Introduction. Combined deficiency of factors V and VIII is a rare hereditary bleeding disorder with a prevalence of 1:1,000,000 in the general population, but the disease is more common in regions where consanguineous marriages are acceptable. Data on this hereditary coagulopathy in the Russian Federation are limited. Aim: to analyze clinical and laboratory characteristics of the course of the disease in patients with hereditary combined deficiency of factors V and VIII in the Russian population. Materials and methods. The retrospective and prospective study involved 6 patients with hereditary combined deficiency of factors V and VIII in the Russian population. Results. The average age of patients was 50 years (32-72 years). The average age at the time of diagnosis was 40 years. Bleeding scores on the ISTH-BAT scale ranged from 17-29, with an average value of 23.5. The average value of activated partial thromboplastin time was 85 seconds, the prothrombin by Quick was 35 %, and the activity of FV and FVIII was 5.7 % and 9.0 %, respectively. The course of the disease was characterized more or less by cutaneous-mucous hemorrhagic syndrome, postoperative, obstetric-gynecological, and life-threatening bleeding. Conclusion. Clinical and laboratory characteristics of patients expand the understanding of hereditary combined deficiency of factors V and VIII and make it possible to accelerate diagnosis verification.

Congenital factor V deficiency is a rare autosomal recessive bleeding disorder, caused by defects in F5 gene and associated with bleeding manifestations of variable severity. In this study we report molecular and functional characterization of a novel F5 variant which causes aberrant splicing and significantly reduces protein expression in a patient with severe FV deficiency. We performed F5 mutation screening and functional study in a proband (FV:C 0.4%) with a history of gastrointestinal bleeding, post-traumatic bleeding, hematomas, ecchymoses, and discomfort in ankle joints since infancy. Sequencing revealed a novel homozygous F5 gene variant NC_000001.10:169519985GC (or NM_000130.5:c.1297 –8CG). Bioinformatics sequence analysis predicted that this variant would lead to the acceptor site loss of the intron 8/exon 9 junction. However mRN-A analysis identified, that it also activated the aberrant splice site located 7 nucleotides upstream of the normal one and was associated with the production of an anomalous F5 transcript with retention of seven nucleotides of intron 8 resulting in a premature stop codon. We revealed no traces of normal transcript in the patient. Our findings confirm that not only changes in canonical splicing dinucleotides could significantly disrupt the splicing sites and impair pre-mRNA processing.

Factor FXI is an essential participant of the blood coagulation cascade and is coded by the F11 gene, mutations in which lead to an extremely rare (1 : 1 000 000) autosomal disease-FXI deficiency, also known as hemophilia C. The most frequently, FXI deficiency is diagnosed in Ashkenazi Jews with three major mutations. The aim of this study was a primary description of the F11 gene mutational spectrum in the Russian population. During the study, we sequenced all functionally important regions of the F11 gene for 11 unrelated patients with hemophilia C. In total, ten different gene defects were revealed: five missense mutations, one nonsense mutation, three frameshift deletions, and one inframe deletion. All of them were uniformly distributed across the gene. Among the most frequent genetic defects in the world population, we found only type II mutation p.Glu135Ter common in Ashkenazi Jews in our sample. Two previously undescribed variants (c.1768del and p.His53Tyr) were evaluated as probably pathogenic. There was a typical picture of incomplete dominance by laboratory parameters-a significant decline of FXI activity level and an increase in APTT when both copies of the gene were damaged and slight deviations from the norm if only one of the copies was impaired. To sum up, we described F11 defects in Russian patients with FXI deficiency. Our findings indicate a high level of heterogeneity of the mutational spectrum leading to hemophilia C in Russia.

Afibrinogenemia is a rare congenital coagulopathy that leads to life-threatening bleeding. In afibrinogenemia, plasma fibrinogen levels are less than 0.1 g/L. The clinical manifestations of the disease can be both bleeding and thromboses of different localizations, which is determined by the multifunctional role of fibrinogen in hemostasis. The described cases demonstrate different clinical phenotypes of the disease. In both cases the diagnosis was confirmed by genetic examinations that revealed homozygous mutations in the fibrinogen A genes. The nature of the mutations assumes consanguineous marriages, as confirmed by the results of a genealogical analysis. Fibrinogen preparations are promising in treating afibrinogenemia in Russia.