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Mechanisms of regulation of the hemostatic system

Federal Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, National Research Center for Hematology (Ministry of Health and Social Development of Russian Federation, Moscow). Alexey Tokarev, PhD. Mechanisms of regulation of the hemostatic system.

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Mechanisms of regulation of the hemostatic system

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  1. Federal Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, National Research Center for Hematology (Ministry of Health and Social Development of Russian Federation, Moscow) Alexey Tokarev, PhD Mechanisms of regulation of the hemostatic system Platelet functioning (adhesion, activation, aggregation) – cell hemostasis Blood clotting – plasma hemostasis Blood flow – carrier Hemostatic plug (health) and thrombus (disease) formation 1/3

  2. Platelet cross-flow distribution Plug/ thrombus growth Blood flow Modeling approach: • Eulerian (PDEs) Tokarev et al., Biophys. J., 2011b Falati et al (2002) Platelet adhesion platelets fibrin Tokarev et al. 2012. Rus. J Num. Anal. Math. Model. platelets+fibrin • Lagrangian (particles) • Platelet activation, secretion, aggregation Tokarev et al., Biophys. J., 2011a wall wall Plasma clotting Ohlmann (2000) Fibrin mesh. SEM made by Jean-Claude Bordet (France). Tosenberger et al. 2012. Rus. J Num. Anal. Math. Model. • Some general questions: • Biological: how plug/thrombus growth stops? Can this stopping result from the interaction between platelet and plasma subsystems? • Methodological: How to mathematically model this complex system in a biology-adequate way? How to deal with platelet activation/signalling? How to connect intra-platelet signalling (detailed model of platelet activation) and changes in platelet properties (simple model of platelet activation)? 2/3

  3. Plasma clotting in non-stirring and slow-flow conditions Reaction-diffusion PDEs (no flow) Reaction-diffusion-convection PDEs Boundary of fibrin clot (flow-resistant) Slow flow Thrombin concentration wave Injury • Some general questions: • What is the mechanism of clotting propagation and stopping? • How can we properly reduce the dimension of the large system of coupled PDEs (~30 eqs. down to 2-3 eqs.)? Dashkevich et al. Thrombin propagates in space during blood coagulation as a traveling wave: a new biological excitable medium. Submitted to PNAS. 3/3

  4. Additional slides

  5. Strong non-uniform platelet distribution across blood flowgenerally arises due to the finiteness of platelet own size Platelet Erythrocyte Excluded volume wall wall Tokarev et al., Biophys. J., 2011, 101 (8): 1835-1843.

  6. Platelet adhesion from blood flow is controlled by near-wall rebounding collisions with erythrocytes Convection + shear-induced diffusion Platelet activation time = const Pushing out by RBC Translocation/activation Detachment Capture Firm adhesion Tokarev et al., Biophys. J., 2011, 100 (4): 799-808.

  7. Platelet activation - pathways

  8. Platelet activation – phenomenological behaviour

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