Russian Research Institute of Hematology and Transfusiology

BACKGROUND. Despite the considerable progress in the treatment of multiple myeloma (MM), infectious complications remain a challenge and one of the main mortality causes for this category of patients. Even in the post-pandemic period, MM patients are at high risk for COVID-19 infection. AIM. To study the characteristic features of COVID-19 in MM patients and to assess the opportunities for its prevention. MATERIALS & METHODS. The study enrolled 100 MM patients with an experience of COVID-19 treated in the hematological clinic of the Russian Research Institute of Hematology and Transfusiology (Saint Petersburg) from 2020 to 2024. The median age was 67.5 years (range 37–84 years). Patients were stratified into two groups depending on COVID-19 severity: with asymptomatic/mild (n = 72) and severe/extremely severe (n = 28) course of the disease. RESULTS. It appeared that the only significant mortality risk factor was severe COVID-19: the 2-year overall survival of patients with mild vs. severe virus infection was 93 % and 59 %, respectively. Lack of tumor remission (odds ratio [OR] 3.94; 95% confidence interval [95% CI] 1.45–11.05; p = 0.008) and lack of vaccination (OR 3.94; 95% CI 1.18–18.09) were significantly associated with a higher risk of severe COVID-19. Probability of COVID-19 recurrence was 16 % in patients with severe and 22.4 % in patients with mild infection (p = 0.34). Competing death risk was significantly higher in patients with severe infection, i.e., 29.2 % vs. 5 % in patients with mild COVID-19 (p < 0.001). CONCLUSION. Non-vaccinated patients with a relapse or progression of MM are at high risk for severe COVID-19. Long-term survival rates and mortality risk in these patients directly depend on the severity of the infection. No relationship between the severity of COVID-19 and probability of infection recurrence has been revealed.

Introduction . Severe complications of the novel coronavirus infection (COVID-19) include arterial or venous thromboses, which not only complicate the disease course but also increase mortality. The development of hypercoagulability, which precedes the occurrence of thrombosis, is associated with a significant activation of the hemostasis system, as well as the appearance of microparticles in circulation. These microparticles, generated by activated blood cells, enhance the procoagulant orientation of hemostasis. In this regard, assessment of the prognostic value of changes in hemostasis system parameters associated with the progression and outcome of COVID-19 represents a relevant research task. Objective . To identify predictors of adverse outcomes of the novel coronavirus infection based on the assessment of parameters characterizing the state of the hemostasis system. Materials and methods . A total of 163 patients (78 males and 85 females, aged 35–90 years, median age 69 years) were examined during the acute phase of the disease with severe and moderate severity. Depending on the disease outcome, the patients were divided into two groups: the group of survivors (n = 120) and the group of the deceased (n = 43). A study of plasma hemostasis parameters was conducted, including Quick’s prothrombin test, fibrinogen concentration, activated partial thromboplastin time, factor VIII activity, ristocetin cofactor activity, von Willebrand factor content, protein C activity, antithrombin, and free protein S. In addition, the characteristics of microparticles were studied. Statistical processing of the results was performed using the Statistica 12.0 software package. Results . In patients with adverse disease outcomes, a significant decrease in Quick’s prothrombin time (PT) and antithrombin activity was observed, along with an increase in von Willebrand factor activity, D-dimer concentration, and platelet microparticle count. The analysis of sensitivity and specificity of these parameters allowed Quick’s PT less than 70% (sensitivity and specificity were 70% and 74.3%, respectively), D-dimer level more than 800 ng/ml (sensitivity and specificity — 72% and 75.2%, respectively), and platelet MP count more than 3.22% (sensitivity and specificity — 77.8% and 72.7%, respectively) to be considered as threshold values associated with lethal outcome from COVID-19. Conclusions . Based on the conducted ROC analysis, predictive models for the risk of adverse outcomes of COVID-19 associated with changes in hemostasis system parameters were obtained. The parameters of D-dimer concentration, Quick’s prothrombin time, and platelet microparticle count can be used as laboratory predictors of unfavorable disease progression.

Immune checkpoints (ICs) represent a broad set of stimulatory and inhibitory signaling pathways playing an important role in regulation of immune responses. Initially, ICs have been considered solely as cell membrane-bound receptor and ligand systems, triggering or blocking immune cell function. Over the past decade they have been proven to exist in soluble forms (sICs). sICs are biologically active regulators involved in paracrine and systemic modulation of immune responses, similar to cytokines. Normally, sICs exert both stimulatory and inhibitory effects on the immune system, and their balance may be disturbed in many malignant neoplasms, COVID-19, HIV infection. There is a lot of data on the connection between sICs and various diseases, but a number of key aspects of their biology have not been fully clarified. The most widely studied are PD-1 (programmed death receptor-1) and its ligands PD-L1 and PD-L2, CTLA-4 (cytotoxic T lymphocyte antigen-4), TIM-3 (T cell immunoglobulin and mucin-domain containing-3), VISTA (V-domain Ig-containing suppressor of T cell activation). The mechanisms of soluble form formation are complex and diverse and include alternative splicing, cleavage of membrane ectodomains, and proteolytic cleavage. The most important molecular mechanisms underlying the synthesis and release of sPD-1 and sPD-L1 are alternative splicing of mRNA and translation of isoforms lacking transmembrane domains, while the formation of sTIM-3 occurs by cleaving the extracellular regions of transmembrane proteins by protease ADAM10. The review article provides data on the main sICs, including sPD-1, sPD-L1, exosomal sPD-L1, sCTLA-4, and several others. The molecular mechanisms of their formation, biological functions in maintaining immune homeostasis, prognostic significance of changes in their content are described in patients with solid malignant tumors (nonsmall cell lung cancer, hepatocellular cancer, breast cancer, kidney cancer, skin cancer, gastric cancer, etc.), as well as for hematologic malignancies (lymphoma, chronic lymphocytic leukemia, acute myeloblastic leukemia, multiple myeloma).

Introduction. Due to the increased requirement for platelet concentrate use in the treatment and prevention of thrombocytopathy, there is a pressing need for the development, improvement and implementation of new approaches to monitoring its quality parameters and safety assessment.Objective. To conduct a systematic review and analysis of literature data, in order to identify promising approaches to evaluating an adequate analysis of the quality of platelet concentrate to improve the effectiveness and safety of transfusions.Discussion. The possibilities and advantages of a rational approach to platelet concentrate transfusion are established, while considering the degree of platelet activation required to optimize the preparation of the component. Special attention was paid to methods for evaluating platelet activation. The detection of microparticles based on dynamic light scattering will make it possible to distinguish activated platelets (with a high content of microparticles) from inactive (with a low content of microparticles) platelets during both therapeutic and preventive transfusions and optimize the use of this scarce blood component.Conclusions. The ability to differentiate platelet concentrates based on the screening of the content of microparticles formed due to activation will contribute to improving the effectiveness and safety of transfusion therapy.

Aim. To evaluate the effect of ruxolitinib therapy on hemostasis in patients with primary myelofibrosis (PMF).Materials and methods. 30 patients with PMF were examined, 16 of them received ruxolitinib (group 1) at the time of examination and 14 were untreated (group 2). The control group consisted of 30 healthy individuals. A complete blood count was performed, the platelets aggregation, the activity of Willebrand factor, factor VIII and natural anticoagulants were evaluated. In the thrombin generation test, the endogenous thrombin potential (ETP, nM×min) was determined; sensitivity to thrombomodulin and coagulation index were calculated. Kruskal-Wallis test with post hoc Dunn test was used to compare groups.Results. Hemoglobin and platelet count were lower in group 1 compared to group 2 and control. Platelet aggregation with collagen was lower in patients with PMF than in the control group, and lower in group 1 than in group 2: 2.2 (1.6; 5.7) % vs 41.6 (3.4; 64.8) %, p < 0.05. In patients in group 1, the activity of Willebrand factor – 150.0 (122.5; 195) % and factor VIII – 173 (148.5; 200) % was higher (p < 0.05) than in the control: 97 (84.8; 110) % and 104 (85; 130) % respectively. Antithrombin did not differ in the PMF and control group. Protein S was reduced in both groups with PMF: group 1 – 70 (58; 86,6) %, group 2 – 65 (43,6; 107,5) %, control – 102 (86; 109,0) %, p < 0.001. ETP and sensitivity to thrombomodulin in groups 1 and 2 were low, p < 0.001. The coagulation index tended to higher values than in the control: 5.3 (3.0; 11.4) – group 1; 3.2 (2.4; 7.3) – group 2; control – 1.9 (1.6; 2.2), p = 0.073.Conclusion. Ruxolitinib therapy leads to the failure of the platelet hemostasis, the procoagulant activity of plasma with an increase in the activity of Willebrand factor and factor VIII and a decrease in the activity of protein S.