Introduction. In most cases, in patients with hereditary fibrinogen deficiency, clinical manifestations are represented by bleeding of varying intensity and localization. However, the clinical picture of hereditary fibrinogen deficiency can also be represented by thrombosis. Aim - to characterize the detected mutations in fibrinogen genes and to analyze prothrombotic factors in patients with hereditary hypofibrinogenemia and thrombosis. Materials and methods. Forty-nine patients with hereditary hypofibrinogenemia were observed, of which 46 patients had no history of thrombosis and 3 patients had a confirmed history of thrombosis. These 3 patients made up the study group. Results. Heterozygous mutations were found in all 3 patients in the fibrinogen gamma chain gene (FGG), one of them had a previously undescribed deletion g.2653_ 2684+211del, p.(Asp167Glufs*2), which removes 32 terminal nucleotides of the fi fth exon of the FGG gene and leads to the formation of a stop codon in place of amino acid 168. In two other patients, there were missense mutations c.1140T>A, p.(Cys365Ser) and c.1114A>T, p.(Asp356Val), which can determine the thrombogenic properties of the altered protein structure of fibrinogen. Other prothrombotic factors were also identified: genetic polymorphisms of low thrombotic risk, surgery, taking combined oral contraceptives. Conclusion. Hereditary fibrinogen deficiency does not play a protective role in relation to the development of thrombosis and may cause the development of thrombosis, which is associated with its multifunctional role in the hemostasis system. The pathogenesis of thrombosis in patients with hereditary hypofibrinogenemia is multifactorial and may be associated with the characteristics of the main protein defect and the coexistence of hereditary and acquired thrombotic risk factors (surgical interventions, taking combined oral contraceptives, etc.).

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.

Hemophilia B is a hereditary X-linked coagulation disorder. This pathology is caused by various defects in the factor IX gene, which is, being about 34 kb long and consisting of eight exons, localized in the Xq27 locus of the X-chromosome long arm. Mutations were revealed in 56 unrelated patients with hemophilia B in this study by using direct sequencing of factor IX gene functionally important fragments. Forty-six mutations were found with prevailing missense mutations (n = 30). The rest of the mutations were nonsense (n = 4) and splicing (n = 4) mutations, large deletions (n = 3), microdeletions (n = 2), microinsertions (n = 2), and promoter mutations (n = 1). Eleven of 46 mutations were previously unknown for human populations.

Acute intermittent porphyria (AIP) is an autosomal dominant hereditary disease, caused by partial deficiency of porphobilinogen deaminase (PBGD), one of the key enzymes of heme biosynthesis. This study describes molecular genetics of AIP in Russia. Mutation analysis of PBGD gene in 70 unrelated patients revealed 47 various genetic defects, 28 of which had not been described previously. Mutations 53delT and Arg173Trp (recorded 8 times, in total 23%) proved to be the most common in Russia. Microdeletion 53delT has monophyletic origin and was found only in Russia. Molecular genetic examination of 132 relatives of AIP patients from 40 families revealed 52 latent carriers of the disease. Low (about 10%) AIP penetrance indicates that a mutation in the PBGD gene is an important but not sufficient prerequisite for clinical manifestation of the disease. Modulation of penetrance in erythropoietic protoporphyria by coinheritance of a mutant allele and a functionally defective wild type allele of ferrochetalase gene has been shown previously. We hypothesized that similar mechanism works in AIP. Sequencing of the full length PBGD genes from unrelated AIP patients as well as SNP analysis, and the analysis of abnormal PBGD mRNA splicing showed that in case of AIP, this hypothesis is not true and some other factors are responsible for the penetrance of this disease.

Острая перемежающаяся порфирия (ОПП) – заболевание с аутосомно-доминантным типом наследования, обусловленное частичным дефицитом порфобилиногендезаминазы (ПБГД), одного из ключевых ферментов системы биосинтеза гема. Данная работа посвящена молекулярно-генетическому исследованию ОПП в России, в ходе которого осуществлен успешный мутационный анализ гена ПБГД для 70 неродственных пациентов. Выявлено 47 различных генных дефектов, 28 из которых ранее в мировой популяции не встречались. Наиболее распространенными в России оказались мутации 53delT и Arg173Trp (встретились по 8 раз, суммарно около 23%). Микроделеция 53delT имеет монофилетическое происхождение и найдена только в России. Проведено молекулярно-генетическое обследование 132 родственников больных ОПП из 40 семей, среди которых выявлено 52 латентных носителя заболевания. Низкая пенетрантность ОПП (около 10%) свидетельствует о том, что мутация в гене ПБГД является необходимым, но не достаточным условием клинического проявления болезни. Ранее была показана модуляция пенетрантности эритропоэтической протопорфирии через сонаследование мутантного аллеля и функционально неполноценного аллеля дикого типа гена феррохелатазы. Мы проверили гипотезу о существовании аналогичного механизма для ОПП. Cеквенирование полноразмерных генов ПБГД у неродственных больных ОПП, SNP-анализ и анализ аномально сплайсированной мРНК ПБГД показали, что в случае ОПП данная гипотеза неверна и пенетрантность этого заболевания определяется какими-то другими факторами.