Threshold of microvascular occlusion: injury size defines the thrombosis scenario

Damage to the blood vessel triggers formation of a hemostatic plug, which is meant to prevent bleeding, yet the same phenomenon may result in a total blockade of a blood vessel by a thrombus, causing severe medical conditions. Here, we show that the physical interplay between platelet adhesion and hemodynamics in a microchannel manifests in a critical threshold behavior of a growing thrombus. Depending on the size of injury, two distinct dynamic pathways of thrombosis were found: the formation of a nonocclusive plug, if injury length does not exceed the critical value, and the total occlusion of the vessel by the thrombus otherwise. We develop a mathematical model that demonstrates that switching between these regimes occurs as a result of a saddle-node bifurcation. Our study reveals the mechanism of self-regulation of thrombosis in blood microvessels and explains experimentally observed distinctions between thrombi of different physical etiology. This also can be useful for the design of platelet-aggregation-inspired engineering solutions.Comment: 7 pages, 5 figures + Supplementary informatio

Modelling of platelet–fibrin clot formation in flow with a DPD–PDE method

International audienceThe paper is devoted to mathematical modelling of clot growth in bloodflow. Great complexity of the hemostatic system dictates the need of usage of themathematical models to understand its functioning in the normal and especially inpathological situations. In this work we investigate the interaction of blood flow,platelet aggregation and plasma coagulation. We develop a hybrid DPD–PDE modelwhere dissipative particle dynamics (DPD) is used to model plasma flow and platelets,while the regulatory network of plasma coagulation is described by a system of partialdifferential equations. Modelling results confirm the potency of the scenario of clotgrowth where at the first stage of clot formation platelets form an aggregate due toweak inter-platelet connections and then due to their activation. This enables the formationof the fibrin net in the centre of the platelet aggregate where the flow velocity issignificantly reduced. The fibrin net reinforces the clot and allows its further growth.When the clot becomes sufficiently large, it stops growing due to the narrowed vesseland the increase of flow shear rate at the surface of the clot. Its outer part is detachedby the flow revealing the inner part covered by fibrin. This fibrin cap does not allownew platelets to attach at the high shear rate, and the clot stops growing. Dependenceof the final clot size on wall shear rate and on other parameters is studied

Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>This mechanism explains the difference between red and white thrombi observed <it>in vivo </it>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.</p

The role of platelets in blood coagulation during thrombus formation in flow

Hemostatic plug covering the injury site (or a thrombus in the pathological case) is formed due to the complex interaction of aggregating platelets with biochemical reactions in plasma that participate in blood coagulation. The mechanisms that control clot growth and which lead to growth arrest are not yet completely understood. We model them with numerical simulations based on a hybrid DPD-PDE model. Dissipative particle dynamics (DPD) is used to model plasma flow with platelets while fibrin concentration is described by a simplified reaction-diffusion-convection equation. The model takes into account consecutive stages of clot growth. First, a platelet is weakly connected to the clot and after some time this connection becomes stronger due to other surface receptors involved in platelet adhesion. At the same time, the fibrin network is formed inside the clot. This becomes possible because flow does not penetrate the clot and cannot wash out the reactants participating in blood coagulation. Platelets covered by the fibrin network cannot attach new platelets. Modelling shows that the growth of a hemostatic plug can stop as a result of its exterior part being removed by the flow thus exposing its non-adhesive core to the flow

Reducing Electric Power Losses in the System of Power Supply Due to Compensation of Higher Harmonics of Currents: Economic and Energy Efficiency Outcomes

The issue of increasing energy efficiency and energy saving is of great importance for the countries with high energy intensity of the gross domestic product, including Russia and the rest of the Commonwealth of Independent States. The measures adopted in Russia on the federal and regional level as part of the State Program on Energy Efficiency and Energy Development are focused on reducing the energy intensity of Russia's gross domestic product and introduce sustainable practices on energy saving in Russia's commercial and budget sectors. This paper presents a case study describing the way to reduce electric power losses in a system of power supply (SPS) of an industrial enterprise. In particular, the case study determines the level of the higher harmonic components of current and voltage at the existing enterprise for the production of reinforced concrete products. The results of the experiment were reproduced using a simulation model of the power supply system in the Matlab/Simulink package. A comparative analysis of using a passive and hybrid filter compensating device to reduce the level of the higher harmonics of current and voltage was carried out by means of modeling. The active losses in the SPS from non-sinusoidal mode are calculated. In addition, the economic effect of using the proposed method is estimated. Keywords: Energy Efficiency, Industry, Electric Power Losses, Higher Harmonics of Currents JEL Classifications: Q29, Q49, L94 DOI: https://doi.org/10.32479/ijeep.769

Avifauna at the Neolithic Sites of the Dnieper-Dvina Basin: the role of birds in the culture of ancient hunter-gatherers of the VI–III Millennium BC

The article presents a study of avifauna at the Neolithic sites of the Dnieper-Dvina basin (Serteya I and II sites). Changes of paleo-environmental conditions and biotopes, archaeological cultures and types of campsites might have determined changes in the cultural and economic model of the ancient population, having an influence on avifauna particularity in different time periods. Four biotopic groups of birds: near-water birds, woodside birds, forest and meadow-steppe birds are singled out. Birds from the near-water group dominate. It can be assumed, that birds played an important role in food ration in spring and autumn. Paleo-ecological studies allow us to reconstruct a change of water body types. That may have caused a change in bird species. Changes in bird nesting and migration areas may also be evidence of paleo-ecological changes in the V–III millennium BC. Despite the widespread practice of making tools and ornaments from bones and animals teeth at the Neolithic sites in Dnieper-Dvina basin, bird bones were used rather seldom. Almost the entire collection dates back to the end of IV–III millennium BC and is represented mainly by tube beads and blanks

Human and birds

The paper presents the study of avifauna from the hunter-gatherer sites at the Dnieper-Dvina basin spanning time period from the 6th to 3rd millennia BC. A total of 669 bird bones were identified and attributed to 46 different bird taxa, representing resident and migrant birds. They belong to four habitat groups: waterfowl, forest, woodside and meadow-steppe. The dominance of waterfowl birds follows the common strategy of aquatic resources exploitation. Changes in the procurement strategies, use and symbolic meanings of birds can be envisaged. Reconstructed regional mean temperature fluctuations suggest a particular influence on breeding biology and migration patterns of different species

Control of platelet CLEC-2-mediated activation by receptor clustering and tyrosine kinase signalling

Platelets are blood cells responsible for vascular integrity preservation. The activation of platelet receptor CLEC-2 could partially mediate the latter function. Although this receptor is considered to be of importance for hemostasis, the rate-limiting steps of CLEC-2 induced platelet activation are not clear. Here we aimed to investigate CLEC-2-induced platelet signal transduction using computational modelling in combination with experimental approaches. We developed a stochastic multicompartmental computational model of CLEC-2 signalling. The model described platelet activation beginning with CLEC-2 receptor clustering, followed by Syk and SFK phosphorylation, determined by the cluster size. Active Syk mediated LAT protein phosphorylation and membrane signalosome formation, which resulted in the activation of Btk, PLC and PI3K, calcium and phosphoinositide signalling. The model parameters were assessed from published experimental data. Flow cytometry, TIRF and confocal microscopy and western blotting quantification of the protein phosphorylation were used for the assessment of the experimental dynamics of CLEC-2-induced platelet activation. Analysis of the model revealed that the CLEC-2 receptor clustering leading to the membrane-based signalosome formation is a critical element required for the accurate description of the experimental data. Both receptor clustering and signalosome formation are among the rate-limiting steps of CLEC-2-mediated platelet activation. In agreement with these predictions, the CLEC-2 induced platelet activation, but not activation mediated by G-protein coupled receptors, was strongly dependent on temperature conditions and cholesterol depletion. Besides, the model predicted that CLEC-2 induced platelet activation results in cytosolic calcium spiking, which was confirmed by single platelet TIRF microscopy imaging. Our results suggest a refined picture of the platelet signal transduction network associated with CLEC-2. We show that the tyrosine kinases activation is not the only rate-limiting step in CLEC-2 induced activation of platelets. Translocation of receptor-agonist complexes to the signalling region and LAT-signalosome formation in this region are limiting CLEC-2-induced activation as well

On Propagation of Excitation Waves in Moving Media: The FitzHugh-Nagumo Model

BACKGROUND: Existence of flows and convection is an essential and integral feature of many excitable media with wave propagation modes, such as blood coagulation or bioreactors. METHODS/RESULTS: Here, propagation of two-dimensional waves is studied in parabolic channel flow of excitable medium of the FitzHugh-Nagumo type. Even if the stream velocity is hundreds of times higher that the wave velocity in motionless medium (), steady propagation of an excitation wave is eventually established. At high stream velocities, the wave does not span the channel from wall to wall, forming isolated excited regions, which we called "restrictons". They are especially easy to observe when the model parameters are close to critical ones, at which waves disappear in still medium. In the subcritical region of parameters, a sufficiently fast stream can result in the survival of excitation moving, as a rule, in the form of "restrictons". For downstream excitation waves, the axial portion of the channel is the most important one in determining their behavior. For upstream waves, the most important region of the channel is the near-wall boundary layers. The roles of transversal diffusion, and of approximate similarity with respect to stream velocity are discussed. CONCLUSIONS: These findings clarify mechanisms of wave propagation and survival in flow