In recent years, an active revision of ideas about the mechanisms of blood clotting has been performed. Traditional views were largely inaccurate, which is the main reason for the inconsistency of the modern standard set of coagulation tests. This set was found to be insensitive, especially to hypercoagulable disorders. In this paper, we consider modern concepts of how blood clotting occurs. From this consideration follows the need for a critical review of existing methods for assessing the status of hemostasis and a standard set of laboratory tests. The lecture ends with a brief examination of which methods are the most informative today and could form the basis of a new informative coagulation testing set.

Pediatric myelodysplastic syndrome (MDS) are a heterogeneous group of clonal disorders often occur in the context of inherited bone marrow failure syndromes, acquired aplastic anemia or gene predisposition. Germ line syndromes predisposing individuals to develop familial MDS or acute myeloid leukemia have recently been identified – mutations in RUNX1, ANKRD, GATA2, ETV6, SRP72, DDX41. Juvenile myelomonocytic leukemia (JMML) occurs in context of inherited and somatic mutations PTPN11, KRAS, NRAS, CBL, NF1. In pathogenesis of these disorders there are a several factors – hypermethylation, clonal hematopoiesis/cytopenia of undetermined significance, disturbances of bone marrow microenvironment, telomeres, immune mechanisms. Allogeneic hematopoietic stem cell transplantation is the main method of MDS and JMML treatment but it is necessary to take into account special indications for refractory cytopenia (infections, dependence on blood transfusions) and be careful for JMML with CBL mutation.

Relevance. Continuous work in the field of optimization of approaches to the diagnosis and treatment of malignant neoplasms (MNP) in children has contributed to increase in overall survival (OS) to 80 % and higher in developed countries. Whereas in resource-limited countries there are some difficulties in access to the medical care leading to significantly lower OS. The key parameters in the improvement of the OS are improving the accessibility of diagnosis and treatment, application of advanced protocols of therapy, early diagnosis and other aspects. 

All these issues can be solved within the working group with the assistance of the leadership of the countries.

The article reflects the results of the work of the expert group on children's oncology for the first half of 2018 on the analysis of the situation in the field of pediatric hematology and oncology of the Commonwealth of Independent countries (CIS).

The view to analyzing has been the identification of the problems of the pediatric hematology-oncology in the CIS countries.

Materials and methods. It was a two steps analysis: 1. There has been an online meeting in February–April, 2018. 2. There has been a master class in Moscow at the venue of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology on April, 23–25, 2018. The initiators of the formation of the working group were World Health Organization, Children’s research hospital of St. Jude, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology and National Society of Pediatric Hematologists and Oncologists. The analysis has been carried out with the use of SWOT technology (S – strengths, W – weaknesses, O – opportunities and T – threats) by which have been identified strengths and weaknesses, potential threats and development prospects for each of the participating countries of the analysis and for the CIS in general. What is more, data on the incidence of MNP in children among the member States were received and outlined the promising avenues for the development. On the master class in Moscow there have been formed 4 working groups in the following areas: scientific work, health organization, developing of the educational technologies and introducing technologies aimed at improving the practical support for the patients.  

Results. Situation analyses of 11 CIS countries have been reviewed and it showed a different level of the development of pediatric hematology-oncology related to differences in the organization of the children’s health care system. Nevertheless, the key ways of the development of the service of pediatric hematology and oncology in the region have been determined: the development of early diagnosis and formation of oncological alertness, the development of uniform approaches to diagnosis and treatment based on the multicentre protocols, elaboration of the unified approaches to registering and recording children with MNP, creation of the unified educational programs for secondary and medical personnel, further elaboration of steps to optimize the children’s health care system.

Differentiation therapy with all trans retinoic acid (ATRA) is successfully used for the treatment of acute promyelocytic leukemia (APL).  At the same time, the development of the resistance and the differentiation syndrome as a side effect is a reason to explore and examine in greater depth the molecular basis of the differentiation therapy and to search the alternative paradigm of the treatment. By the use of ATRA-treated HL-60 cell line as a model object, we have estimated 76 activated and 101 inhibited proteins by the label-free mass-spectrometric profiling. By applying the bioinformatic approach we have obtained model schemes of regulation of the inhibited and  activated  proteins  whose  key  molecules  turn  out  to  be  the  histone  deacetylase  1  (HDAC1)  and  the  transcriptional  corepressor (RNF96) respectively. Both of predicted key molecules have been detected in HL-60 cell line at the proteome level in conjunction with Cdk2, DNA-PKcs, Ubc9 and HMGIY molecules in the model scheme regulating the activated protein cluster and the protein kinase p38 alpha involved in the regulating scheme of the inhibited proteins. The pharmacological targeting of these molecules may have an antiproliferative effect and provide the alternative approach to APL treatment.

Introduction. Leukemia accounts for 40 % of all malignant neoplasms under the age of 15 years in children. Determination of the genetic portrait of patients with acute lymphoblastic leukemia (ALL) helps to identify polymorphisms in the genes responsible for the metabolism of drugs included in standard treatment protocols.

Materials and methods. 51 children with confirmed diagnosis of acute lymphoid leukemia (ALL) were included in the analysis of the frequency of polymorphism of TPMT gene. The detection of polymorphisms TPMT*2, TPMT*3A and TPMT*3 was performed using a set of reagents “AmpliSens® Pyroskrin” & “FARMA-screen-2b”.

Results. Polymorphisms in the TPMT gene of 51 patients were found in 6 (11.8 %) children. Of these, 4 patients have variant alleles TPMT*3A and TPMT*3C and 2 patients have only TPMT*3C. Of the 6 patients with TPMT polymorphism, two have a translocation t(12;21).

Relevance. The development of a new recombinant blood coagulation factor VIII preparation is a promising step towards optimizing the treatment of hemophilia A. An introduction of a new medication into clinical practice precedes a clinical trials to evaluate the efficacy and safety.

Materials and methods. The efficacy and safety of the domestic recombinant B-domain deleted blood coagulation factor VIII (FVIII) (moroctocog alfa, Octofactor®, JSC “GENERIUM”) were studied in the preventive treatment of 31 patients aged 21 to 52 years with severe haemophilia A. The Octofactor was administered in doses of 40 ± 5 IU/kg 3 times per week at intervals of at least 48 hours for 21 ± 1 weeks.

Results. The efficacy of therapy was evaluated in 30 patients, since 1 patient refused to participate in the trial after the first injection of the study medication. There were registered 43 episodes of bleeding among 11 patients in the course of the preventive treatment with Octofactor. The average number of bleeding episodes was 1.4 ± 2.58. There were 43 bleeding episodes, 9 (20.9 %) of them were posttraumatic, 34 (79.1 %) of them were spontaneous. The average number of the spontaneous bleeding episodes (a major criterion of the efficacy) was 1.13 ± 2.19, which showed a low incidence of exacerbations of the hemorrhagic syndrome in the course of preventive treatment with Octofactor. Among all registered bleeding episodes there were 6 (14 %) mild episodes, 37 (86 %) moderate episodes. Among all spontaneous bleedings there were 6 mild episodes (17.6 %), 28 (82.4 %) moderate episodes. All posttraumatic bleedings were moderate. The vast majority (36, or 83.7 %) of bleeding episodes were stopped with administration of the Octofactor. The average number of administrations of the Octofactor for arresting 1 bleeding episode was 1.2 ± 0.56, for 1 spontaneous bleeding episode – 1.2 ± 0.59. On average, it was required to administer 3534.9 ± 2329.02 IU of the Octofactor to stop 1 episode of bleeding. In the vast majority of patients with severe hemophilia A (83.3–86.7 %),  the remaining activity FVIII was 1 % or more after the administration of the Octofactor in 48 hours. The total amount of the Octofactor, introduced for the prevention of bleeding, was 6,107,000 IU, to stop bleeding – 152,000 IU. The safety of therapy was evaluated in 31 patients. There were recorded 25 adverse events (AE) in 17 patients. Among them the laboratory ones prevailed in 23 (92 %) cases, which is not associated with the use of the trial medication. There were noted nausea and an unpleasant aftertaste in the mouth in 1 patient during the first administration of the Octofactor, and therefore he refused to continue to participate in the trial. Causality 2 AE with the study drug was regarded as definite. Such AE are expected and described in the instructions to the preparation. All AE were not serious and mild and resolved without outcomes. There were no presented thromboembolic events and immunogenic reactions.

Conclusions. The obtained data testify to the efficacy and safety of the Octofactor both for preventive measures and for stopping bleeding in adult patients with severe hemophilia A.

Children with acute leukemia are faced with high risks of thrombotic and hemorrhagic complications. The pathogenesis of haemostasis disorders in hemoblastoses is complex because, in addition to the disease itself, the aggressiveness of the therapy and the need for numerous invasive manipulations also make a significant contribution. Patients with hemoblastoses are equally susceptible to thrombosis and hemorrhage, which makes it possible to speak of multidirectional shifts in the balance of the hemostatic system in each individual patient. Standard laboratory hemostasis tests (clotting times, marker tests) are designed to assess the concentrations of individual proteins and the functioning of individual components of the hemostasis, and in do not assess the balance between its procoagulant and anticoagulant components. Global hemostatic tests designed to assess the coagulation balance, such as thromboelastography, thrombin generation test, and thrombodynamics, can be the alternative for the standard coagulation assays. The review focuses on the mechanisms of various laboratory hemostasis tests, as well as an assessment of their informative value in frequent complications of the underlying disease (sepsis leading to the development of disseminated intravascular coagulation (DIC) syndrome, thrombocytopenia) and catheterization, which is present in the majority of patients with hemoblastosis. General screening tests of the blood coagulation system have little diagnostic value in the DIC syndrome in patients with acute leukemia, mainly due to their insensitivity to hypercoagulability. Standard markers (for example, D-dimers) are non-specific and only confirm the clinical manifestations of clotting disorder in sepsis and septic shock, but are unable to predict the dynamics of this process at earlier stages of the inflammatory response. In this case, the thrombin generation test and thrombodynamics make it possible to reveal the hypercoagulable phase of the DIC syndrome. Thrombocytopenia accompanies almost all protocols of chemotherapy. In this case, the degree of bleeding does not always depend only on the concentration of platelets, since chemotherapeutic drugs can affect not only the quantity, but also the functional characteristics of platelets, which are not determined by standard examination of patients. The catheterization that accompanies the treatment of hemoblastoses is the leading cause of thrombosis in children with acute leukemia. Thromboembolism of the pulmonary artery due to thrombosis in the central vein system occurs in 8–15 % of patients. The prediction of catheter-associated thromboses using standard laboratory methods for assessing the state of the hemostasis is not possible. Absence of sensitive tests in modern diagnostic schemes leads to the fact that the attending physician is forced to focus exclusively on the clinical picture of thrombosis or bleeding. The development of new functional methods of hemostasis allows one to think that today the existing standard panel of coagulation tests can be expanded and made much more informative in terms of the prediction of thrombohemorrhagic complications in pediatric hematology-oncology.

Patients with a severe and moderate form of hemophilia A have traditionally been prescribed standard prevention with a coagulation factor VIII (FVIII), the goal of which is to achieve zero bleedings per year and a remaining activity of FVIII no fewer than 1 %. The standard approach does not allow achieving these goals in many patients due to a variety of factors: age of the patient, lifestyle, level of physical activity, condition of joints, muscle tone, patient compliance, individual pharmacokinetic (PK) response to FVIII administration. The target remaining activity of FVIII may be 2, 3 or even 5 % depending on the level of physical activity. Nowadays an individualized approach to the treatment of patients with severe hemophilia A based on the patient's PK profile is actively being explored and implemented in clinical practice. Individualization of prevention in patients with severe hemophilia is a real need for the physician and patient. There is a high variability in the values of the half-life period of FVIII in different patients. It is necessary to monitor the duration of the time period when the remaining activity of FVIII is less than 1 %, i.e., the period which is directly linked to the risk of spontaneous hemorrhage. For the patients getting treatment of Octocog alfa there has been developed the software (SW) myPKFiT* on the basis of web application which allows to simulate a dosage regimen taking into account the patient's PC profile based on the determination of FVIII activity in 2 blood sample. The SW allows changing (increase) the target level of the remaining activity of FVIII considering the lifestyle and the level of physical activity of the patient. The ability of SW allows the patient to demonstrate the activity of FVIII at various doses and intervals of drugs, as well as identify the risks that arise when a drug is missed. Therefore, myPKFiT solves an important task of the individualized approach to selection and correction of therapy, improves the collaboration and mutual understanding between the physician and the patient, up regulates of the patient adherence to the therapy and achieves optimal results.

This paper reviews the clinical applications of tandem mass spectrometry in diagnosis and screening for inherited metabolic diseases. The broad-spectrum of diseases covered, specificity, ease of sample preparation, and high throughput provided by the MS/MS technology has led to the development of multi-disorder newborn screening programs in many countries for amino acid disorders, organic acidurias, and fatty acid oxidation defects. The application of MS/MS in selective screening has revolutionized the field and made a major impact on the detection of certain disease classes such as the fatty acid oxidation defects. New specific and rapid tandem mass spectrometry (MS/MS) and high performance liquid chromatography–MS/MS methods are supplementing or replacing some of the classical gas chromatography– MS/MS methods for a multitude of metabolites and disorders. In the near future, we should expect the emergence of new promising methods for diagnosing not only individual nosologic forms, but also entire groups of inherited metabolic diseases.

The article represents a case of observation the patient aged 1 year 9 months with an isolated thrombocytopenia with a drop in platelets to 98 thousand/μL, that had been progressed during 1 year to three-stage cytopenia, which was the result of a congenital cavernous transformation of the portal vein. The differential diagnosis of young children’s cytopenia is a complex clinical task, which can be followed by errors in the diagnosis and, accordingly, the choice of therapy. The care of clinicians regarding only hematological pathology can lead to the confusion. The absence of clinical manifestations and moderate deviations in the hemogram (Hb – 98 g/l, RBC– 4.64 × 10¹²/l, PLT – 98 × 10⁹/l, WBC – 5.0  × 10⁹/l, GR – 0.79  × 10⁹/l) made the diagnostic search rather difficult in this case.

The authors of the translation: G.M. Muftakhova, N.A. Rybalko

This work is devoted to the analysis of problems associated with the state of the cardiovascular system (CVS) in patients who have experienced a malignant tumor in childhood. The main diseases and pathosis that can develop in this population have been considered. Risks of the development of abnormal changes on the side of the CVS, treatment and prevention have been described. The impact of various types of antitumor therapy on the CVS has been analyzed separately. Advices provided on the definition of risk groups, physical activity and recommended actions are given.

Children’s oncology, hematology and chemotherapy department of the Regional Children’s Clinical Hospital of the Vologda celebrated its 5^th anniversary in January, 2018. Opening of a specialized department allowed to treat children with malignant neoplasms and severe hematological diseases in the Vologda region at a higher level. In the department children aged 1 month to 18 years with various forms of tumors of the hematopoietic system, solid neoplasms, tumors of the central nervous system, anemia and cytopenia of various genesis, disorders of the blood clotting system undergo examination and treatment. This article describes the main stages in the development of a cancer care for children of the Vologda region, the possibilities of service and the prospects for development.