraz, southern Iran., Methods: We examined 201 Moslems and 187 Jewish subjects who were selected by random sampling. For diagnosis of thalassemia, complete blood count and hemoglobin electrophoresis were carried out and for G6PD deficiency, fluorescent spot test methods were used as a screening test., Results: Among Moslem subjects, 14 cases (7.0%) were diagnosed as carriers of beta-thalassemia minor, whereas no carriers were detected among Jewish subjects. Seven Moslems (7%) and eight Jewish subjects (7.5%) were found to have G6PD deficiency. Among both groups the most common mutation was the Mediterranean type (563 C>T). In one Moslem subject, the detected mutation was 1003 (G>A) and in two Jewish subjects the mutations were 1376 (G>T) and G6PD A-., Conclusions: Whereas the frequency of beta-thalassemia minor among Moslems is higher than in the Jews in Shiraz, the frequency of G6PD deficiency was not significantly different in the two populations. These findings suggest that obligatory premarital beta-thalassemia screening for Jews in the community is not necessary, whereas neonatal screening for G6PD could be useful for both Jews and Moslems.

Purpose: To determine the prevalence and geographic distribution of thalassemia and to evaluate the success of the thalassemia prevention and treatment programs in Iran., Methods: Data were obtained from the National Thalassemia Registry of Iran, Iranian Blood Transfusion Organization, genetic laboratories involved in prenatal diagnosis, related pharmaceutical companies, and centers performing bone marrow transplantation for thalassemic patients., Results: A total of 13,879 living patients have been registered, mostly from the northern and southern parts of Iran with the median age of 15 years. Twenty-three percent of patients were older than 20 years. The number of newly diagnosed cases has been decreased considerably after the start of the prevention program. Since the introduction of prenatal diagnosis, 2819 couples (2549 fetuses) have been tested, with only 6 false results. Elective abortion was not performed in 10 affected fetuses. Most common mutations detected were IVS II-1 and IVS I-5. In 2003, approximately 25% of the national blood products and 6 million vials of desferal were used for thalassemic patients. Overall, 340 patients have received allogeneic bone marrow transplantation, of those 46 patients deceased. Bloodborne infections have also been decreased significantly owing to the national screening of blood products for bloodborne viral infections., Discussion: Owing to the national prevention program and provided special care, the age distribution of thalassemic patients in Iran is getting adapted to a full prevention and treatment program and life expectancy of these patients has been increased considerably. This shift in the age distribution of thalassemia, a traditionally considered pediatric disease, will face us with new challenges and the health care system should be prepared for this new face of thalassemia.

Introduction: Impaired glucose tolerance and diabetes are well known complications in beta-Thalassaemic multitransfused patients (beta-Th). Iron overload and chronic liver disease, viral infections and/or genetic factors may play an important role in the development of glucose intolerance. The present study aimed to investigate whether in beta-thalassemic patients the hepatitis C virus (HCV) infection may be an additional risk factor for the development of diabetes mellitus., Patients and Methods: The study included 98 beta-Th multitransfused patients, 50 females and 48 males (mean age 15.9 -/+ 4 years; range: 8-32 years). Forty six (47%) patients were seropositive for HCV by ELISA. Six patients were diagnosed as diabetic before the present study. In the remaining oral glucose tolerance test was performed according to the recommendations of National Diabetes Data Group. Prevalence of diabetes and impaired glucose tolerance were compared in HCV-seropositive and HCV-seronegative groups., Results: The prevalence of diabetes in HCV (+) adult beta-Th patients was higher compared to HCV (-) patients (15.2% vs. 1.9%, p: 0.02). No difference was observed in HCV-RNA (-) in the younger group of beta-Th patients., Conclusions: The prevalence of diabetes in adult thalassemic patients is significantly increased by HCV infection, but there is no difference between HCV(+) group and HCV(-) group in age range of 8-15 years. It is probable that the existence of hemosiderosis makes the effect of HCV infection on glucose metabolism clinically more evident.