Цель исследования: провести анализ перинатальных, неонатальных и генетических факторов риска и определить их роль в развитии тромбозов у новорожденных. Материалы и методы. В когортное обсервационно-аналитическое сравнительное исследование были включены 113 детей: 47 новорожденных с тромбозами, развившимися в неонатальном периоде, и 66 здоровых доношенных ребенка из семей без тромбофильного анамнеза. Проводилась клиническая, лабораторная и инструментальная диагностика тромбозов и заболеваний неонатального периода. Молекулярно-генетическое исследование включало определение 8 полиморфизмов плазменного, тромбоцитарного и фибринолитического звеньев гемостаза и 4 генов ферментов фолатного цикла. Результаты. Перинатальными факторами риска тромбозов у новорожденных детей являются хроническая фетоплацентарная недостаточность, преэклампсия, анемия, гестационная артериальная гипертензия, неспецифические инфекционно-воспалительные заболевания малого таза, дистресс плода, синдром задержки роста плода, маловодие, хронический пиелонефрит у матерей во время беременности. Генетическими предикторами развития тромбозов у новорожденных являются: минорный аллель А полиморфизма гена фибриногена FGB -455 (OШ = 2,55; 95% ДИ = 1,07–6,04), полиморфизм гена ингибитора активатора плазминогена PAI-1 -675 4G/4G (OШ = 11,4; 95% ДИ = 3,58–36,8) и аллель 4G полиморфизма гена PAI-1 -675 (OШ = 7; 95% ДИ = 2,84–17,41), полиморфизм гена интегрина альфа-2 ITGA2 807 T/T (OШ = 7,2; 95% ДИ = 1,90–27,24). Заключение. Определена роль перинатальных, неонатальных и генетических факторов риска и дана количественная оценка их вклада в развитие тромбозов у новорожденных. Выявленные предикторы тромбозов позволяют прогнозировать их развитие на этапе до клинической реализации, и могут составлять основу разработки программ профилактики сосудистых катастроф у детей в периоде новорожденности. Objective: to analyze perinatal, neonatal, and genetic risk factors and to identify their role in newborns thromboses. Materials and Methods. A cohort observational analytical comparative study included 113 children: 47 newborns with thrombosis that developed in the neonatal period and 66 healthy full-term children from families without thrombophilia history. Clinical, laboratory, and instrumental diagnostics of thromboses and diseases of the neonatal period was carried out. Molecular genetic study determined 8 polymorphisms of plasma, platelet, and fibrinolytic hemostatic links and 4 genes of folate cycle enzymes. Results. Perinatal risk factors for thromboses in newborns include chronic fetoplacental insufficiency, preeclampsia, anemia, gestational arterial hypertension, nonspecific infectious and inflammatory diseases of the small pelvis, fetal distress, fetal growth retardation syndrome, oligohydramnios, chronic pyelonephritis in mothers during pregnancy. Genetic predictors of thromboses in newborns comprise minor allele A of the fibrinogen gene polymorphism FGB -455 (OR = 2.55; 95% Cl = 1.07–6.04), plasminogen activator inhibitor gene polymorphism PAI-1 -675 4G/4G (OR = 11.4; 95% Cl = 3.58–36.8) and allele 4G gene polymorphism PAI-1 -675 (OR = 7; 95% Cl = 2.84–17.41), integrin alpha-2 gene polymorphism ITGA2 807 T/T (OR = 7.2; 95% Cl = 1.90–27.24). Conclusion. We determined the role of perinatal, neonatal, and genetic risk factors and provided a quantitative assessment of their contribution to thromboses. The identified thromboses predictors may predict their development before clinical manifestation, and can be the basis for the programs to prevent vascular accidents in children during the neonatal period.

Introduction. The problem of neonatal thrombosis is becoming increasingly urgent in clinical practice due to its importance in the development of a complicated course of the neonatal period in children with hereditary and acquired thrombogenic risk factors. The aim of the investigation is to present a clinical case of multiple thromboses in a premature newborn infant with congenital heart disease on the background of multigenic thrombophilia, complicated by neonatal sepsis. Materials and methods. Materials for the investigation were the primary medical records: history of the newborn, medical history of the patient-newborn child with the established diagnosis of great-vessel thrombosis, with the congenital heart disease and the presence of genetic thrombophilia, who was under observation for 2 months. The findings of objective, laboratory (clinical blood tests, investigation of hemostasis parameters, homocysteine concentration, molecular-genetic study of hemostasis enzymes genes, folate cycle enzymes genes) and instrumental (CT angiography, ultrasonic examination of abdominal cavity and retroperitoneal organs, ECHO cardiography, ultrasonic Dopplerography) research methods were evaluated. Results and Discussion. In the clinical observation under consideration, there was a burdened molecular genetic background consisting of carriage of plasminogen activator inhibitor gene polymorphisms and folate cycle enzyme genes: MTHFR 677 – C/T, MTHFR 2756 – A/G, MTRR 66 – G/G, and hyperhomocysteinemia were the factors responsible for multiple thrombosis in a patient born with critical congenital heart disease (CHD), contributed to generalization of the infection process with the development of multiple organ failure, and exacerbated the postoperative period after correction of heart disease. Conclusion. The clinical case demonstrates the development of multiple thrombosis and septic process in a child born with CHD. The results of molecular genetic study proved the presence of hereditary thrombophilia in the child, which was a predictor of thrombosis development and probably a risk factor aggravating the severity of generalized infectious process, which complicated pre- and postoperative periods of the main disease, CHD.

Введение. Вспомогательные репродуктивные технологии (ВРТ) проводятся у бесплодных пар, имеющих в том числе факторы тромбогенного риска, которые наследуются их детьми и могут быть причиной формирования инвалидности при развитии сосудистых катастроф. Оценка экономического потенциала ВРТ должна учитывать заболеваемость, инвалидность и смертность детей, зачатых при помощи этих методик. Цель исследования: оценить экономический потенциал ВРТ у ребенка, зачатого при помощи репродуктивных методик, и имеющего инвалидность. Материалы и методы. Проведено наблюдательное исследование за ребенком, зачатым при использовании ВРТ, имеющим наследственную тромбофилию. Оценка экономического потенциала ВРТ проводилась с учетом показателя валового регионального продукта. Результаты. Ребенок на фоне наследственной тромбофилии в генах плазменного (FGB –455 G > A), фибринолитического (PAI-1–675 5G > 4G) и тромбоцитарного (ITGA2 807 C > T) звеньев гемостаза, генах фолатного цикла, гипергомоцистеинемии тяжелой степени имел артериальный тромбоз брюшного отдела аорты, который послужил причиной ампутации стопы и голени, нефрэктомии и формирования инвалидности. Заключение. Учитывая показатель младенческой смертности (4,5‰) и инвалидности (2,9%) в группе детей, зачатых при помощи ВРТ (n = 2206), в регионе отмечается 11,8-кратный возврат затраченных правительством вложений при трудовой занятости в производстве будущего специалиста. Дети, рожденные в семьях, имеющих факторы тромбогенного риска, нуждаются в получении услуг ранней помощи. Introduction. Assisted reproductive technologies (ART) are performed in infertile couples who have, among other things, thrombogenic risk factors that are inherited by their children and can cause disability in the development of vascular catastrophes. The assessment of ART economic potential should take into account the morbidity, disability and mortality of children conceived using these methods. Objectives: to assess ART economic potential in a child conceived with reproductive methods and who has a disability. Patients/Methods. An observational study was conducted on a child conceived using ART and having hereditary thrombophilia. The assessment of ART economic potential was carried out taking into account the indicator of the gross regional product. Results. The child with hereditary thrombophilia in the genes of plasma (FGB –455 G > A), fibrinolytic (PAI-1–675 5G > 4G) and platelet (ITGA2 807 C > T) units of hemostasis, in folate cycle genes, and severe hyperhomocysteinemia had disseminated arterial thrombosis of the abdominal aorta, which caused amputation of the foot and lower leg, nephrectomy and the formation of disability. Conclusions. Taking into account the infant mortality rate (4.5%) and disability (2.9%) in the group of children conceived with ART (n = 2206), the region has an 11.8-fold return on the government’s investment in employment in the production of future specialists. Children born in families with thrombogenic risk factors need early care services.

The article considers the analysis results of the occurrence frequency of genotypes and alleles of plasma, platelet and fibrinolytic hemostasis in full-term newborns with arterial and venous thrombosis of various localization. Gene polymorphisms were studied by real-time PCR in human DNA samples obtained from buccal epithelium and venous blood lymphocytes. The control group was a group of healthy full-term newborns from families without a thrombophilic history. Predictors of arterial and venous thrombosis in children are such as polymorphism of the plasminogen activator inhibitor gene PAI-1-675 4G/4G (OR=5,6 [2,3-13,8]), combinations of polymorphisms PAI-1-675 4G/4G + factor VII G10976A G/G (OR=5,8 [1,7-19,1]), combinations of polymorphisms PAI-1 -675 4G/4G + factor VII G10976A G/G + factor XIII Val34Leu G/G (% AR=61), fibrinogen FGB -455 G/A (OR=3,75 [1,4-9,4]) and integrin alpha 2 ITGA2 807 T/T (OR=15,56 [1,9-126,7]). Thus, the study of polymorphisms of the plasminogen activator inhibitor, fibrinogen, integrin alpha 2 can serve as one of the criteria for identifying a high-risk group for the development of arterial and venous thrombosis in newborns and should be taken into account when evaluating individual thrombophilia risk.

Background. The severity of thrombosis clinical course, poor prognosis, upcoming disability and permanent organ failure in newborns necessitate further search and study of thrombotic conditions predictors in order to prevent them. Aim of the study is to analyze the frequency of gene variants of plasmic, thrombocytic and fibrinolytic hemostasis components and determine their role in the thrombosis development in newborn children. Methods. The study included 46 full-term newborns with thromboses of different localization – cases group. Inclusion criteria were: child age 28 days or less, gestational period >37 weeks, informed consent on participation in the study. The control group included children of I and II health groups. Vascular thrombosis was diagnosed via instrumental imaging methods: vascular ultrasound, computer tomography, magnetic resonance imaging. Thrombophilic anamnesis and pregnant woman’s health condition was analyzed according to pregnancy medical records. The molecular genetic testing included 8 single nucleotide polymorphisms definition of the following genes: FGB -455 G>A (rs1800790), F2 20210 G>A (rs1799963), F5 1691 G>A (rs6025), F7 10976 G>A (rs6046), F13 G>T (rs5985), ITGA2 807 C>T (rs1126643), ITGB3 1565 T>C (rs5918), PAI-1 -675 5G>4G (rs1799889). Results. Molecular genetic predictors of thrombosis in newborns have been revealed: variants of fibrinogen gene FGB -455 G>А (AP, %=66), plasminogen activator inhibitor gene PAI-1 -675 4G > 4G (AP, % = 89), genotype associations PAI-1 -675 4G/>4G /F7 10976 G>G (AP, % = 82), PAI-1 -675 4G>4G / F13 34 G>G (AP, % = 63)PAI-1 -675 4G>4G / F7 10976 G>G / F13 34 G>G(AP, % = 61), and integrin alpha 2 gene ITGA2 807 T/T (AP, % = 93). Maternal factor of thrombosis development in children is impaired uteroplacental circulation in pregnant woman (AP, % = 66). Conclusion. The role of gene variants of plasmic, thrombocytic and fibrinolytic hemostasis components in development of thrombosis in newborns was determined, as well as quantitative estimation of their contribution was presented.

Whether the type (ischemlc or hemorrhagic) of childhood stroke might be predicted from the obstetric/gynecological and perinatal history data (clinical notes from maternity hospitals, 43 indicators) of mothers and infants who had sustained hemorrhagic stroke (и=53), ischemic stroke (и=101), and transient ischemic attack (и=44) was assessed. The patients' families were interviewed using questionnaires to clarify information about family thrombophilic and hemorrhagic predispositions, the mothers were examined for carriage of 12 prothrombotic gene polymorphisms. The study showed the specific features of maternal pregnancy and labor and an adaptation period in infants with acute cerebrovascular accident; weak correlation pairs were recorded for each type of disease (r=0,41—0,58;/> <0,05); the probability of a correct recognition from this information was low. A set of maternal obstetric/gynecological, family, thrombophilic, and hemorrhagic history data and molecular genetic examination results has led to the statement of a prognostic rule that can recognize the type of cerebrovascular disorder with a high degree of accuracy, by using 13 indicators from the mentioned data block (hemorrhagic stroke (83,3%), ischemic stroke or transient ischemic attack (95,6%)). The developed prognostic algorithm may be used to seek groups at risk for acute cerebrovascular disorder in childhood.

The data on the risk factors and etiology of ischemic stroke in 31 infants, aged under 3 years, are summarized. The results of genotyping of blood coagulation and folic acid gene polymorphisms in patients and 83 healthy people are presented. Significant differences were found for -455 G>A FGB (р=0.03) and 807 C>T ITGA2 (р=0,005) polymorphisms. Different gene-gene combinations that can cause hypercoagulation and arterial thrombosis in this age were identified. The most frequent combinations include polymorphisms of genes for FGB, fibrinolysis system and folate cycle enzymes (OR=3,79 and more, p<0.05). A clinical case of ischemic stroke in a girl, aged 10 months, after operated congenital heart malformation is presented.

© коллектив авторов, 2012 e-mail: olvova@bk.ru тел. 8 (343) 372 32 59 [львова О. А. (* контактное лицо) — кандидат медицинских наук, доцент, заведующая кафедрой неврологии детского возраста и неонатологии; ковтун О. П. — доктор медицинских наук, профессор, заведующая кафедрой педиатрии и неонатологии ФПк и ПП; кузнецов Н. Н. — кандидат медицинских наук, доцент кафедры педиатрии и неонатологии ФПк и ПП; Вольхина С. А. — аспирант кафедры неврологии детского возраста и неонатологии; баранов д. А. — аспирант кафедры педиатрии и неонатологии ФПк и ПП; Пряхина О. П. — врач-неонатолог; зобнина Ю. В. — врач-интерн кафедры неврологии детского возраста и неонатологии]. Удк 616.831-056.7-053.3-07

Methods: We compared 55 ART children (born after IVF or ICSI) to 55 matched control group. Patients were screened for SNPs in following genes: fibrinogen (F1 A455G), protrombin (F2 A20210G), Factor V (Leiden G1691A), plasminogen activator inhibitor-1 (PAI-1675 4G/5G), MTHFR (C677T), the endothelial nitric oxide synthase (eNOS C298T) and platelet receptor (ITGA2 -C807T), ITGB3 (T1565C). The polymorphisms were genotyped using real-time PCR (DNA-Technology, Moscow). Statistical analysis was based on connected criterion of Mac-Nemar; 2-tailed P value <0.05 was chosen as the level of significance.