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Vlasova O.,Moscow State University | Urnova E.,National Research Center for Hematology | Margolin O.,National Research Center for Hematology | Soloveva A.,National Research Center for Hematology | And 4 more authors.
PLoS ONE | Year: 2014

Background and Objective: Using an in vitro experimental model of immobilized tissue factor-initiated clot growth in platelet-free plasma (thrombodynamics), we observed formation of activator-independent isolated spontaneous clots (SC) throughout the plasma volume in patients with cardiac infarction, acute leukemia, hemolytic anemia, and some other disorders. The aim of this work was to characterize this phenomenon and to identify the mechanisms of SC formation. Methods and Results: Tissue factor inhibitor (VIIai) prevented SC in only 2 out of 23 patient plasma samples. Specific inhibitors of factors IXa and XIa were efficient in all 8 cases that we tested. Also, only factors IXa and XIa added to normal donors' plasma induced SC formations from isolated centers, in a pattern similar to that in patients' plasma. In contrast, factors VIIa, Va, tissue factor induced uniform plasma clotting. SC disappeared after high-speed centrifugation. However, phospholipid supplementation of centrifuged plasma returned them at least partially in 5 out of 22 patients' plasmas, indicating some other role of microparticles than providing phospholipid surface. Circulating procoagulant microparticles isolated from plasma directly activated factor XII in buffer and in diluted plasma. Flow cytometry revealed an increase in procoagulant microparticles in patients' plasmas with SC. Conclusion: Our data suggest that combination of circulating active factors (specifically, factors IXa and XIa) with circulating procoagulant and contact-pathway-activating microparticles is the predominant mechanism causing spontaneous clotting in patient plasma. © 2014 Lipets et al.


Averbuch D.,Hebrew University of Jerusalem | Orasch C.,University of Lausanne | Cordonnier C.,University Paris Est Creteil | Livermore D.M.,University of East Anglia | And 10 more authors.
Haematologica | Year: 2013

Owing to increasing resistance and the limited arsenal of new antibiotics, especially against Gram-negative pathogens, carefully designed antibiotic regimens are obligatory for febrile neutropenic patients, along with effective infection control. The Expert Group of the 4th European Conference on Infections in Leukemia has developed guidelines for initial empirical therapy in febrile neutropenic patients, based on: i) the local resistance epidemiology; and ii) the patient's risk factors for resistant bacteria and for a complicated clinical course. An 'escalation' approach, avoiding empirical carbapenems and combinations, should be employed in patients without particular risk factors. A 'deescalation' approach, with initial broad-spectrum antibiotics or combinations, should be used only in those patients with: i) known prior colonization or infection with resistant pathogens; or ii) complicated presentation; or iii) in centers where resistant pathogens are prevalent at the onset of febrile neutropenia. In the latter case, infection control and antibiotic stewardship also need urgent review. Modification of the initial regimen at 72-96 h should be based on the patient's clinical course and the microbiological results. Discontinuation of antibiotics after 72 h or later should be considered in neutropenic patients with fever of unknown origin who are hemodynamically stable since presentation and afebrile for at least 48 h, irrespective of neutrophil count and expected duration of neutropenia. This strategy aims to minimize the collateral damage associated with antibiotic overuse, and the further selection of resistance. © 2013 Ferrata Storti Foundation.


Tokarev A.A.,National Research Center for Hematology | Butylin A.A.,Moscow State University | Ermakova E.A.,RAS Semenov Institute of Chemical Physics | Shnol E.E.,Russian Academy of Sciences | And 2 more authors.
Biophysical Journal | Year: 2011

Blood flows through vessels as a segregated suspension. Erythrocytes distribute closer to the vessel axis, whereas platelets accumulate near vessel walls. Directed platelet migration to the vessel walls promotes their hemostatic function. The mechanisms underlying this migration remain poorly understood, although various hypotheses have been proposed to explain this phenomenon (e.g., the available volume model and the drift-flux model). To study this issue, we constructed a mathematical model that predicts the platelet distribution profile across the flow in the presence of erythrocytes. This model considers platelet and erythrocyte dimensions and assumes an even platelet distribution between erythrocytes. The model predictions agree with available experimental data for near-wall layer margination using platelets and platelet-modeling particles and the lateral migration rate for these particles. Our analysis shows that the strong expulsion of the platelets from the core to the periphery of the blood vessel may mainly arise from the finite size of the platelets, which impedes their positioning in between the densely packed erythrocytes in the core. This result provides what we believe is a new insight into the rheological control of platelet hemostasis by erythrocytes. © 2011 Biophysical Society.


Korendyaseva T.K.,National Research Center for Hematology | Martinov M.V.,National Research Center for Hematology | Dudchenko A.M.,Institute of General Pathology and Pathophysiology | Vitvitsky V.M.,National Research Center for Hematology
Amino Acids | Year: 2010

Methionine is an essential amino acid involved in many significant intracellular processes. Aberrations in methionine metabolism are associated with a number of complex pathologies. Liver plays a key role in regulation of blood methionine level. Investigation of methionine distribution between hepatocytes and medium is crucial for understanding the mechanisms of this regulation. For the first time, we analyzed the distribution of methionine between hepatocytes and incubation medium using direct measurements of methionine concentrations. Our results revealed a fast and reversible transport of methionine through the cell membrane that provides almost uniform distribution of methionine between hepatocytes and incubation medium. The steady-state ratio between intracellular and extracellular methionine concentrations was established within a few minutes. This ratio was found to be 1.06 ± 0.38, 0.89 ± 0.26, 0.67 ± 0.16 and 0.82 ± 0.06 at methionine concentrations in the medium of 64 ± 19, 152 ± 39, 413 ± 55, and 1,204 ± 104 μmol/L, respectively. The fast and uniform distribution of methionine between hepatocytes and extracellular compartments provides a possibility for effective regulation of blood methionine levels due to methionine metabolism in hepatocytes. © 2010 Springer-Verlag.


Vitvitsky V.,University of Michigan | Vitvitsky V.,National Research Center for Hematology | Martinov M.,National Research Center for Hematology | Ataullakhanov F.,Moscow State University | And 2 more authors.
Mechanisms of Ageing and Development | Year: 2013

Changes in sulfur-based redox metabolite profiles in multiple tissues of long-lived Snell dwarf mice were compared with age- and sex-matched controls. Plasma methionine and its oxidation products, hypotaurine and taurine, were increased in Snell dwarfs while cystine and glutathione levels were decreased, leading to an oxidative shift in the redox potential. Sexual dimorphism in renal cystathionine β-synthase (CBS) activity was observed in control mice but not in Snell dwarfs. Instead, female Snell mice exhibited ~2-fold higher CBS activity, comparable to levels seen in male Snell dwarf and in control mice. Taurine levels were significantly higher in kidney and brain of Snell dwarf versus control mice. Methionine adenosyltransferase (MAT) was higher in liver of Snell dwarfs, and the higher concentration of its product, S-adenosylmethionine, was correlated with elevated global DNA methylation status. Application of a mathematical model for methionine metabolism revealed that the metabolite perturbations in Snell dwarfs could be explained by decreased methionine transport, increased MAT and increased methyltransferase activity. Our study provides a comprehensive map of systemic differences in the sulfur network between Snell dwarfs and controls, providing the necessary foundation for assessment of nutrition-linked metabolic status in long-lived versus control animals. © 2013 Elsevier Ireland Ltd.


Biderman B.V.,National Research Center for Hematology | Yakutik I.A.,National Research Center for Hematology | Khamaganova E.G.,National Research Center for Hematology | Kuzmina L.A.,National Research Center for Hematology | Savchenko V.G.,National Research Center for Hematology
Tissue Antigens | Year: 2015

HLA-C*12:138 differs from HLA-C*12:03:01:01 by a single change, resulting in an amino acid substitution. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Gladkikh A.,National Research Center for Hematology | Potashnikova D.,National Research Center for Hematology | Korneva E.,National Research Center for Hematology | Khudoleeva O.,National Research Center for Hematology | Vorobjev I.,National Research Center for Hematology
Experimental Hematology | Year: 2010

Objective: Cyclin D1, an important component of cell cycle machinery and a protein with known oncogenic potential, is downregulated in normal mature B lymphocytes. Its expression detected in a number of malignancies, including B-cell lymphomas, may be important for oncogenesis. Materials and Methods: In our work, we determined the level of cyclin D1 expression in various B-cell lymphomas (i.e., mantle cell lymphoma, B-cell chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and compared it with normal B cells. For cyclin D1 level evaluation, the real-time quantitative polymerase chain reaction data was normalized. We tested five reference genes for stability on our sample set and using the three most stable ones (YWHAZ, ubiquitin c, and HPRT) obtained rather small intra-group variance for cyclin D1 expression in most lymphomas. This allowed their statistically significant ranking according to cyclin D1 expression level. Results: Median values of normalized cyclin D1 expression determined by real-time quantitative polymerase chain reaction were 1.32 for mantle cell lymphoma, 0.02 for B-cell chronic lymphocytic leukemia, 0.009 for diffuse large B-cell lymphoma, 0.004 for marginal zone lymphoma, 0.002 for follicular lymphoma compared with 0.0003 for reactive lymphoid tissue, and 0.00004 for sorted B cells of healthy donors. Conclusions: Our data demonstrate that mantle cell lymphoma, a lymphoma with t(11;14)(q13;q32) translocation, has the level of cyclin D1 increased by four orders of magnitude, while other B-cell lymphomas without t(11;14)(q13;q32) translocation still have the level of cyclin D1 significantly elevated above that of normal lymphocytes (2 orders for B-cell chronic lymphocytic leukemia and an order for other lymphomas) and suggests more than one method of its upregulation in malignant B cells. © 2010 ISEH - Society for Hematology and Stem Cells.


Libiad M.,University of Michigan | Yadav P.K.,University of Michigan | Vitvitsky V.,University of Michigan | Martinov M.,National Research Center for Hematology | Banerjee R.,University of Michigan
Journal of Biological Chemistry | Year: 2014

Sulfide oxidation is expected to play an important role in cellular switching between low steady-state intracellular hydrogen sulfide levels and the higher concentrations where the physiological effects are elicited. Yet despite its significance, fundamental questions regarding how the sulfide oxidation pathway is wired remain unanswered, and competing proposals exist that diverge at the very first step catalyzed by sulfide quinone oxidoreductase (SQR). We demonstrate that, in addition to sulfite, glutathione functions as a persulfide acceptor for human SQR and that rhodanese preferentially synthesizes rather than utilizes thiosulfate. The kinetic behavior of these enzymes provides compelling evidence for the flow of sulfide via SQR to glutathione persulfide, which is then partitioned to thiosulfate or sulfite. Kinetic simulations at physiologically relevant metabolite concentrations provide additional support for the organizational logic of the sulfide oxidation pathway in which glutathione persulfide is the first intermediate formed. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Tarandovskiy I.D.,Center for Theoretical Problems of Physicochemical Pharmacology | Balandina A.N.,Center for Theoretical Problems of Physicochemical Pharmacology | Kopylov K.G.,National Research Center for Hematology | Konyashina N.I.,National Research Center for Hematology | And 3 more authors.
Thrombosis Research | Year: 2013

Background Hemophilia A (HA) patients with similar factor VIII levels can demonstrate varying bleeding tendencies. In particular, 10-15% of all severe HA patients (FVIII:C < 1 IU dL-1) do not require regular replacement therapy. Modern global coagulation assays can help to detect and study this "mild" bleeding phenotype. Here, we investigated the coagulation status of different bleeding phenotypes using various types of global coagulation assays. Materials and Methods Ten HA patients with severe phenotype and eleven patients with mild phenotypes were included in the study. For each patient, thromboelastography (TE), thrombodynamics (TD), and kaolin- or tissue factor-induced thrombin generation (TG) were measured. TG in platelet-rich plasma (PRP) was investigated using our original modification when the thrombin generation curve showed two peaks, previously shown to depend on platelet activity. We also utilized TG and TD with the addition of thrombomodulin. Results The second peak amplitude and ETP of PRP TG were the only parameters that were significantly higher in mild bleeders (peak 41.6 ± 3.5 nM, ETP 1966 ± 169 nM*min) than in patients with severe bleeding (peak 28.3 ± 3.3 nM, ETP 1359 ± 130 nM*min). Conclusions Our results suggest that severe and mild HA phenotypes could be distiguished by TG assay in PRP suggesting that difference in platelet activity can be involved in the phenotype formation. According to our previous results we can suppose that the mechanism of the phenotypic heterogeneity is linked with TG mediated by PS-expressing platelets. © 2013 Elsevier Ltd.


Shibeko A.M.,National Research Center for Hematology | Lobanova E.S.,Duke University | Panteleev M.A.,National Research Center for Hematology | Ataullakhanov F.I.,Moscow State University
BMC Systems Biology | Year: 2010

Background: Blood coagulation is a complex network of biochemical reactions, which is peculiar in that it is time- and space-dependent, and has to function in the presence of rapid flow. Recent experimental reports suggest that flow plays a significant role in its regulation. The objective of this study was to use systems biology techniques to investigate this regulation and to identify mechanisms creating a flow-dependent switch in the coagulation onset.Results: Using a detailed mechanism-driven model of tissue factor (TF)-initiated thrombus formation in a two-dimensional channel we demonstrate that blood flow can regulate clotting onset in the model in a threshold-like manner, in agreement with existing experimental evidence. Sensitivity analysis reveals that this is achieved due to a combination of the positive feedback of TF-bound factor VII activation by activated factor X (Xa) and effective removal of factor Xa by flow from the activating patch depriving the feedback of "ignition". The level of this trigger (i.e. coagulation sensitivity to flow) is controlled by the activity of tissue factor pathway inhibitor.Conclusions: This mechanism explains the difference between red and white thrombi observed in vivo at different shear rates. It can be speculated that this is a special switch protecting vascular system from uncontrolled formation and spreading of active coagulation factors in vessels with rapidly flowing blood. © 2010 Shibeko et al; licensee BioMed Central Ltd.

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