A Large-Scale Prospective Cohort Study on Factor XIII Deficiency in Southeast of Iran

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.