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Shibeko A.M.,Center for Theoretical Problems of Physicochemical Pharmacology | Panteleev M.A.,Moscow Institute of Physics and Technology
Briefings in Bioinformatics | Year: 2016

Blood coagulation is a complex biochemical network that plays critical roles in haemostasis (a physiological process that stops bleeding on injury) and thrombosis (pathological vessel occlusion). Both up- and down-regulation of coagulation remain a major challenge for modern medicine, with the ultimate goal to correct haemostasis without causing thrombosis and vice versa. Mathematical/computational modelling is potentially an important tool for understanding blood coagulation disorders and their treatment. It can save a huge amount of time and resources, and provide a valuable alternative or supplement when clinical studies are limited, or not ethical, or technically impossible. This article reviews contemporary state of the art in the modelling of blood coagulation for practical purposes: to reveal the molecular basis of a disease, to understand mechanisms of drug action, to predict pharmacodynamics and drug-drug interactions, to suggest potential drug targets or to improve quality of diagnostics. Different model types and designs used for this are discussed. Functional mechanisms of procoagulant bypassing agents and investigations of coagulation inhibitors were the two particularly popular applications of computational modelling that gave non-trivial results. Yet, like any other tool, modelling has its limitations, mainly determined by insufficient knowledge of the system, uncertainty and unreliability of complex models. We show how to some extent this can be overcome and discuss what can be expected from the mathematical modelling of coagulation in not-so-far future. © The Author 2015. Published by Oxford University Press.

Yakimenko A.O.,HemaCore Hematological Corporation | Verholomova F.Y.,HemaCore Hematological Corporation | Kotova Y.N.,Center for Theoretical Problems of Physicochemical Pharmacology | Ataullakhanov F.I.,Moscow State University | Panteleev M.A.,Moscow State University
Biophysical Journal | Year: 2012

Blood platelets are anucleate cell fragments that play a critically important role in hemostasis and thrombosis. Platelets are activated with various agonists that allow them to aggregate, thus forming either hemostatic plugs or pathologic thrombi. Recent studies have revealed that at least two activated platelet subpopulations are formed upon potent stimulation of platelets with collagen and/or thrombin. One of these subpopulations consists of so-called coated platelets that express high levels of phosphatidylserine and retain α-granule proteins, including fibrinogen, on their surface. They also have reduced levels of the main aggregation receptor-activated glycoprotein IIb-IIIa, which might indicate a defect in their proaggregatory ability. In this study, the proaggregatory abilities of coated and noncoated platelets were assessed by means of light transmission aggregometry of suspensions with varying ratios of platelets from one subpopulation to those of a different subpopulation. A mathematical model of platelet aggregation in heterogeneous mixtures was developed to assist in the analysis of experimental data. Flow cytometry was employed to monitor platelet recruitment into aggregates and the ability of platelets to bind external fibrinogen. Finally, confocal microscopy was used to image coated platelets involved into aggregates formed by mechanical shaking. The obtained data revealed to our knowledge a novel mechanism regulating aggregate formation of platelet subpopulations: coated platelets cannot aggregate with each other but can be recruited into aggregates by noncoated platelets. © 2012 by the Biophysical Society.

Nikulina O.F.,National Research Center for Hematology | Tsvetaeva N.V.,National Research Center for Hematology | Rodionova M.N.,National Research Center for Hematology | Gribkova I.V.,National Research Center for Hematology | And 6 more authors.
International Journal of Hematology | Year: 2014

Sensitive methods for assessment of the hemostatic state are essential for providing adequate therapy to patients with β-thalassemia. The present study was designed to monitor the changes in the hemostatic state of a patient with β-thalassemia at the primary stage and under heparin treatment following splenectomy. The hemostatic state of the patient was assessed using conventional tests (activated partial thromboplastin time, prothrombin index, thrombin time), fibrinogen and D-dimer assays, thromboelastography (TEG), thrombin generation test, and a novel thrombodynamics clot growth assay. Thrombodynamics parameters indicated the hypercoagulation state on the primary evaluation which progressed after splenectomy: stationary clot growth velocity increased from 32 to 38 μm/min (normal range 20-30 μm/min). Hypercoagulation state was confirmed by Doppler echocardiography, which detected portal vein thrombosis on day 23 after surgery. The results of the other tests' parameters were in the normal ranges before splenectomy. The TEG parameters were sensitive to low molecular weight heparin (LMWH) injections; but the values were close to the normal ranges before and after injections. The thrombodynamics assay demonstrated a high sensitivity to LMWH injections, and registered a decrease of the hypercoagulability in the course of therapy (P < 0.05). TGT was not performed during LMWH therapy. This clinical case demonstrates the potential of the thrombodynamics assay to serve as a sensitive method for coagulation system monitoring and prediction of prothrombotic tendencies in patients with hemolytic anemias. © 2014 The Japanese Society of Hematology.

Parunov L.A.,U.S. Food and Drug Administration | Parunov L.A.,LLC Hematological Corporation | Soshitova N.P.,LLC Hematological Corporation | Ovanesov M.V.,U.S. Food and Drug Administration | And 2 more authors.
Birth Defects Research Part C - Embryo Today: Reviews | Year: 2015

This review is focused on the epidemiology of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), associated with pregnancy. Superficial vein thrombosis, a less hazardous and less studied type of thrombosis in pregnant women, is beyond the scope of this review. This study discusses the VTE incidence rate in women from developed countries for both antepartum and postpartum periods and for subpopulations of women affected by additional risk factors, such as thrombophilias, circulatory diseases, preeclampsia of varying degrees of severity, and Caesarean section. To minimize bias due to historical changes in medical and obstetric practices, lifestyle, diet, etc., this review is generally limited to relatively recent studies, i.e., those that cover the last 35 years. The absolute risk or incidence rate was used to ascertain risk of VTE associated with pregnancy. For the studies where the direct incidence rates of VTE were not reported, we calculated an estimate of the observed but not reported absolute incidence rates using the data presented in respective articles. © 2015 Wiley Periodicals, Inc.

Parunov L.A.,Center for Theoretical Problems of Physicochemical Pharmacology | Fadeeva O.A.,National Research Center for Hematology | Balandina A.N.,Center for Theoretical Problems of Physicochemical Pharmacology | Soshitova N.P.,National Research Center for Hematology | And 7 more authors.
Journal of Thrombosis and Haemostasis | Year: 2011

Background:Tissue factor pathway inhibitor (TFPI) is a major regulator of clotting initiation and a promising target for pro- and anticoagulation therapy. The aptamer BAX499 (formerly ARC19499) is a high-affinity specific TFPI antagonist designed to improve hemostasis. However, it is not clear how stimulation of coagulation onset by inactivating TFPI will affect spatial and temporal clot propagation. Objective:To examine the BAX499 effect on clotting in a spatial, reaction-diffusion experimental system in comparison with that of recombinant activated factor VII (rVIIa). Methods: Clotting in plasma activated by immobilized tissue factor (TF) was monitored by videomicroscopy. Results:BAX499 dose-dependently improved coagulation in normal and hemophilia A plasma activated with TF at 2pmolem -2 by shortening lag time and increasing clot size by up to ∼2-fold. The effect was TFPI specific as confirmed by experiments in TFPI-depleted plasma with or without TFPI supplementation. Clotting improvement was half-maximal at 0.7nm of BAX499 and reached a plateau at 10nm, remaining there at concentrations up to 1000nm. The BAX499 effect decreased with TF surface density increase. RVIIa improved clotting in hemophilia A plasma activated with TF at 2 or 20pmolem -2, both by shortening lag time and increasing spatial velocity of clot propagation; its effects were strongly concentration dependent. Conclusions:BAX499 significantly improves spatial coagulation by inhibiting TFPI in a spatially localized manner that is different to that observed with rVIIa. © 2011 International Society on Thrombosis and Haemostasis.

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