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Mild FXIII deficiency is an under-diagnosed disorder because the carriers of this deficiency are often asymptomatic and reveal a phenotype only under special circumstances like surgery or induced trauma. Mutational reports from this type of deficiency have been rare. In this study, we present the phenotypic and genotypic data of nine patients showing mild FXIII-A deficiency caused by eight novel heterozygous missense mutations (Pro166Leu, Arg171Gln, His342Tyr, Gln415Arg, Leu529Pro, Gln601Lys, Arg703Gln and Arg715Gly) in the F13A1 gene. None of these variants were seen in 200 healthy controls. In silico structural analysis of the local wild-type protein structures (activated and non-activated) from X-ray crystallographic models downloaded from the protein databank identified potential structural/functional effects for the identified mutations. The missense mutations in the core domain are suggested to be directly influencing the catalytic triad. Mutations on other domains might influence other critical factors such as activation peptide cleavage or the barrel domain integrity. In vitro expression and subsequent biochemical studies in the future will be able to confirm the pathophysiological mechanisms proposed for the mutations in this article.

With 473 patients, Iran has about one third of the world's patients with severe congenital factor XIII (FXIII) deficiency. A considerable number of patients with FXIII deficiency (FXIIID) are affected by life-threatening bleeding episodes, such as central nervous system (CNS) bleeding or recurrent miscarriage and umbilical cord bleeding (UCB), that cause a high rate of morbidity and mortality in Iranian patients with FXIIID. Among 317 Iranian patients with FXIIID, 145 cases experienced 166 CNS bleeds (CNSBs) that recurred in 21 cases. CNSB caused different types of neurological complications in 69 patients. A total of 62 miscarriages were observed in 24 women of childbearing age, and 21 deaths were observed due to umbilical cord bleeding or mucosal bleeding. In fact, 49 deaths (15.4 %) were observed in these patients, which highlight the importance of early diagnosis and intensive health care among patients with FXIIID.

Intracranial hemorrhage (ICH) is one of the most severe and life-threatening manifestations occurring in the patients with factor XIII (F XIII) deficiency. The aim of this study was to describe the ICH pattern in the patients suffering from F XIII deficiency. In this case series, we investigated 38 patients with severe F XIII deficiency in south of Iran from January to May 2012. ICH pattern, neurologic complications, efficacy of treatment, and incidence of recurrence were reported. The site of ICH was intraparenchymal in 35 patients (92.1 %), subdural in 2 patients (5.2 %), and epidural hemorrhage in 1 patient (2.6 %). Besides, neurologic complications occurred in 21 patients (55.2 %), including locomotor disability in 8, psychological impairment in 7, mental disorders in 5, speech impairment in 4, and visual impairment in 2. Prophylaxis was started with a dose of 10 IU/kg Fibrogammin every 4-6 weeks for all the patients, except for one. All the patients on prophylaxis showed good response without any episodes of recurrence, except for one. The most frequent site of ICH in our patients was intraparenchymal. It seems that long-term prophylactic treatment with a dose of 10 IU/kg Fibrogammin could be effective in the prevention of CNS bleeding in the patients with F XIII deficiency. Moreover, all the patients with severe F XIII deficiency even without severe bleeding symptoms are recommended to undergo prophylactic treatment.

Mild factor XIII deficiency is an underdiagnosed coagulation disorder. Considering the large number of coding and non-coding polymorphisms identified in the F13A1 gene, there is a possibility that some of these might result in alterations of plasma FXIII levels and cause mild FXIII deficiency. Recently, a homozygous F13A1 gene intron 1 variant (IVS1+12C>A) was found in a patient with FXIII deficiency. In vitro expression studies for this variant demonstrated its lowering effect on FXIII levels. In order to determine the impact of this variant on a population level, we analysed the prevalence of this variant in three clinically and genetically defined population cohorts: an apparently healthy control cohort C1 (n = 102), a mild FXIII deficiency cohort C2 with no detectable F13A1 or F13B gene mutations (n = 183) and a mild FXIII-A deficiency cohort C3 exhibiting heterozygous F13A1 mutations (n = 37). FXIII activity was determined using photometric assay on plasma samples. The F13A1 gene intron 1 variant was analysed by direct sequencing. The C1 cohort showed a normal distribution of FXIII activity (mean 114.1 ± 20.86 %). Mean FXIII activity levels for the C2 and C3 cohorts were 54.45 ± 11.12 % and 44.21 ± 10.16 %, respectively. The frequencies of minor allele (A) were 0.07 in C1 cohort, 0.19 in C2 cohort and 0.11 in C3 cohort. The difference in minor allele frequencies for the C1 and C2 cohorts were highly significant (p

Inherited factor XIII (FXIII) deficiency is a rare bleeding disorder characterized by an umbilical bleeding during the neonatal period, delayed soft tissue bruising, mucosal bleeding spontaneous intracranial hemorrhage, and soft tissue hemorrhages. Congenital FXIII deficiency is an autosomal recessive disorder, usually attributed to a defect in the FXIIIA and B subunits coding, respectively, by F13A and F13B genes. The aim of this study was to determine the molecular defects responsible for congenital factor XIII deficiency in eight Tunisian families. Molecular analysis was performed by direct DNA sequencing of polymerase chain reaction amplified fragments spanning the coding regions and splice junctions of the FXIIIA subunit gene (F13A) in probands and in families' members and compared with the reported sequence of this gene. In all patients, FXIIIA activity was undetectable and the FXIIIB was within the normal range. Direct sequencing of the F13A gene in all probands showed two mutations: the c.869insC mutation found in eight patients and the c.1226G > A transition found in only one. We also confirmed the presence of a founder effect for the first frequent mutation by using two microsatellite markers, HUMF13A01 and a generated ployAC marker (HUMF13A02). We describe here molecular abnormalities found in nine Tunisian probands diagnosed with FXIIIA deficiency. The identification of the founder mutation and polymorphisms allowed a genetic counseling in relatives of these families, and the antenatal diagnosis is now available.

We report a case of a 4-week-old female who presented with late hemorrhagic disease of the newborn (HDN). The newborn was previously healthy, and she received 1 mg of intramuscular vitamin K at birth. She was exclusively breast-fed. At 4 weeks she began bleeding at the umbilicus and 4 days after she suffered an intracranial hemorrhage. Coagulation studies showed a deficiency of vitamin K-dependent coagulation factors, and the normalization of all clotting studies after administration of vitamin K confirmed the diagnosis of HDN. Our conclusions are that physicians must be alert to mild bleeding in newborns and that prophylaxis with 1 mg of intramuscular vitamin K at birth may be insufficient to prevent late HDN.