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Open accessJournal ArticleDOI: 10.1016/J.JBIOMECH.2021.110349

Mechanobiology of shear-induced platelet aggregation leading to occlusive arterial thrombosis: A multiscale in silico analysis

02 Mar 2021-Journal of Biomechanics (Elsevier)-Vol. 120, pp 110349
Abstract: Occlusive thrombosis in arteries causes heart attacks and strokes. The rapid growth of thrombus at elevated shear rates (~10,000 1/s) relies on shear-induced platelet aggregation (SIPA) thought to come about from the entanglement of von Willebrand factor (VWF) molecules. The mechanism for SIPA is not yet understood in terms of cell- and molecule-level dynamics in fast flowing bloodstreams. Towards this end, we develop a multiscale computational model to recreate SIPA in silico, where the suspension dynamics and interactions of individual platelets and VWF multimers are resolved directly. The platelet-VWF interaction via GP1b-A1 bonds is prescribed with intrinsic binding rates theoretically derived and informed by single-molecule measurements. The model is validated against existing microfluidic SIPA experiments, showing good agreement with the in vitro observations in terms of the morphology, traveling distance and capture time of the platelet aggregates. Particularly, the capture of aggregates can occur in a few milliseconds, comparable to the platelet transit time through pathologic arterial stenotic sections and much shorter than the time for shear-induced platelet activation. The multiscale SIPA simulator provides a cross-scale tool for exploring the biophysical mechanisms of SIPA in silico that are difficult to access with single-molecule measurements or micro-/macro-fluidic assays only.

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Topics: Platelet activation (59%)
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6 results found


Open accessJournal ArticleDOI: 10.1007/S10439-021-02845-5
Abstract: von Willebrand Factor is a mechano-sensitive protein circulating in blood that mediates platelet adhesion to subendothelial collagen and platelet aggregation at high shear rates. Its hemostatic function and thrombogenic effect, as well as susceptibility to enzymatic cleavage, are regulated by a conformational change from a collapsed globular state to a stretched state. Therefore, it is essential to account for the conformation of the vWF multimers when modeling vWF-mediated thrombosis or vWF degradation. We introduce a continuum model of vWF unfolding that is developed within the framework of our multi-constituent model of platelet-mediated thrombosis. The model considers two interconvertible vWF species corresponding to the collapsed and stretched conformational states. vWF unfolding takes place via two regimes: tumbling in simple shear and strong unfolding in flows with dominant extensional component. These two regimes were demonstrated in a Couette flow between parallel plates and an extensional flow in a cross-slot geometry. The vWF unfolding model was then verified in several microfluidic systems designed for inducing high-shear vWF-mediated thrombosis and screening for von Willebrand Disease. The model predicted high concentration of stretched vWF in key regions where occlusive thrombosis was observed experimentally. Strong unfolding caused by the extensional flow was limited to the center axis or middle plane of the channels, whereas vWF unfolding near the channel walls relied upon the shear tumbling mechanism. The continuum model of vWF unfolding presented in this work can be employed in numerical simulations of vWF-mediated thrombosis or vWF degradation in complex geometries. However, extending the model to 3-D arbitrary flows and turbulent flows will pose considerable challenges.

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Topics: Hemostatic function (52%)

1 Citations


Open accessJournal ArticleDOI: 10.1007/S10439-021-02845-5
Abstract: von Willebrand Factor is a mechano-sensitive protein circulating in blood that mediates platelet adhesion to subendothelial collagen and platelet aggregation at high shear rates. Its hemostatic function and thrombogenic effect, as well as susceptibility to enzymatic cleavage, are regulated by a conformational change from a collapsed globular state to a stretched state. Therefore, it is essential to account for the conformation of the vWF multimers when modeling vWF-mediated thrombosis or vWF degradation. We introduce a continuum model of vWF unfolding that is developed within the framework of our multi-constituent model of platelet-mediated thrombosis. The model considers two interconvertible vWF species corresponding to the collapsed and stretched conformational states. vWF unfolding takes place via two regimes: tumbling in simple shear and strong unfolding in flows with dominant extensional component. These two regimes were demonstrated in a Couette flow between parallel plates and an extensional flow in a cross-slot geometry. The vWF unfolding model was then verified in several microfluidic systems designed for inducing high-shear vWF-mediated thrombosis and screening for von Willebrand Disease. The model predicted high concentration of stretched vWF in key regions where occlusive thrombosis was observed experimentally. Strong unfolding caused by the extensional flow was limited to the center axis or middle plane of the channels, whereas vWF unfolding near the channel walls relied upon the shear tumbling mechanism. The continuum model of vWF unfolding presented in this work can be employed in numerical simulations of vWF-mediated thrombosis or vWF degradation in complex geometries. However, extending the model to 3-D arbitrary flows and turbulent flows will pose considerable challenges.

... read more

Topics: Hemostatic function (52%)

Open accessJournal ArticleDOI: 10.1371/JOURNAL.PCBI.1009331
Abstract: Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case-mechanical or biochemical-could help define improved strategies for thrombosis prevention tailored for each patient.

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Topics: Platelet activation (62%), Thrombosis (56%), Platelet (55%) ... show more

Open accessJournal ArticleDOI: 10.3390/MATH9070759
01 Apr 2021-
Abstract: Blood cell platelets form aggregates upon vessel wall injury. Under certain conditions, a disintegration of the platelet aggregates, called “reversible aggregation”, is observed in vitro. Previously, we have proposed an extremely simple (two equations, five parameters) ordinary differential equation-based mathematical model of the reversible platelet aggregation. That model was based on mass-action law, and the parameters represented probabilities of platelet aggregate formations. Here, we aimed to perform a nonlinear dynamics analysis of this mathematical model to derive the biomedical meaning of the model’s parameters. The model’s parameters were estimated automatically from experimental data in COPASI software. Further analysis was performed in Python 2.7. Contrary to our expectations, for a broad range of parameter values, the model had only one steady state of the stable type node, thus eliminating the initial assumption that the reversibility of the aggregation curve could be explained by the system’s being near a stable focus. Therefore, we conclude that during platelet aggregation, the system is outside of the influence area of the steady state. Further analysis of the model’s parameters demonstrated that the rate constants for the reaction of aggregate formation from existing aggregates determine the reversibility of the aggregation curve. The other parameters of the model influenced either the initial aggregation rate or the quasi-steady state aggregation values.

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Journal ArticleDOI: 10.1039/D1LC00465D
Scott L. Diamond1, Jason M Rossi1Institutions (1)
28 Sep 2021-Lab on a Chip
Abstract: Point-of-care diagnostics of platelet and coagulation function present demanding challenges. Current clinical diagnostics often use centrifuged plasmas or platelets and frozen plasma standards, recombinant protein standards, or even venoms. Almost all commercialized tests of blood do not recreate the in vivo hemodynamics where platelets accumulate to high densities and thrombin is generated from a procoagulant surface. Despite numerous drugs that target platelets, insufficient coagulation, or excess coagulation, POC blood testing is essentially limited to viscoelastic methods that provide a clotting time, clot strength, and clot lysis, while used mostly in trauma centers with specialized capabilities. Microfluidics now allows small volumes of whole blood (<1 mL) to be tested under venous or arterial shear rates with multi-color readouts to follow platelet function, thrombin generation, fibrin production, and clot stability. Injection molded chips containing pre-patterned fibrillar collagen and lipidated tissue factor can be stored dry for 6 months at 4C, thus allowing rapid blood testing on single-use disposable chips. Using only a small imaging microscope and micropump, these microfluidic devices can detect platelet inhibitors, direct oral anticoagulants (DOACs) and their reversal agents. POC microfluidics are ideal for neonatal surgical applications that involve small blood samples, rapid DOAC testing in stroke or bleeding or emergency surgery situations with patients presenting high risk cofactors for either bleeding or thrombosis.

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Topics: Fibrin (54%), Coagulation (53%), Thrombosis (53%) ... show more

References
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46 results found


Journal ArticleDOI: 10.1126/SCIENCE.347575
George I. Bell1Institutions (1)
12 May 1978-Science
Abstract: A theoretical framework is proposed for the analysis of adhesion between cells or of cells to surfaces when the adhesion is mediated by reversible bonds between specific molecules such as antigen and antibody, lectin and carbohydrate, or enzyme and substrate. From a knowledge of the reaction rates for reactants in solution and of their diffusion constants both in solution and on membranes, it is possible to estimate reaction rates for membrane-bound reactants. Two models are developed for predicting the rate of bond formation between cells and are compared with experiments. The force required to separate two cells is shown to be greater than the expected electrical forces between cells, and of the same order of magnitude as the forces required to pull gangliosides and perhaps some integral membrane proteins out of the cell membrane.

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Topics: Adhesion (58%), Cell membrane (54%), Membrane (53%) ... show more

3,752 Citations


Open accessJournal ArticleDOI: 10.1161/01.ATV.5.3.293
Abstract: Fluid velocities were measured by laser Doppler velocimetry under conditions of pulsatile flow in a scale model of the human carotid bifurcation. Flow velocity and wall shear stress at five axial and four circumferential positions were compared with intimal plaque thickness at corresponding locations in carotid bifurcations obtained from cadavers. Velocities and wall shear stresses during diastole were similar to those found previously under steady flow conditions, but these quantities oscillated in both magnitude and direction during the systolic phase. At the inner wall of the internal carotid sinus, in the region of the flow divider, wall shear stress was highest (systole = 41 dynes/cm2, diastole = 10 dynes/cm2, mean = 17 dynes/cm2) and remained unidirectional during systole. Intimal thickening in this location was minimal. At the outer wall of the carotid sinus where intimal plaques were thickest, mean shear stress was low (-0.5 dynes/cm2) but the instantaneous shear stress oscillated between -7 and +4 dynes/cm2. Along the side walls of the sinus, intimal plaque thickness was greater than in the region of the flow divider and circumferential oscillations of shear stress were prominent. With all 20 axial and circumferential measurement locations considered, strong correlations were found between intimal thickness and the reciprocal of maximum shear stress (r = 0.90, p less than 0.0005) or the reciprocal of mean shear stress (r = 0.82, p less than 0.001). An index which takes into account oscillations of wall shear also correlated strongly with intimal thickness (r = 0.82, p less than 0.001). When only the inner wall and outer wall positions were taken into account, correlations of lesion thickness with the inverse of maximum wall shear and mean wall shear were 0.94 (p less than 0.001) and 0.95 (p less than 0.001), respectively, and with the oscillatory shear index, 0.93 (p less than 0.001). These studies confirm earlier findings under steady flow conditions that plaques tend to form in areas of low, rather than high, shear stress, but indicate in addition that marked oscillations in the direction of wall shear may enhance atherogenesis.

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Topics: Shear stress (61%)

2,484 Citations


Journal ArticleDOI: 10.1161/CIR.0000000000000757
03 Mar 2020-Circulation
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovas...

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Topics: Heart disease (58%), Stroke (55%)

2,399 Citations


Open accessJournal ArticleDOI: 10.1016/S0092-8674(00)81607-4
04 Sep 1998-Cell
Abstract: We have used confocal videomicroscopy in real time to delineate the adhesive interactions supporting platelet thrombus formation on biologically relevant surfaces. Type I collagen fibrils exposed to flowing blood adsorb von Willebrand factor (vWF), to which platelets become initially tethered with continuous surface translocation mediated by the membrane glycoprotein Ib alpha. This step is essential at high wall shear rates to allow subsequent irreversible adhesion and thrombus growth mediated by the integrins alpha2beta1 and alpha(IIb)beta3. On subendothelial matrix, endogenous vWF and adsorbed plasma vWF synergistically initiate platelet recruitment, and alpha2beta1 remains key along with alpha(IIb)beta3 for normal thrombus development at all but low shear rates. Thus, hemodynamic forces and substrate characteristics define the platelet adhesion pathways leading to thrombogenesis.

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Topics: Platelet Glycoprotein GPIb-IX Complex (58%), Platelet (52%), Thrombus (52%) ... show more

797 Citations


Journal ArticleDOI: 10.1182/BLOOD-2006-12-027698
Shaun P. Jackson1Institutions (1)
15 Jun 2007-Blood
Abstract: Platelet aggregation, the process by which platelets adhere to each other at sites of vascular injury, has long been recognized as critical for hemostatic plug formation and thrombosis. Until relatively recently, platelet aggregation was considered a straightforward process involving the noncovalent bridging of integrin alpha(IIb)beta(3) receptors on the platelet surface by the dimeric adhesive protein fibrinogen. However, with recent technical advances enabling real-time analysis of platelet aggregation in vivo, it has become apparent that this process is much more complex and dynamic than previously anticipated. Over the last decade, it has become clear that platelet aggregation represents a multistep adhesion process involving distinct receptors and adhesive ligands, with the contribution of individual receptor-ligand interactions to the aggregation process dependent on the prevailing blood flow conditions. It now appears that at least 3 distinct mechanisms can initiate platelet aggregation, with each of these mechanisms operating over a specific shear range in vivo. The identification of shear-dependent mechanisms of platelet aggregation has raised the possibility that vascular-bed-specific inhibitors of platelet aggregation may be developed in the future that are safer and more effective than existing antiplatelet agents.

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Topics: Platelet (50%)

586 Citations


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