Introduction. Currently, considerable attention is being given to the study of the interaction of the von Willebrand factor (vWF) and its specific regulator of metalloprotease ADAMTS13 in various clinical conditions accompanied by the development of thrombosis.

Aim — to assess the change in the activity of ADAMTS13 metalloprotease and vWF factor antigen in patients with acute coronary syndrome during the first five days after the onset of an anginal attack.

Patients and methods: The study included 90 patients aged 42 to 86 years (Me — 61.5 y.o.) hospitalized with a diagnosis of acute coronary syndrome. Of these, 69 were men (Me — 59 y.o.) and 21 women (Me — 63 y.o.). All patients were tested for ADAMTS13 activity, ADAMTS13 antigen, and vWF antigen. Blood samples for the study were obtained upon admission to the hospital (arterial and venous blood), as well as 24, 72 and 120 hours after hospitalization (venous blood).

Results. It was found that at all points of the study, in patients without coronary artery thrombosis, the average value of the ADAMTS13 activity indicator was significantly higher compared to the group of patients with coronary artery thrombosis. At the same time, there were no statistically significant differences in the average values of the ADAMTS13 antigen between the compared groups of patients. The mean value of vWF antigen in patients with coronary artery thrombosis was significantly higher compared to that of patients without coronary artery thrombosis.

Conclusion. An increase in ADAMTS13 activity was noted more often in patients with acute coronary syndrome without coronary artery thrombosis than in patients with coronary artery thrombosis, which may indicate the antithrombotic effect of ADAMTS13 metalloprotease. No differences were found in ADAMTS13 antigen levels when comparing the study groups of patients, which indicates a greater significance for the anticoagulant activity of the functional characteristics of ADAMTS13. Significantly higher levels of the vWF antigen in patients with coronary artery thrombosis were due to the response to ischemic myocardial injury and stress but were not the primary cause of the thrombotic event.

Introduction. Von Willebrand disease (vWD) is caused by von Willebrand factor (vWF) dysfunction resulting from pathogenic variants in the vWF gene coding the vWF protein. vWD type 2N is of particular interest, as it is characterized by almost normal vWF antigen level (Ag:vWF) and vWF loss of ability to bind FVIII and protect it from premature clearance, which leads to a low FVIII coagulation activity (FVIII:C). Therefore, the same phenotype occurs in patients with 2N type of vWD and hemophilia A.

Aim — to identify patients with 2N type vWD using molecular genetic methods.

Methods. Data from the medical histories of vWD patients were used. The major parameter in consideration was FVIII:C to vWF:Ag ratio, which is expected to be below 0.7 in type 2N of vWD. Pathogenic variants in exons and exon-intron junctions of the vWF gene were identified by Sanger sequencing. Due to recessive inheritance of type 2N, verification of the 2N vWD diagnosis required the identification of two pathogenic variants.

Results. Three patients were considered as suffering from type 2N of vWD according to hemostasis parameters (FVIII:C/vWF:Ag < 0.7). One patient with a preliminary hemophilia A diagnosis was included after sequencing of the F8 gene, which showed no alterations, so 2N type of vWD was suspected. In all cases, sequencing of the relevant functional regions of the vWF gene led to verification of vWD type 2N. One woman (patient # 4) had a homozygous pathogenic variant p.Arg854Gln (c.2561 G>A) associated with type 2N vWD. One woman (patient # 3) was a compound heterozygote for the pathogenic variant p.Arg816Trp (c.2446 C>T) associated with type 2N and a newly described insertion c.2098_2099insG, that leads to a frameshift. The woman with FVIII:C/vWF:Ag < 0.7 (patient # 1) and the patient # 2 with preliminary hemophilia А diagnosis were both compound heterozygotes for the same combination of pathogenic variants — c.2435delC and p.Thr791Met (c.2372 C>T). Pathogenic variant p.Thr791Met is associated with type 2N, while the deletion c.2435delC should lead to allele disabling.

Conclusion. Molecular methods allow more precise differentiation of type 2N from other types of vWD and hemophilia A.

Introduction. Packed red blood cells (pRBCs) are the most required component of blood used for transfusion. Storage of erythrocytes in blood bank conditions causes a disruption of the molecular structure of long-stored pRBC membranes. This “disruption” can affect the quality and safety of transfused red blood cells.

Aim — to analyze the dynamics of pathological changes in the morphology, nanostructure, cytoskeleton network, and mechanical properties of RBC membranes during long-term storage of pRBCs, and the relationship of these changes with storage time.

Materials and methods. Hermetic bags of pRBCs with anticoagulant CPD in resuspending solution SAGM were stored for 42 days at +4 °С. Samples were taken on days 3, 12, 19, 21, 24, 28, 35, and 42 of storage and images of morphology, nanostructure, and cytoskeleton were obtained by atomic force microscopy. Young’s modulus was used to assess the stiffness of native cell membranes using atomic force spectroscopy.

Results. During storage of pRBCs, their cell morphology changed. After 20–24 days of storage an irreversible transformation of discocytes into echinocytes, spheroequinocytes and other cell forms occurred. It was found that during storage of pRBCs, topological defects in the form of domains with grains appeared on the surface of RBC membranes, the configuration of the cytoskeleton network transformed structurally, and the Young’s modulus increased.

Conclusions. During long-term storage of pRBCs (up to 42 days, 4 °С, CPD/SAGM) the molecular structure of RBCs undergoes irreversible disorders. These changes occur, as a rule, after 20–24 days of storage.

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 fifth 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.).

Introduction. Chronic graft versus host disease (GVHD) is a frequently occurring complication after transplantation of allogeneic hematopoietic cells associated with a decrease in the quality of life and long-term administration of immunosuppressive drugs. Extracorporeal photopheresis (ECP) is a second line of therapy after treatment failure with glucocorticoids.

Aim — to evaluate the effects of ECP treatment in patients with glucocorticosteroids (GCS)-refractory, GCS-dependent or GCS -intolerant chronic GVHD.

Materials and methods. 24 patients with GCS-refractory, GCS-dependent or GCS-intolerant chronic GVHD were included in the therapy with ECP. Nine patients had moderate chronic GVHD, and 15 had a severe chronic GVHD. Skin and mucous membranes were the most frequently targeted organs, 21 and 20 of 24 patients respectively, liver damage was detected in 8 patients. The maximum duration of treatment was 33 months (median — 8.5 months). The number of procedures of ECP ranged from 6 to 48 (median — 22).

Results. A response was determined in 23 patients with one patient being excluded from the assessment due to a relapse of acute leukemia. 16 (69.5 %) patients achieved an overall response to ECP treatment. Three patients had complete response and full reduction of immunosuppressive therapy. When assessing organ-specific response, the most notable improvement was observed in the mucous membranes of 17 patients (89.4 %), skin — 17 (85 %), and liver — 7 (75 %). Along with achieving a general overall response, 78.2 % of patients partly reduced or completely canceled immunosuppressive therapy.

Conclusion. ECP is an effective and promising second line treatment method for chronic GVHD in patients with GCS-refractory, GCS-dependent or GCS-intolerant forms.

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by life-threatening conditions.

Aim — an analysis of the life-threatening complications in recipients of allogeneic hematopoietic stem cells (allo-HSCs)

Main findings. From 10 to 50 % of allo-HSC recipients need to be admitted to the intensive care unit (ICU) due to the development of life-threatening complications. The reasons for ICU admission are acute respiratory failure, sepsis, graft-versus-host disease, veno-occlusive disease, thrombotic microangiopathy, cytokine release syndrome, engraftment syndrome, etc. Conditioning regimen, donor type, stem cell source, underlying disease state and patient comorbidity are the risk factors associated with development of life-threatening conditions. The main prognostic factors of unfavorable ICU outcomes in allo-HSC recipients are the severity of multiple organ dysfunction and the need for organ support.

Introduction. Immunomodulatory drugs (IMiDs) are a class of chemical derivatives of thalidomide with numerous immunomodulatory, antiangiogenic, anti-inflammatory, and cytostatic effects in multiple myeloma (MM).

Aim — to highlight the history of the discovery of IMiDs and discuss the molecular mechanisms of their therapeutic activity.

Basic information. In 2010, more than half a century after the German company Chemie Grünenthal began the clinical use of thalidomide, the first understanding of the molecular mechanism of thalidomide and its structural derivatives appeared. Hiroshi Handa and colleagues from the Tokyo Medical University discovered that the drug thalidomide binds to the protein Cereblon (CRBN), a substrate receptor of the CRL4^CRBN E3 ubiquitin ligase. Subsequent generations of immunomodulatory drugs (IMiDs) — lenalidomide and pomalidomide, are structurally like thalidomide. The glutarimide ring of IMiDs is inserted into the receptor pocket of the CRBN. In this case, the variable phthalimide part of the drug protrudes from the binding domain, changing the configuration of the CRBN in such a way that it allows it to interact with proteins (neosubstrates) with which it does not react under physiological conditions. It was later found that ubiquitin-mediated degradation of two transcription factors (Ikaros and Aiolos) underlies the antitumor and immunomodulatory activity of IMiDs, which have shown unique clinical efficacy in the treatment of multiple myeloma. A natural continuation of the success of IMiDs was the creation of a series of therapeutic molecules (Iberdomide, etc.) belonging to a new class of drugs called CELMoDs (Cereblon E3 Ligase Modulating Drugs). The presented literature review is devoted to the history of the discovery of IMiDs and a discussion of the molecular mechanisms of their therapeutic activity.

Introduction. D-dimer is an important indicator, which reflects the activation of intravascular blood coagulation and fibrinolytic system. There are some data confirming that D-dimer is associated with stroke development in patients with atrial fibrillation. However, D-dimer is not included in modern stoke risk stratification scales in patients with atrial fibrillation.

Aim — to analyze the data devoted to the role of D-dimer in stroke risk stratification in patients with atrial fibrillation.

General findings. D-dimer, despite several limitations, could be used in clinical practice as an indicator that is associated with stroke development in patients with atrial fibrillation. D-dimer level estimation could help to decide whether to use anticoagulant treatment in patients with low risk of stroke development or in those patients with a single non-sex CHA₂DS₂-VASc score risk factor.

Introduction. In 2018 emicizumab was approved in Russia for prophylactic treatment in patients with hemophilia A (HA) with inhibitors and in 2019 for patients with severe HA without inhibitors. A significant amount of data has been accumulated from clinical trials and real-world data, which allow us to resolve most of the questions that hematologists may have when to prescribe emicizumab.

Aim — to provide information on the management of patients on emicizumab.

Results. The recommendations accumulated the currently available information and world experience in the management of patients receiving emicizumab in order to facilitate decision-making when prescribing and using emicizumab. Information on the use of emicizumab in patients with HA with FVIII inhibitors and severe HA without FVIII inhibitors is presented. Possible complications and measures for their prevention and treatment are presented.

Introduction. Acquired hemophilia is a rare autoimmune disease caused by an inhibitor to clotting factor VIII (FVIII). It complicates the course of many diseases, in particular autoimmune diseases, and in women is often associated with pregnancy.

Aim — to present a case of successful treatment of a patient with acquired hemophilia using long-term continuous infusion of rFVIIa and inhibitor eradication as a result of immunosuppressive therapy.

Main findings. A clinical observation of severe hemorrhagic syndrome in a patient with acquired hemophilia associated with pregnancy is presented. Uterine bleeding in the patient after spontaneous delivery, refractory to standard hemorrhagic syndrome treatment, required multiple surgical interventions. Laboratory tests showed prolongation of APTT, CT in the INTEM rotational thromboelastometry test, a decrease in plasma FVIII activity and presence of inhibitor to FVIII. Vacuum-assisted closure was applied to treat infected laparotomy wound. Therapy for acquired hemophilia consisted of hemostatic therapy and the inhibitor eradication. Hemostatic therapy included a continuous infusion of rFVIIa at a rate of 30 μg/kg/h with a gradual decrease up to 9.6 μg/kg/h, as well as its fractional administration before every surgery at a dosage of 80 μg/kg. The effectiveness of the therapy was assessed by the dynamics of CT in the INTEM test and the shortening of the APTT. The inhibitor eradication was achieved by prednisolone therapy, combined immunosuppression with rituximab and azathioprine, followed by its replacement with cyclophosphamide. As a result, the hemorrhage was stopped, reference plasma activity of FVIII and eradication of the inhibitor were reached.

Introduction. The period of formation of the donor community in the USSR fell on the 30–40s of the twentieth century. The first measures to organize the donor community were of a spontaneous nature. However, beginning in the 1930’s, with the support of the state and public organizations in the USSR, on the eve of the war, a mass donor community arose based on the ideology of the time and system of motivations.

Aim — to reconstruct the measures of social support for blood donors, which contributed to the formation of the donor community in the USSR and to identify the role of the state in organizing the donor community in the USSR.

Main findings. To conduct the study, a set of methods was used, including the study and generalization of experience based on archival sources, monographic description, and narrative analysis. A number of archival materials are introduced into scientific circulation for the first time. Decrees of the Council of People’s Commissars of the RSFSR, issued in the 30–40s of the 20th century, which formed the basis of the legal framework for organizing social support for donors, are given. This article is devoted to the emergence and development of the donor community in the USSR. A number of measures of social support for blood donors are described, which are characteristic of various stages in the development of the donor community (“attracting and retaining” donors in the 1930s, “survival” of donors at the beginning of the Great Patriotic War, and their “encouragement” at the final stage of the Great Patriotic War). Measures of social support for blood donors, which arose in the pre-war period, proved their effectiveness (attracting about 5.5 million people into the ranks of donors, from whom 1.7 million liters of blood were harvested) during the Great Patriotic War, and with some changes, maintain their relevance today.