ALBERT

Description: Background Deep venous thrombosis (DVT) refers to the formation of a thrombus within a deep vein that frequently occurs after surgical procedures, trauma, in the presence of cancer and immobilization conditions. DVT is a major health problem that causes high rate of morbidity and mortality in the general population. Hyper coagulation states such as antithrombin-III, protein-C and protein-S deficiencies, contribute to formation of DVT. Congenital and acquired gene mutations are other risk factors that stimulate formation of thrombus. Our aims in this study was to molecularly analyze the patients with DVT and assess the impact of common mutations of MTHFR (C677T) (A1298C), PAI-1, Prothrombin 20210 and FV Leiden mutation on occurrence of deep venous thrombosis. Methods This long-term study was conducted from June 2009 to July 2013 on 221 patients with deep venues thrombosis. Two hundred and twenty-one age and sex matched individuals were also chosen as control group. The diagnosis of venous thromboembolic disease was based on patient’s history, clinical findings and D-dimer test. Finally deep venous thrombosis was confirmed with Doppler ultrasonography. In addition, all participants were asked to complete a standardized questionnaire on acquired risk factors for venous thrombosis. After confirmation of DVT, both groups were assessed molecularly for five mutations including, MTHFR C677T, MTHFR A1298C, PAI-1 4G/5G, Prothrombin 20210 and FV Leiden. The relationship between these mutations and the risk of DVT was calculated using logistic regression and expressed as an OR with a 95% confidence interval (CI). Results The mean age of patients and control group were 38±0.8 and 3.7± 0.7 years. Our results revealed that the MTHFR C677T (OR 2.9, 95% 95% CI 1.1 to 7.5) and MTHFR A1298C in heterozygote manner (OR 4.3, 95% CI 1.4 to 13.7) were each associated with an increased risk of DVT. The OR associated with being a carrier of the PAI-1 4G/5G genotype was 2.9 (95% CI 1.14 to 7.5). There was a 4-fold increased risk of DVT associated with Prothrombin 20210 mutation in heterozygote manner (OR 4.3, 95% CI 1.4 to 13.7). For patients who were heterozygous for FV Leiden mutation OR DVT was 2.6 (95% CI 1.3 to 5.0). Conclusion Our findings suggest that genetic risk factors have a contributory role on occurrence of DVT. Disclosures: No relevant conflicts of interest to declare.

Description: Background FXIII deficiency is one of the rare bleeding disorder (RBD) that has a highest incidence in Sistan and Baluchistan province around the world. This disorder represents with different clinical manifestations ranging from mild to severe bleeding tendency including CNS bleeding. The aim of this study is to evaluate the role of PAI-14G/5Gpolymorphism in central nervous bleeding (intra and extracranial hemorrhage) system in factor XIII deficiency. Methods In this case control study was studied 32 FXIII deficient patients with CNS bleeding and also 32 patients with factor XIII deficiency without history of CNS bleeding as control group. Initially both groups were evaluated for the previously reported polymorphism of factor XIII (Trp187Argpolymorphism) in order to confirm their disorder. Then all patients were assessed for PAI-14G/5G polymorphism. Eventually obtained data was analyzed by SPSS software. Results The result of this study revealed that all study patients were homozygote for Trp187Arg polymorphism. We also found that the equal numbers of patients (4 individuals) in case and control groups were heterozygote for PAI-14G/5G polymorphism and none of patients were homozygote for this polymorphism. All heterozygote patients had intracranial hemorrhage and patients with extracranial hemorrhage had no mutation of PAI-14G/5G. Intraparenchymal was the most common site of hemorrhage and was observed in 26 patients (92.8%).We also observed subdural and epidural hemorrhage in two patients (7.1%).Anatomic regions in patients with intraparenchymal hemorrhage, were temporal in nine (32.2%), occipital in eight (28.6%), diffused intraparenchymal hemorrhage in seven (25%), tempro-occipital in two (7.1%) and subdural with temporal in two (7.1%) patients. Conclusion: It seems that PAI-14G/5G polymorphism did not any effect on occurrence of intra and extracranial hemorrhage in patients with factor XIII deficiency. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3376 Background: Prophylaxis is the management strategy in FXIII deficient patients. Life-long prophylactic therapy by 10–20 U/kg FXIII (every 4–6 weeks) is recommended in patients with severe FXIII deficiency to prevent life-threatening spontaneous bleeding. In this study we evaluated of the efficacy and safety of prophylaxis program in a large study group consisting of 182 FXIII deficient Iranian patients. Material and methods: A total of 182 FXIII deficient patients (98 male and 84 female, mean age 26 years old) from south and south-east Iran were selected as a study group. Continual prophylaxis was done in all patients for periods of 6–168 months (mean 66.6 months). The patients received Fibrogamin-P (Dade Behring, Marburg, Germany) 10–20 U/kg every 4–6 weeks and before availability of this concentrate in Iran the prophylaxis was done by FFP 15–20 ml/kg every 20–30 days. All of patients were followed up for any bleeding diathesis and adverse effects during the prophylaxis period. Results: A total of 189 bleeding episodes including epistaxis, gum bleeding, bleeding after dental extraction, hemarthrosis, hematoma, hematuria, wound bleeding, menorrhagia and abortion were detected in 182 patients after prophylaxis program. Life-threatening intracranial bleeding was found in 34 patients before starting prophylaxis; however, there were no reports after prophylaxis. The bleeding episodes and bleeding score were significantly decreased after prophylaxis in compare to before starting prophylaxis (P

Description: Background: Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder with an estimated incidence of 1 per 2 million which has the highest global incidence in the southeast of Iran. Hence, this cohort study was designed to assess the prevalence of FXIIID, its molecular basis and clinical manifestations of FXIII deficiency (FXIIID) in Sistan and Baluchestan Province, southeast Iran. Methods: All data about the prevalence of this disorder, its genotype and phenotype were collected prospectively from 2010 to 2016. Results: In total , 410 patients were identified within the study period, a prevalence of 1 per ~ 7,000 in this area. The mean age of patients was 12 years (range, 1 month to 55 years), of which 51% (n: 209) were female. The main clinical presentation leading to the diagnosis of FXIIID was umbilical cord bleeding (82%). Three hundred and eighty patients were receiving regular prophylaxis of 10 IU/Kg of FXIII concentrate (Fibrogammin) every 28 days. This therapeutic dose was successful in the management of major and minor bleeding and the prevention of life-threatening bleeding in this cohort. But despite receiving prophylaxis, 63 minor bleeding episodes were recorded: 70% lower extremity ecchymoses, 25% oral cavity bleeding and 5% of menorrhagia. The prophylaxis interval for 5 patients was reduced to 21 days due to these bleeding events. Molecular analysis showed that 407 of the patients had a unique Trp187Arg mutation in exon 4 of the FXIII-A subunit gene, while the three remaining patients did not have a detectable underlying mutation.. During the study period, 70 patients underwent minor and major surgeries that were managed by 10-50 IU/Kg Fibrogammin without any significant bleeding. Furthermore, 32 successful deliveries were reported, consisting of 17 normal deliveries and 14 cases of Caesarian section, with a dose of 10-25 IU/Kg. No blood-borne disease was detected in patients receiving Fibrogammin. Discussion: FXIIID has the highest global incidence in the southeast of Iran. The Trp187Arg mutation im the FXIII-A gene is the sole underlying mutation in this area due to the founder effect. Fibrogammin is a safe and suitable therapeutic choice for prophylaxis and management of major and minor bleeding. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Concentrated factor VIII replacement therapy in severe hemophilia prevents disabling arthropathy, life-threatening bleeding, improves health related quality of life and increase life expectancy. Patients with neutralizing antibodies (inhibitors) did not respond to usual doses of FVIII and they need higher doses of FVIII or bypassing agents (eg. rFVIIa, FEIBA) to control bleeding. The aim of this study was to compare the efficacy of a new biosimilar recombinant factor VIIa (Aryoseven ™) with Novoseven® in controlling bleeding episodes in hemophilia A patients with inhibitors. Methods: A randomized double blind clinical trial study was conducted in eight comprehensive hemophilia care centers in Iran. We randomized 66 male patients in two groups, with 4 consecutive block randomization when bleeding occurred. All patients entered the study with only one bleed. Informed consent signed by all patients or their parents. Group A (31 patients, 47%) received Aryoseven ™ and group B (35 patients, 53%) received Novoseven®. rFVIIa dosage was 90 -120 μg/kg intravenously every 2 hours. Results: During the study 66 patients (All male) were enrolled in two arms. The mean age was 20.5±10.9 years. Comparison of baseline data between the two showed no significant difference. The distributions of these variables were similar between the two groups. Other factors, such as vital signs, coagulation tests, liver, renal function tests, and blood count were not significantly different between the two groups. Median plasma level of FVII clotting activity (FVII: C) in group A and B was 103.8±38.4 IU/ dl and 98.6±26.7 IU/dl before injection respectively. Median plasma level of FVIII inhibitor in group A and B was 15.0 BU (IQR: 8.8-58.0) and 19.0 BU (IQR: 11.0-31.0). The average time from onset of bleeding to start treatment were 1246± 1104 and 2301 ± 1693 minutes (p = 0.311) in group A and B respectively. This study results showed that increased levels of factor VII were comparable between two groups after rFVIIa injection. A comparison of the Kavakli global response scores after injection and the treatment success rate in terms of achieving to score 6 or higher showed that both groups were comparable in treatment success rates. The global treatment response rate was 96.8% in group A and 91.4% in group B. Administration of either Aryoseven™ or Novoseven® had comparable effect on controlling pain and joint mobility. Reported side effects were minor (headache, nausea, and rash) and occurred in similar frequency. Discussion: The present study showed increased FVII levels and clinical efficacy in the control of the bleeding episodes in Hemophilia A patients with inhibitor for both drugs. Some similarities exist between our findings and the previous clinical trials designed for Novoseven®. In other studies, the treatment success rate by using the global response scoring system has been 70% -86% by different rFVIIa dosage regimen, in our study was above 90% in both treatment groups. In most studies, it was reported more than 90% achieving to cessation of bleeding at 9 hours after first injection of rFVIIa as response time which was also similar to our study. Conclusion: This study showed non-inferiority of Aryoseven ™ compared to Novoseven® in cessation of bleeding episodes in hemophilia A patients with inhibitor. There was no evidence of significant difference between the efficacy and safety of two drugs. There were no clinically meaningful differences between the biosimilar product and the original product in terms of the safety, purity, and efficacy. Biosimilar rFVIIa is effective in treatment of acute joint bleeding in patients with inhibitor in comparison to Novoseven®. Disclosures Mehrvar: Aryogen Zist Darou: Employment. Khoein:Aryogen Zist Darou: Employment. Kaymar:Aryogen Zist Darou: Employment. Mahbodi:Aryogen Zist Darou: Employment. Vaziri:Aryogen Zist Darou: Employment.

Description: Background Factor XIII deficiency (FXIIID) is a rare bleeding disorder (RBD) with high bleeding tendency. A wide spectrum of bleeding episodes was reported in patients with severe FXIIID. These bleeding diathesis include delay wound bleeding, intracranial hemorrhage, epistaxis and gum bleeding. A plasma level 3% to 10% of factor XIII is sufficient to prevent occurrence of bleeding in these patients. Here we design a study with two groups including heterozygote of FXIIID and normal population as a control group to assessed present of bleeding episodes in heterozygote patients. Method This prospective study was carried out on 53 (50 females and 3 males) heterozygote patients of FXIIID as well as the same number of normal population in duration of 3 months. All heterozygote individuals were selected from homozygote patients’ family. Healthy individuals were selected randomly from different parts of provinces. Both groups were age and sex matched (p=0.3). All individuals were assessed for factor XIII deficiency by FXIII activity assay and molecular analysis for Trp187Arg; the only previously reported polymorphism of factor XIII-A subunit in southeast Iran. Initially the clinical manifestations of all cases were assessed retrospectively and recorded. Then we assessed and compared the bleeding tendency in both groups by using the adult bleeding questionnaire and in one-month intervals. Results The mean ages of study populations were 34.8±8.4 (Ranges from 20 to 48 years) and 33.9±9.1 (Ranges from 21 to 49.5 years) in case and control groups, respectively. FXIII activity of the patient group was between 50-70 % and molecular analysis revealed that all the patients were heterozygote for Trp187Arg mutation. By regards to ethnicity, most of individuals in case group were Baluch (Number: 50 (94.3%)) and remained minority was Zaboli (Number: 3 (5.7%)). Distribution of ethnicity among case group was completely matched with control group (p=0.3). None of study individuals had a history of liver or kidney diseases or other bleeding susceptibility disorders. Clinical investigations indicated that 3 patients had a history of umbilical cord bleeding and delayed separation of the umbilical cord which led to administration of FXIII concentrate. All the 3 patients later presented with delayed post-circumcision bleeding. The mean age of menorrhagia in 50 females was 13.9±1.1 (Ranges from 12 to 16 years). Menstrual intervals range from 20 to 60 days with a mean of 29±5.2 days, but half of the patients had a normal interval of 30 days. Twenty three females had experienced menstruations with the need for a new pad every 2 hours. Among affected females 15 had an abnormal menstruation with duration of more than 7 days. Eight females were complicated by menorrhagia. This phenomenon observed in only one female of control group and therefore a significant difference was found between cases and controls (p