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Siberian Scientific Medical Journal

2019 year, number 1

1.
SYSTEMIC HEMOSTATIC AND PROTHROMBOTIC EFFECTS OF FIBRIN-MONOMER IN EXPERIMENT WITH DOSED LIVER THERAPY

Andrey Pavlovich MOMOT1,2, Vyacheslav Mikhaylovich VDOVIN3,2, Igor Ilyich SHAKHMATOV3,2, Igor Gennadievich TOLSTOKOROV4, Dmitriy Andreevich OREKHOV5, Valentin Olegovich SHEVCHENKO4, Natalya Alexandrovna LYCHEVA3,2, Alexey Vladimirovich KUDINOV3, Galina Gennadievna BELOZERSKAYA6, Valeriy Ivanovich KISELEV3,2
1National Research Center for Hematology of Minzdrav of Russia, Altai Branch
2Research Institute of Physiology and Fundamental Medicine
3Altai State Medical University of Minzdrav of Russia
4Consulting Diagnostic Center В«Dobryi Doktor» Ltd
5Altai Regional Cardiology Health Center
6National Research Center for Hematology of Minzdrav of Russia
Keywords: система гемостаза, фибрин-мономер, травма печени, паренхиматозное кровотечение, гемостатический эффект, кролики, hemostatic system, fibrin monomer, liver injury, parenchymal hemorrhage, hemostatic effect, rabbits

Abstract >>
Objective of the study is to experimentally evaluate system hemostatic and prothrombotic effects of intravenous fibrin monomer (FM). Materials and methods. Eighty two Chinchilla rabbits weighing 3-4 kg were used in the study. In addition to the placebo, animals were administered an aqueous solution of fibrin monomer (FM) intravenously at doses of 0.1, 0.25, 0.5, 1.0, 2.5 and 5.0 mg/kg. After 1 hour, a standard liver injury was performed and the blood loss (% of the circulating blood volume) resulting from parenchymal hemorrhage was estimated. Hemostatic system examination included platelet number in venous blood and fibrinogen and D-dimer levels in blood plasma. Results and discussion. Blood loss after dosed injury with placebo was 10.0 [4.0; 15.7] % blood volume (median [25th percentile; 75th percentile]). FM preparation doses of 0.25, 2.5 and 5.0 mg/kg resulted in a decrease of blood loss by 6.3 (p < 0.001), 7.8 (p < 0.001) and 2.7 times (p = 0.04) (1.6 [1.0; 3.0], 1.3 [0.6; 1,6] and 3.7 [2.8; 5.3] % blood volume, respectively).High doses of FM preparation (2.5 and 5.0 mg/kg) minimized blood loss due to activation of coagulation and thrombus formation, which was illustrated by a 7.0-8.0-fold increase in D-dimer level (compared to placebo). 0.25 mg/kg of FM preparation did not lead to an increase of D-dimer content, although the blood loss was greatly reduced. Conclusion. The data obtained show the presence of unique hemostatic properties in low-dose FM preparation (0.25 mg/kg), which allows creating system hemostatic agents of a new generation.



2.
INDIVIDUAL BALANCE OF DEFENSIVE AND APPETITIVE MOTIVATIONAL SYSTEMS OF THE BRAIN AS A LIKELY NEUROPHYSIOLOGICAL ENDOPHENOTYPE OF DEPRESSION IN THE METRIC OF COGNITIVE EVOKED POTENTIALS

Lyubomir Ivanovich AFTANAS1, Svetlana Markovna PUSTOVOYT1, Natalya Vladimirovna NOVOZHILOVA1, Olga Aleksandrovna AKHMETOVA1, Anatoliy Aleksandrovich OVCHINNIKOV2
1Scientific Research Institute of Physiology and Basic Medicine
2Novosibirsk State Medical University of Minzdrav of Russia
Keywords: большое депрессивное расстройство, зрительные вызванные потенциалы, поздний позитивный потенциал, индивидуальный баланс мотивационных систем, нейрофизиологический эндофенотип, major depressive disorder, visual evoked potentials, late positive potential, individual balance of motivational systems, neurophysiological endophenotype

Abstract >>
The aim of the study was to investigate the characteristics of the individual balance of the activity of brain defensive and reinforcing systems in patients with major depressive disorder. Material and methods. In 41 patients with major depressive disorder and 32 healthy subjects, we investigated visual evoked potentials in the emotional Oddball paradigm in perception of high and low arousal motivational signals of reward and threat. Results and discussion. It was established that reduced amplitude of the neuronal response in the perception of high arousal motivational signals of reward and, in a less degree, threat, is associated with an indicator of the clinical severity of depression. It supports the model of emotion context insensitivity in depression. However, a more pronounced reduce in the neuronal response to stimuli of reward may indicate a prevailing deficiency of the reinforcement system. Thus, the late positive potential magnitude of visual evoked potentials for high arousal motivational signals of reward and threat can be viewed as a promising objective neurobiological marker for monitoring the dynamics of the disturbed individual balance of the defensive and reinforcing brain systems in major depressive disorder patients which can become an important tool of personalized prevention and treatment strategy.



3.
CLINICAL VALUE OF CELL CONTENT WITH ISOLATED INTERSTITIAL DELetion 13q14 IN CHRONIC LYMPHATIC LEUKEMIA

Tamara Pavlovna ZAGOSKINA1, Ekaterina Nikolaevna ZOTINA2
1Kirov State Medical University of the Ministry of Healthcare of the Russian Federation
2Kirov Scientific Research Institute of Hematology and Blood Transfusion of FMBA of Russia
Keywords: хронический лимфолейкоз, делеция 13q14, клинический исход, прогноз, chronic lymphocytic leukemia, 13q14 deletion, clinical outcome, prognosis

Abstract >>
Currently, it is urgent to search for new prognostic factors that improve the stratification of patients into risk groups and allow the determination of indications for various CLL therapy programs with the aim of increasing their clinical effectiveness. Material and methods. The research presents the data on chromosomal aberrations with the help of the FISH method in 224 CLL patients during the diagnosis, among them 49 patients are in stage A, 166 patients - in stage B and 29 patients - in stage C. Results and discussion. Chromosomal abnormalities were detected in 176 (72 %) patients. The most frequent aberration in CLL was del13q14, which was found in 124 (51 %) patients and occurred alone or in combination with other chromosomal changes. As the only chromosomal abnormality, del13q14 was found in 77 patients who differed from each other in the number of tumor cells that had isolated del13q14. We have studied the prognostic value of the content of tumor cells with isolated 13q14 deletion in CLL patients during the diagnosis. A comparative analysis of 2 groups of patients who had the percentage of leukemia cells with this deletion (it was ≥ 60 % or < 60 %) was conducted. It has been established that the number of cells with isolated del13q14 is an independent predictor of survival, free from treatment, as well as the overall survival of CLL patients and may serve as an additional prognostic factor.



4.
THE MORPHOLOGICAL SUBSTRATE AND IMMUNOHYSTOARCHITECTURAL PATTERNS IN NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA

Irina Alexandrovna SHUPLETSOVA, Alla Mikhaylovna KOVRIGINA, Tatyana Nikolaevna MOISEEVA, Elena Igorevna DOROKHINA
National Research Center for Hematology of Minzdrav of Russia
Keywords: нодулярная лимфома Ходжкина с лимфоидным преобладанием, морфология, иммунофенотип, иммуногистоархитектоника, nodular lymphocyte predominant Hodgkin lymphoma, morphology, immunophenotype, immunohistoarchitectonics

Abstract >>
The aim of the study is to compare the tumour growth pattern with immunohystoarchitectural patterns in patients with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in the debut of the disease. Material and methods. The diagnosis of NLPHL in the debut of the disease was established in 60 patients (male/female ratio is 3.6:1, median age - 37 (range 17-68)) using morphology an expanded immunohistochemical study. The tumor growth pattern was determined by morphological study and immunohistochemical patterns (WHO 2017) - using antibodies to CD20 and clinical stages (Ann Arbor). Results and discussion. All patients were divided into 3 immunohystoarchitectural patterns (subject to immunohystoarchitectonics in reaction with antibodies to CD20): A - LP cells are located within B cell nodules; B - LP cells are located intra- and extranodular with the preservation of B cell nodules or in the presence of a border of B-lymphocytes; C - predominant (> 50 % of section area) diffuse or large-focal discrete arrangement of LP cells without the presence of a B cell border. Concerning to the immunohystoarchitectural patterns, all the patients were divided into three groups: I (immunohistochemical pattern A - 17 cases, 28 %, stage - I-II 82 %, stage III - 18 %, nodular growth - 100 %), II (immunohistochemical pattern B - 30 cases, 50 %, stage I-II - 40 %, stage III-IV - 60 %, nodular growth - 3 %, nodular growth with a significant number of extranodular LP cells - 43 %, nodular-diffuse growth - 53 % cases), III (immunohistochemical pattern C - 12 patients, 20 %; II stage - 8 %, tumor cell-rich case, stage III-IV - 92 %; nodular-diffuse growth - 75 % cases, mainly diffuse growth - 25 % cases), 1 case with transformation in DLBCL (2 %, IV stage). Conclusions. NLPHL is characterized by variable morphological immunohistochemical patterns among which we’ve revealed 4 morphological variants and 3 immunohistochemical patterns considered as sign of immunohistochemical transformation within the continuum of the same entity of NLHLP. The immunohistochemical patterns are not always a predictor of the clinical course of the disease. «Tumor cell-rich» cases require further detailed research.



5.
CARDIOTOXICITY AND METHODS OF ITS DIAGNOSIS IN HEMATOLOGY PATIENTS (REVIEW)

Tatyana Pavlovna KUZMINA1, Igor Leonidovich DAVYDKIN1, Olga Vladimirovna TERESHINA2, Olesya Evgenevna DANILOVA1,2, Alexandr Semenovich SHPIGEL1, Tengiz Shotovich BETANELI1, Kseniya Victorovna NAUMOVA1, Natalya Sergeevna POPELNYUK1
1Samara State Medical University of Minzdrav of Russia
2Clinics Samara State Medical University of Minzdrav of Russia
Keywords: кардиотоксичность, химиотерапевтическое лечение, трехмерная эхокардиография, фракция выброса, глобальная продольная деформация миокарда, стресс-эхокардиография, тропонины Т и I, натрийуретический пептид, cardiotoxicity, chemotherapy, three-dimensional echocardiography, ejection fraction, global longitudinal myocardial deformation, stress echocardiography, troponins T and I, natriuretic peptide

Abstract >>
The article is devoted to the modern concept of cardiotoxicity, induced chemotherapy in patients with hematological pathology and methods of its diagnosis. The study of cardiotoxicity is one of the current trends in oncology and oncohematology, as the side effects of chemotherapy drugs on the cardiovascular system affect the quality and life expectancy of patients, regardless of the prognosis associated with oncohematological disease. While modern strategies for the treatment of oncohematological diseases make it possible to achieve stable remissions and increase the duration and quality of life of patients, such successes can be offset by an increase in mortality in this group of patients due to the development of side effects of chemotherapy in relation to the cardiovascular system. In the review problems and prospects of cardiotoxicity diagnosis in patients with hematological diseases on the background of chemotherapy are presented at modern level of medical science development. The use of such methods as three-dimensional echocardiography, echocardiography with determination of global longitudinal myocardial deformation, stress echocardiography with determination of contractile reserve, determination of troponin and natriuretic peptide levels for diagnosis of cardiotoxicity makes it possible to detect manifestations of cardiotoxicity at an earlier stage and thus will reduce mortality in patients with oncohematological profile receiving chemotherapy for non-hematological reasons.



6.
ASSESSMENT OF BONE MINERAL DENSITY IN PATIENTS WITH HODGKIN’S LYMPHOMA

Mariya Sergeevna VOYTKO1, Tatyana Ivanovna POSPELOVA1, Vadim Valerievich KLIMONTOV1,2, Olga Nikolaevna FAZULLINA2, Elena Viktorovna MEZIT1
1Novosibirsk State Medical University of Minzdrav of Russia
2Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics of SB RAS
Keywords: лимфома Ходжкина, минеральная плотность костной ткани, остеопороз, денситометрия, двухэнергетическая рентгеновская абсорбциометрия, Hodgkin’s lymphoma, bone mineral, osteoporosis, densitometry, dual-energy X-ray absorptiometry

Abstract >>
Currently, Hodgkin’s lymphoma (HL) is considered as a potentially curable disease. The polychemotherapy including various combinations of cytostatic drugs and glucocorticoids appears the standard of treatment in patients with HL. Patients with early stage disease (stage I to II) receive several cycles of chemotherapy followed by the radiotherapy. The possibility of achieving persistent disease-free survival poses a problem of ensuring a satisfactory quality of life and preventing the long-term consequences of antitumor therapy. One of those consequences may be a change in bone mineral density (BMD). Aim of the study was to assess the BMD in patients with HL. Material and methods. BMD was measured by dual-energy X-ray absorbtiometry using a stationary LunarProdigy bone densitometer (GE, USA). The Russian FRAX model was used in this study. The model uses clinical data to calculate the major low-energy fractures and the hip fractures. Results. The decreased BMD was revealed in 36 observed HL subjects (48.6 %). Patients with osteoporosis were generally older, had a lower body mass index as compared to patients with normal BMD ( p < 0.05). Based on FRAX assessment, the 10-year risk of major low-energy fractures and the hip fractures was expectedly higher in patients with osteoporosis and osteopenia as compared to subjects with normal BMD ( p < 0.05). More patients with radiotherapy in anamnesis had decreased BMD compared to patients who received chemotherapy only (χ2 = 5.47; р = 0.0194). More than half of the patients (59.1 %) receiving regimens containing glucocorticosteroids had BMD decrease. A comparative analysis revealed that patients younger than 50 years old had lower values of BMD and Z-score of the lumbar spine in the early stages of HL as compared to patients with stage III-IV. In turn, in patients older 50 years and postmenopausal women at the early stages of HL was a significant decrease of BMD and T-score of the femoral neck as compared to patients with advanced stages of the disease. This research suggests that the decrease in BMD in stages I-II of HL can be associated with radiotherapy as the generally accepted standard for the treatment of early stages of the disease.



7.
CLINICAL SIGNIFICANCE OF THE TP53 MUTATION STATUS IN DIFFUSE LARGE B-CELL LYMPHOMA

Elena Nikolaevna VOROPAEVA1, Tatyana Ivanovna POSPELOVA2, Mikhail Ivanovich VOEVODA1, Vladimir Nikolaevich MAKSIMOV1
1Research Institutе of Internal and Preventive Medicine - Branch of Federal Research Center Institute of Cytology and Genetics of SB RAS
2State Medical University of Minzdrav of Russia
Keywords: ген ТР53, мутации, диффузная В-крупноклеточная лимфома, ритуксимаб, прогноз, таргетная терапия, gene TP53, mutations, diffuse large B-cell lymphoma, rituximab, prognosis, target therapy

Abstract >>
Objective: to reveal the clinical significance of the mutation status of the TP53 gene in the group of receiving rituximab therapy patients with diffuse large B-cell lymphoma (DLBCL) in Novosibirsk. Material and methods. A total of 74 patients with DLBCL, who have been hospitalized at the City Hematology Center in Novosibirsk for the period 2012-2015, were examined. All patients received therapy with rituximab. The nucleotide sequence of the coding region of the TP53 gene (exons 5-10) and adjacent regions of introns was analyzed by the Sanger direct capillary sequencing. Functional analysis of the revealed mutations was carried out. The results of the patients` therapy were evaluated. Results and discussion. For the first time, it has been revealed in the course of the study of Russian patients with DLBCL setting that TP53 mutation status is associated with the greater incidence of B-symptoms, splenomegaly, leukemia of the lymphoma, and poor prognostic groups according to the International Prognostic Index. A tendency toward a greater frequency of achieving complete clinical and hematologic remission during the therapy was revealed in the subgroup of patients with DLBCL having a canonical sequence of a gene or a mutation in TP53 with an unproven oncogenic potential. Patients with functionally significant TP53 mutations had a lower overall survival rates. Conclusion. For this reason, hopefully therapeutic approaches aimed at the inactivated pathway of TP53 can further improve clinical outcomes in DLBCL.



8.
QUALITY OF LIFE IN PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS (REVIEW)

Igor Leonidovich DAVYDKIN, Natalya Sergeevna POPELNYUK, Kseniya Viktorovna NAUMOVA, Elizaveta Vladimirovna MORDVINOVA, Tatyana Yurevna STEPANOVA, Svetlana Petrovna KRIVOVA, Anastasiya Aleksandrovna ROGOZINA, Tatyana Pavlovna KUZMINA
Samara State Medical University of Minzdrav of Russia
Keywords: миелопролиферативное заболевание, хронический миелолейкоз, истинная полицитемия, качество жизни, myeloproliferative disease, chronic myeloid leukemia, polycythemia vera, quality of life

Abstract >>
The target drugs use showed high efficiency and raised the patients’ life expectancy approaching it to average on population and became the new era in hematooncology. Given the currant tendency, the investigation of problems of patients’ quality of life and the affecting factors is actual. We have analyzed the modern foreign and domestic literature data concerning the quality of life of patients with myeloproliferative diseases and their variation principal causes and parameters reflecting the phenomenon. Also, we state the basic information on diseases where the myeloid lineage hyperplasia is the root cause. The pathophysiological and clinical features of the blood system pathologies are specified. The high-priority factors influencing quality of life of patients with myeloproliferative diseases are highlighted. The basic mechanisms of cardiovascular and thrombotic events development, playing a key role in the patients quality of life forming are in more detail described on the example of chronic myeloid leukemia and polycythemia vera. Moreover, the expediency of search of new diagnostic approaches to the assessment of myeloproliferative diseases course and the patients’ quality of life on a background of modern therapy have been shown.



9.
EPIGENETIC MECHANISMS OF TUMOR PROGRESSION IN CHRONIC LYMPHOID LEUKEMIA

Rasilya Rakhim’yanovna BASHAROVA1, Mekhti Magomedovich AGAKISHIEV2, Ol’ga Valer’yevna BEREZINA1, Igor’ Borisovich KOVYNEV1, Tat’yana Ivanovna POSPELOVA1
1Novosibirsk State Medical University of Minzdrav of Russia 630091, Novosibirsk, Krasny av., 52
2City Hematological Center
Keywords: miR-155, miR-223, хронический лимфоидный лейкоз, опухолевая прогрессия лимфом, miR-155, miR-223, chronic lymphoid leukemia, tumor progression of lymphomas

Abstract >>
The data on studies of the expression of microRNA regulatory molecules miR-155 and miR-223 in bone marrow and peripheral blood cells in patients with chronic lymphoid leukemia (CLL) at various stages of the disease progression are presented. The microRNAs were determined by the method of highly sensitive PCR in various peripheral blood substrates (plasma, lymphocytes, extracellular vesicles) and bone marrow in patients with CLL. The expression rates correlated with clinical data and the effectiveness of standard therapy. It is noted that an increase in the miR-155 expression and decrease in the miR-223 expression are associated with poor prognosis, resistance to therapy and high rate of the tumors progression of chronic lymphocytic leukemia. MiR-155 overexpression in all studied blood substrates (plasma, lymphocytes, extracellular vesicles) and bone marrow and decrease in miR-223 expression in lymphocytes, bone marrow and plasma were significantly associated with the stages of chronic lymphocytic leukemia according to J. Binet. The patients with CLL with the miR-223 low level in the bone marrow, extracellular vesicles and plasma and the miR-155 high level before treatment initiation did not achieve an optimal response to the therapy.



10.
INFECTIOUS DISEASES IN HEMATOLOGIST’S PRACTICE: VISCERAL LEYSHMANIASIS IN HIV-INFECTED PATIENT

Yuliya Nikolaevna OBGOLTS1, Natalya Grigorievna SAMOYLOVA2, Svetlana Semenovna FED`2, Svetlana Aleksandrovna KARMANOVSKAYA2, Igor Borisovich KOVYNEV3, Tatyana Ivanovna POSPELOVA3
1City Hematological Center
2City Clinical Hospital No. 2
3Novosibirsk State Medical University of Minzdrav of Russia
Keywords: висцеральный лейшманиоз, ВИЧ-инфекция, гематологический синдром, патология костного мозга при паразитарной инфекции, visceral leishmaniasis, HIV infection, hematological syndrome, bone marrow involvement in parasitic infection

Abstract >>
The clinical case of visceral leishmaniasis and HIV coinfection, associated with bone marrow involvement, which is uncommon in Siberia, was demonstrated. The detailed literature review on the issue was given. The data analysis of leishmaniasis prevalence dynamics in northern latitudes was conducted and the features of disease epidemiology were highlighted. The clinical forms of this parasite invasion and the contemporary ideas about mechanism of lieshmania escape from phagocytosis were described on the basis of recent data. The algorithm of differential diagnosis, diagnosis criterions and treatment standards were developed. The comprehensive approach to diagnosis and management of the zoonosis and HIV coinfection were described. The disease hematological features such as pancytopenia, lymphadenopathy, hepatosplenomegaly and fever were revealed. The significant of bone marrow hematopoiesis examination in leishmaniasis was specified. The analysis of the literature on the transformation of modern visceral leishmaniasis was carried out: an increase in the number of erased clinical debut forms, an increase in the duration of the latent period of the disease up to 130-160 days after transfection, an increase in the role of immunodepression factors in the clinical manifestation of the disease. The data on the epidemiological sources of zoonosis - insect vectors, conditions of infection, methods of prevention have been performed.



11.
FORMATION OF IRON EXCESS IN PATIENTS WITH INTERMEDIATEAND LOWER-RISK MYELODYSPLASTIC SYNDROME

Tatyana Nikolaevna BABAEVA1, Tatyana Ivanovna POSPELOVA1, Irina Nikolaevna NECHUNAEVA2
1Novosibirsk State Medical University of Minzdrav of Russia
2Novosibirsk Clinical Hospital No. 2
Keywords: миелодиспластический синдром (МДС), неэффективный гемопоэз, гепсидин, ферритин, трансфузионная зависимость, феррокинетика, обмен железа, избыток железа, myelodysplastic syndrome, ineffective hematopoiesis, hepcidin, ferritin, transfusion dependence, ferrokynetics, iron metabolism, iron excess

Abstract >>
The aim of study was to determine main types of iron overload in the intermediate- and lower-risk patients with myelodysplastic syndrome by using the research data of clinical and biochemical features of iron metabolism. Material and methods. A total of 22 patients with myelodysplastic syndrome, treated in Novosibirsk Hematological Centre, were examined. The average age was 62.6 ± 12.2 years. Among them, 14 (63.6 %) patients were transfusion-dependent and 8 (36.4 %) patients without transfusion dependence. To analyze the iron metabolism, the standard measures of iron status (serum iron and ferritin content, total and latent iron binding capacity, transferrin saturation) as well as additional markers, measured by ELISA (serum hepcidin content) were used. Results and discussion. The role of multiple transfusions in formation of iron excess in patients with myelodysplastic syndrome was demonstrated. In the transfusion-dependent group of patients the serum iron was 31.56 ± 15.59 μmol/l, transferrin saturation level - 64.1 ± 32.92 %, total and latent iron binding capacity - 48.87 ± 11.7 and 17.32 ± 12.66 μmol/l, serum ferritin level - 689.08 ± 104.98 ng/ml (in non-transfusion dependent group - 24.6 ± 7.58 μmol/l, 31.28 ± 19.48 %, 51.6 ± 17.41 and 35.86 ± 16.98 μmol/l, respectively). The trends in associated changes of ferritin and hepcidin level depending on the number of obtained transfusions showed the following results: less than 9 transfusions - r = 0.96 ( n = 6; p < 0.001), from 9 to 24 erythrocyte units - r = 0.009 ( n = 9; p > 0.06), more than 24 transfusions per year - r = -0.55 ( n = 7; p < 0.05). It proved the loss of sensitivity of hepcidin level to ferritin level in patients with high transfusion burden. Conclusion. The study demonstrated the role of ineffective hematopoiesis in the regulation disorders of hepcidin level in patients with myelodysplastic syndrome and iron overload formation without connection with transfusions.



12.
RARE DISEASES OF THE BLOOD SYSTEM: A CLINICAL CASE OF VIRUS-ASSOCIATED BONE MARROW APLASIA IN A PATIENT WITH A HEREDITARY MEMBRANOPATHY (REVIEW)

Andrey Vladimirovich ZABELA, Vitaliy Sergeevich SELIVANOV, Tatyana Nikolaevna BABAEVA, Igor Borisovich KOVYNEV
Novosibirsk State Medical University of Minzdrav of Russia
Keywords: парвовирус В19, HPV-B19, анемия беременных, наследственная гемолитическая анемия, апластический криз, parvovirus B19, HPV-B19, anemia among pregnant women, hereditary hemolytic anemia, aplastic crisis

Abstract >>
The aim of study was to research and present literature data regarding the investigations of some combined types of anemia in pregnancy and to describe the clinical case of pregnancy associated with primary parvovirus B19 infection and newly diagnosed hereditary erythrocyte membrane disorder. The contemporary information about the etiology, the prevalence, structure and some features of pathogenesis of parvovirus infection based on literature data was given. The huge prevalence of this infection (according to data of different sources the serum level of parvovirus B19 specific antibodies may be detect in 90 % of population), its threat for fetus and risk of severe complications in patients with immunodeficiency, as well as possibility of development of total depression of hematopoiesis in patients with hereditary erythrocyte membrane disorders, such as Minkowsky-Chauffard disease, determine the relevance and significance of the discussed topic. Furthermore, this clinical case, which illustrates the features of primary parvovirus B19 infection in patient with hereditary hemolytic anemia and the difficulties of differential diagnosis, demonstrates the importance of parvovirus infection markers detection, which is not available in the most TORCH-panel.



13.
ADULT-ONSET STILL’S DISEASE: ASPECTS OF THE HEMATOLOGY CLINIC

Mekhti Magomedovich AGAKISHIEV1, Inna Ivanovna MULINA2, Anna Mikhaylovna POPOVA3, Irina Nikolaevna NECHUNAEVA1, Lyudmila Mikhaylovna MASLOVA1, Igor’ Borisovich KOVYNEV3, Tat’yana Ivanovna POSPELOVA3
1City Hematological Center
2Republican Hospital No. 1 - National Center of Medicine
3Novosibirsk State Medical University of Minzdrav of Russia
Keywords: болезнь Стилла взрослых, миелоидная саркома, дифференциальный диагноз лимфаденопатии, adult-onset Still’s disease, myeloid sarcoma, differential diagnosis of lymphadenopathy

Abstract >>
The analysis of literature data on modern approaches in the diagnosis and treatment of adult-onset Still’s disease has been performed. A clinical case of Still’s disease associated with lymphadenopathy syndrome was demonstrated. It is noted that the diagnosis of adult Still’s disease requires a doctor to exclude a complex of a tumor, rheumatological and infectious pathology. It is important for a hematologist not to miss a blood tumor and to prevent a diagnostic error. The authors showed the criteria for exclusion of myeloblastic hematosarcoma and malignant lymphoma in a patient with Still’s disease. The importance of taking into account the clinical data is noted: the absence of progressive sarcomal growth of lymph nodes, the lack of generalization and dissemination of myeloblastic substrate in the body, the reduction of fever with steroids and nonsteroidal anti-inflammatory drugs. The role of monitoring clinical and biochemical blood parameters has been proved such as: blood ferritin level, C-reactive protein, hemogram parameters. The relative value of positron emission computed tomography data, which can be falsely interpreted, is shown. Correct diagnosis, rejection of an incorrect diagnosis of hematological tumor will prevent the administration of myeloablative polychemotherapy, which is dangerous for an adult patient with Still’s disease. The article outlines the differential diagnosis algorithm, presents the criteria for diagnosis and approaches to therapy. A feature of the clinical case was the detection of antibodies against yersenia. A meeting with an infectious agent could be a trigger for the development of a multisystem form of Still’s disease in a patient.



14.
TELOMERES AND TELOMERASE ACTIVITY IN CHRONIC MYELOID LEUKEMIA (REVIEW)

Anna Sergeevna LYAMKINA, Tatyana Ivanovna POSPELOVA
Novosibirsk State Medical University of Minzdrav of Russia
Keywords: теломеры, теломераза, хронический миелолейкоз, telomeres, telomerase, chronic myeloid leukemia

Abstract >>
A review of literature data on the change in telomere length and telomerase activity at various stages of chronic myeloid leukemia (CML) has been performed. It has been shown that telomere length is reduced faster in the BCR-ABL-positive cells due to their rapid division. It has been reported that telomere length correlates with the remaining time until the disease progresses. Thus, the accelerated reduction of telomeres can be regarded as a sign of a poor prognosis of the disease. It was found that the rate of contraction of telomere length during the progression of the disease was 10-20 times higher than that observed in normal granulocytes and blast cells (tumor samples underwent at least 30-60 additional divisions from the base length of Ph-telomeres). More than 50 % of patients with CML (blast crisis) had a 50-fold increase in telomerase activity. The length of telomeres gradually increased when the cytogenetic response was achieved in the treatment of CML by imatinib or interferon-alpha. Inhibition of telomerase is a new possible therapeutic approach to the treatment of myeloproliferative and solid tumors. Various therapeutic approaches to the inhibition of telomerase have been developed.



15.
POLYMORPHISM OF THROMBOPHILIA GENES AND THEIR ROLE IN DEVELOPMENT OF DIFFERENT DISEASE PHENOTYPES AND THROMBOTIC COMPLICATIONS IN HEMOPHILIA PATIENTS

Tatyana Yuryevna POLYANSKAYA, Irina Serafimovna FEVRALEVA, Evgeniy Evgenyevich KARPOV, Nadezhda Viktorovna SADYKOVA, Magomet Sultanovich SAMPIEV, Georgiy Vladimirovich MISHIN, Aleksandr Viktorovich GOLOBOKOV, Dmitriy Yuryevich PETROVSKIY, Anastasiya Aleksandrovna KOROLEVA, Gennadiy Martinovich GALSTYAN, Andrey Borisovich SUDARIKOV, Vladimir Yuryevich ZORENKO
National Research Center for Hematology of Minzdrav of Russia
Keywords: гемофилия, фенотипы гемофилии, полиморфизм генов тромбофилии, hemophilia, hemophilia phenotypes, thrombophilia gene polymorphism

Abstract >>
Objective was to study genetic markers of thrombophilia in patients with hemophilia, which can affect the course of the disease and contribute to thrombotic complications. Material and methods. The study included 96 patients with severe hemophilia: 75 (78.1 %) - hemophilia A, 16 (16.7 %) - hemophilia B, 5 (5.2 %) - hemophilia with inhibitor form. All patients were with severe hemophilic arthropathyand and underwent knee or hip replacement. The average age of patients was 39.6 years. All patients were examined for markers of thrombophilia. Results. Ninety three patients had either a heterozygous or homozygous form of thrombophilia marker polymorphism. One of thrombophilia markers was present in 15 (15.6 %) patients and in 78 (81.3 %) there was a combination of several markers. In patients with hemophilia B homozygous mutations in the MTHFR gene (A1298C and C677T) were more than 2 times more frequent than in patients with hemophilia A. Conclusion. The frequency of occurrence of polymorphism of FV (G1691A), MTHFR (C677T) and PAI-1 in the studied group of patients with hemophilia is higher than in the general Russian population.



16.
CHARACTERISTICS OF BONE MARROW MICROENVIRONMENT IN MULTIPLE MYELOMA BEFORE AND AFTER TREATMENT

Viktor Ivanovich RUGAL1, Stanislav Semenovich BESSMELTSEV1, Natalya Yurevna SEMENOVA1, Sergey Vasilevich GRITSAEV1, Ivan Ivanovich KOSTROMA1, Natella Iosifovna ENUKASHVILI2, Anna Vadimovna CHUBAR3, Dmitriy Aleksandrovich IVOLGIN3
1Russian Research Institute of Hematology and Transfusiology of FMBA of Russia
2Institute of Cytology of RAS
3Pokrovsky Stem Cell Bank
Keywords: множественная миелома, костный мозг, ниша гемопоэтических стволовых клеток, АутоТГСК, микроокружение, ангиогенез, multiple myeloma, bone marrow, hematopoietic stem cell niche, AutoHSCT, microenvironment, angiogenesis

Abstract >>
The purpose of the study is to evaluate the morphological and functional features of the tumor microenvironment and the cultural characteristics of mesenchymal stromal cells (MSC) of patients with multiple myeloma (MM) before and after treatment. Material and methods. Parenchymal and stromal bone marrow tissue in iliac bone trepanobiopsy of 32 patients with MM aged from 48 to 78 years (median age 56 years) before and after treatment was investigated. The study applied histological, immunohistochemical and cultural methods. Results and discussion. Сhanges of stromal microenvironment of bone marrow in all patients with MM have been revealed: increased microvascular density and the number of endosteal stromal cells, strengthening of reticulin fiber in subendosteal and perivascular spaces. Increased angiogenesis correlates with the number of plasma cells in the myelogram ( r = 0.58; p < 0.05) and with the type of bone marrow infiltration ( r = 0.85; р < 0.05), as well as with osteodestructive changes in the patient’s history ( r = 0.65; p < 0.05). Significant changes in MSC cultures, both before and after therapy, including autologous hematopoietic stem-cell transplantation, were shown. Bone marrow MSC of patients with MM had decreased speed of proliferation (2.4 times on average), total time of passaging from 7 to 5 passages, increased expression of markers associated with myofibroblastic phenotype and aging (smooth muscle actin, β-galactosidase) compared to healthy donors. Conclusion. MSC cultures and BM niche forming elements of patients with MM have signs of tumor-associated microenvironment, despite the treatment of the underlying disease.



17.
THE CASTLEMAN DISEASE, POEMS-SYNDROME AND PRODUCTIVE VASCULITIS IN MICROVASCULAR NETWORK OF DIFFERENT TISSUES

Anatoliy Mikhaylovich MIKHAYLOV1, Stanislav Semenovich BESSMELTSEV2, Vsevolod Gennad'yevich POTAPENKO3, Victor Ivanovich RUGAL2, Nataliya Yurievna SEMENOVA2, Nataliya Mikhaylovna KHMELNITSKAYA1
1North-West State Medical University n.a. I.I. Mechnikov
2Russian Research Institute of Hematology and Transfusiology of FMBA of Russia
3City Clinical Hospital No. 31
Keywords: болезнь Кастлемана, РОЕМS-синдром, лимфатические узлы, внутренние органы, васкулит, Castleman’s disease, POEMS syndrome, lymph nodes, internal organs, vasculitis

Abstract >>
Objective: to study the condition of microvascular network in the tissues surrounding the biopsied lymph nodes: in the fat and connective tissue capsule, and to match these findings with the clinical picture of the disease. Material and methods. Our research included 24 patients with Castleman’s disease (CD), all negative for HIV and herpes virus-8 type, at the age of 36-70 years (men-14, women-10). 10 patients had hyaline-vascular type of CD, 14 patients had plasma-cell multicenter type. Of the 24 patients, 10 patients developed POEMS syndrome. The diagnosis of CD was confirmed by the histological examination of the lymph node and immunohistochemical study of the distribution of B- and T- lymphocytes in the node tissue. Vessels showed immunohistochemical positivity with antibodies to CD34, plasma cells with antibodies to CD138. Four patients with POEMS syndrome did not receive treatment, 6 patients received various types of therapy. Of these, 2 patients underwent therapy with autologous stem cell transplantation of bone marrow. Both patients were in remission of CD and POEMS for 10 years. Two patients received 5 cycles of therapy according to VCD scheme. They were alive for 5 years with the reduction of POEMS’s symptoms. 1 patient with POEMS and autoimmune hemolysis has received 10 courses of R-CHOP and has resulted in remission for 3 years. Two of the 6 deceased patients with POEMS syndrome underwent autopsy. Results and discussion. In all patients, regardless of the histological variant of CD, productive vasculitis in microvascular network was found and it had following characteristics: thickening of the walls due to lymph-histiocytic infiltration, fibrosis, swelling of endothelial cells, which narrowed or completely obstruct the vessel’s lumen. The most severe sclerosis of small vessels in the lymph node tissue was observed in patients with POEMS, in which perivascular infiltration included plasma cells. Patients with POEMS showed extensive involvement in the sclerotic process nearby vessels. The study of the microvascular network on the autopsy material revealed its systemic damage in all internal organs. Conclusion. Regardless of the histological variant of Castleman’s disease, in all 24 cases there was a lesion of microvascular network in the form of plasma cell productive vasculitis, with the most severe changes in group of patients with POEMS syndrome.



18.
THE ROLE OF ENDOTHELIAL DYSFUNCTION AS A PART OF SYSTEMIC INFLAMMATORY RESPONSE IN PATHOGENESIS OF AGGRESSIVE AND INDOLENT NON-HODGKIN’S LYMPHOMAS

Olga Borisovna SEREGINA1, Tatyana Nikolaevna BABAEVA1,2, Tatyana Ivanovna POSPELOVA1
1Novosibirsk Medical State University of Minzdrav of Russia
2Novosibirsk Clinical Hospital № 2
Keywords: типовые формы эндотелиальной дисфункции, системная воспалительная реакция, неходжкинские злокачественные лимфомы, цитокиновый дисбаланс, антивоспалительная резистентность, types of endothelial dysfunction, systemic inflammatory response, non-Hodgkin’s lymphomas, cytokines imbalance, anti-inflammatory resistance

Abstract >>
Objective. To study of manifestation of angiogenic and hemostatic forms of endothelial dysfunction and systemic inflammatory response in patients with non-Hodgkin’s lymphomas at the onset of disease. Material and methods. A total of 99 patients were enrolled in this study, including 55 patients with aggressive variants and 44 patients with indolent variants. The average age was 60.71±10.63 years. The serum level of vascular endothelial growth factor (VEGF) was measured as a marker of angiogenic form of endothelial dysfunction, the serum levels of thrombomodulin, D-dimers, soluble fibrin-monomer complex (SFMC) and level of Willebrand factor activity were used for evaluation of hemostatic form of endothelial dysfunction. To assess the degree of systemic inflammation response the serum levels of proinflammatory cytokines - TNF-α, IL-1β, IL-6 were measured, as well as serum level of acute phase proteins - C-reactive protein (CRP), fibrinogen. The serum level of IL-4 was used to evaluate antinflammation resistance. Results and discussion. Proinflammatory cytokine (TNF-α, IL-1β and IL-6) content was higher in both studied groups compare to the control group. Serum concentration of anti-inflammatory cytokine IL-4 in studied groups did not differ from the level in the controls group. CRP and fibrinogen serum content was increased only in group of patients with aggressive variants. There was a significant correlation between the level of CRP and proinflammatory cytokines in aggressive lymphoma group. Serum content of VEGF, thrombomodulin, D-dimers, SFMC and Willebrand factor activity were increased in both studied group in comparison with the control group. Concentration of thrombomodulin, D-dimers, SFMC and Willebrand factor activity was higher in patients with aggressive than in patients with indolent lymphomas. Conclusion. The signs of angiogenic and hemostatic forms of endothelial dysfunction in patients with aggressive and indolent variants of non-Hodgkin’s lymphoma were detected, as well as manifestation of systemic inflammatory response and attenuation of anti-inflammatory resistance with development of cytokines imbalance with proinflammatory cytokines predominance. The manifestations of systemic inflammatory response and hemostatic type of endothelial dysfunction with activation of coagulation were displayed more prominently in the aggressive lymphoma group.



19.
METROLOGICAL EVALUATION OF QUALITY CONTROL METHODS OF ERYTHROCYTE-CONTAINING BLOOD COMPONENTS

Nataliya Sergeevna NIKULINA, Elena Nikolaevna KALININA
Kirov Research Institute of Hematology and Blood Transfusion of FMBA
Keywords: валидация, эритроцитсодержащие компоненты крови, контроль качества, методики анализа, метрологические характеристики, validation, erythrocyte-containing blood components, quality control, methods of analysis, metrological characteristics

Abstract >>
Objective - to evaluate experimentally the suitability of quality control methods used to control the quality of erythrocyte-containing blood components. Material and methods. In order to assess the metrological characteristics of the techniques, 46 samples of erythrocyte-containing blood components were analyzed: 10 samples of erythrocyte mass, 26 samples of erythrocyte suspension, 6 samples of erythrocyte suspension of leukoreduced and 4 samples of leukoreduced platelet concentrate. For determining the hemoglobin content as a negative control («placebo» sample), «Sodium chloride, 0.9 % infusion solution» was used. The hemoglobin content (total and free) was determined by three methods: hemiglobincyanide method, non-cyanide SLS method using a hematology analyzer «Sysmex XT-4000i-1», and photometric method using a portable analyzer «HemoCue Hb 201+». Two methods were used to determine hematocrit: a unified method of centrifugation in hematocrit capillaries, a conductometric method using a hematology analyzer «Sysmex XT-4000i-1». Counting the number of residual leukocytes was performed by three methods: a unified method of counting in 2 Goryaev chambers, flow cytometry using a «Sysmex XT-4000i-1» hematology analyzer, and flow cytometry using a «FACS CantoTMII analyzer». Results and discussion. The maximum values of coefficients of variation of the analysis methods of total hemoglobin and the hemolysis degree by the hemiglobincyanide method, hematocrit - by the unified method, were 3.03, 20.71 and 1.83 %, respectively. When using the analyzer «Sismex XT-4000i-1», the coefficients of variation of the methods for determining the hemoglobin content ranged from 0.29 to 0.54 %, hematocrit from 0.58 to 1.87 %. In the course of comparing the three methods for determining the amount of residual leukocytes in the leukoreduced blood components, it was concluded that it is advisable to use the flow cytometry method on the «FACS CantoTMII analyzer». The attributed characteristic of the technique was 19.8 %. Conclusion. For the control of total hemoglobin and the degree of hemolysis, the hemiglobincyanide method and the uncyanide SLS method using the «Sysmex XT-4000i» hematology analyzer are recommended. Hematocrit determination should be carried out using a unified method and using a «Sysmex XT-4000i» hematology analyzer. The amount of residual leukocytes in leukoreduced components is recommended to be determined by flow cytometry using a «FACS CantoTMII» analyzer.



20.
OPTIMIZATION OF MEDICAL EXAMINATION OF BLOOD DONORS AS AN ELEMENT OF LEAN HEALTHCARE IN NOVOSIBIRSK CLINICAL BLOOD CENTER

Yuliya Vladimirovna MOOR1,2, Konstantin Vasilyevich KHALZOV2,3, Tatyana Ivanovna POSPELOVA2
1Novosibirsk Clinical Blood Center
2Novosibirsk State Medical University
3Ministry of Health of Novosibirsk region
Keywords: Новосибирский клинический центр крови, доноры, оптимизация, медицинское освидетельствование, бережливое здравоохранение, Novosibirsk Clinical Blood Center, donors, optimization, medical examination, lean health care

Abstract >>
Objective was to assess the possibility of optimizing the process of medical examination of blood donors and its components based on the principles of lean health care, to reduce the average working time of the sites involved in the procedure of medical examination of donors. Material and methods. The analysis of the general timing of procedures of medical examination of registration of donors, primary clinical and laboratory research, medical examination in two non-conjugated groups of donors in the amount of 200 people, the results of a sociological survey of donors of the blood Center in the amount of 1137 people has been carried out. Results and discussion. In order to reduce the time spent by donors at the donor center, the organization of donor flows during registration and medical examination has been changed in the blood center, for which various administrative decisions have been taken and implemented. The areas of work were: the creation of the necessary infrastructure, the introduction of an open registry, electronic document management, reducing queues, waiting time for a transfusiologist and clinical and laboratory studies, the formation of a comfortable environment for donors in the Novosibirsk clinical blood center. The activities carried out allowed to optimize the processes of interaction with blood and its components donors, to improve the quality of donor service and to reduce the total time of medical examination: the average time of medical examination for donors was reduced by 2.2 times - from (51.9 ± 0.8) minutes to (23.6 ± 0.5) minutes, the capacity of the registry was increased by 1.6 times, the area of recruitment of donor personnel and the laboratory was reduced by 1.8 times, the satisfaction of donors with the conditions provided in the blood Center was increased by 23.1 %. Conclusion. The introduction of the principles of lean health care into the routine practice of donor admission allowed the Novosibirsk clinical blood center to improve the work of medical personnel, optimize the process of medical examination, accelerate the execution of tests, simplify the registration for donation and, as a result, increase donor satisfaction with the conditions of donation provided in the Novosibirsk clinical blood center.