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

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

Tubulin bond energies and microtubule biomechanics determined from nanoindentation in silico

Microtubules, the primary components of the chromosome segregation machinery, are stabilized by longitudinal and lateral non-covalent bonds between the tubulin subunits. However, the thermodynamics of these bonds and the microtubule physico-chemical properties are poorly understood. Here, we explore the biomechanics of microtubule polymers using multiscale computational modeling and nanoindentations in silico of a contiguous microtubule fragment. A close match between the simulated and experimental force-deformation spectra enabled us to correlate the microtubule biomechanics with dynamic structural transitions at the nanoscale. Our mechanical testing revealed that the compressed MT behaves as a system of rigid elements interconnected through a network of lateral and longitudinal elastic bonds. The initial regime of continuous elastic deformation of the microtubule is followed by the transition regime, during which the microtubule lattice undergoes discrete structural changes, which include first the reversible dissociation of lateral bonds followed by irreversible dissociation of the longitudinal bonds. We have determined the free energies of dissociation of the lateral (6.9+/-0.4 kcal/mol) and longitudinal (14.9+/-1.5 kcal/mol) tubulin-tubulin bonds. These values in conjunction with the large flexural rigidity of tubulin protofilaments obtained (18,000-26,000 pN*nm^2), support the idea that the disassembling microtubule is capable of generating a large mechanical force to move chromosomes during cell division. Our computational modeling offers a comprehensive quantitative platform to link molecular tubulin characteristics with the physiological behavior of microtubules. The developed in silico nanoindentation method provides a powerful tool for the exploration of biomechanical properties of other cytoskeletal and multiprotein assemblie

Ring coupler moving via the 'forced walk' mechanism [Microtubule depolymerization as a biological machine]

This video shows the microtubule-depolymerization dependent motions of a ring coupler. Although the plane of the ring oscillates slightly, it remains motionlessly on the microtubule wall until the shortening end comes by (thermal energy is not sufficient to cause Brownian 'random walks' with any appreciable frequency). Bending protofilaments, however, can push on the linkers, forcing the ring to walk in front of the protofilaments' flare. This directed motion is highly deterministic, but the exact pathway of the ring's transitions between successive minimum energy configurations is stochastic and varies in repeated calculations. A strongly bound ring retards the rate with which the protofilaments bend, so it slows the rate of microtubule shortening. Furthermore, such tight binding reduces the useful work that can be performed by the microtubule, e.g. in moving a cargo, but it ensures a stable ring's attachment to the microtubule end, even if the flared protofilaments shorten or the microtubule begins to polymerize. It has been therefore suggested that a reasonable compromise between a reduced efficiency of force transduction and an increased strength of attachment might be appropriate for the coupler in an organism like S. cerevisiae, where a kinetochore is stably attached to only one microtubule and the chromosomes do not move far during Anaphase AComponente Curricular::Educação Superior::Ciências Biológicas::Morfologi

Finite platelet size could be responsible for the platelet margination effect

International audienceBlood 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

Ring coupler moving via the 'forced walk' mechanism [Microtubule depolymerization as a biological machine]

This video shows the microtubule-depolymerization dependent motions of a ring coupler. Although the plane of the ring oscillates slightly, it remains motionlessly on the microtubule wall until the shortening end comes by (thermal energy is not sufficient to cause Brownian 'random walks' with any appreciable frequency). Bending protofilaments, however, can push on the linkers, forcing the ring to walk in front of the protofilaments' flare. This directed motion is highly deterministic, but the exact pathway of the ring's transitions between successive minimum energy configurations is stochastic and varies in repeated calculations. A strongly bound ring retards the rate with which the protofilaments bend, so it slows the rate of microtubule shortening. Furthermore, such tight binding reduces the useful work that can be performed by the microtubule, e.g. in moving a cargo, but it ensures a stable ring's attachment to the microtubule end, even if the flared protofilaments shorten or the microtubule begins to polymerize. It has been therefore suggested that a reasonable compromise between a reduced efficiency of force transduction and an increased strength of attachment might be appropriate for the coupler in an organism like S. cerevisiae, where a kinetochore is stably attached to only one microtubule and the chromosomes do not move far during Anaphase AComponente Curricular::Educação Superior::Ciências Biológicas::Morfologi