Blog
About

7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      A General Shear-Dependent Model for Thrombus Formation

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Modeling the transport, activation, and adhesion of platelets is crucial in predicting thrombus formation and growth following a thrombotic event in normal or pathological conditions. We propose a shear-dependent platelet adhesive model based on the Morse potential that is calibrated by existing in vivo and in vitro experimental data and can be used over a wide range of flow shear rates (

          ). We introduce an Eulerian-Lagrangian model where hemodynamics is solved on a fixed Eulerian grid, while platelets are tracked using a Lagrangian framework. A force coupling method is introduced for bidirectional coupling of platelet motion with blood flow. Further, we couple the calibrated platelet aggregation model with a tissue-factor/contact pathway coagulation cascade, representing the relevant biology of thrombin generation and the subsequent fibrin deposition. The range of shear rates covered by the proposed model encompass venous and arterial thrombosis, ranging from low-shear-rate conditions in abdominal aortic aneurysms and thoracic aortic dissections to thrombosis in stenotic arteries following plaque rupture, where local shear rates are extremely high.

          Author Summary

          Hemostasis (thrombus formation) is the normal physiological response that prevents significant blood loss after vascular injury. The resulting clots can form under different flow conditions in the veins as well as the arteries. The excessive and undesirable formation of clots (i.e., thrombosis) in our circulatory system may lead to significant morbidity and mortality. Some of these pathologies are deep vein thrombosis and pulmonary embolism and atherothrombosis (thrombosis triggered by plaque rupture) in coronary arteries, to name a few. The process of clot formation and growth at a site on a blood vessel wall involves a number of simultaneous processes including: multiple chemical reactions in the coagulation cascade, species transport and platelet adhesion all of which are strongly influenced by the hydrodynamic forces. Numerical models for blood clotting normally focus on one of the processes under a specific flow condition. Here, we propose a general numerical model that encompass a wide range of hemodynamic conditions in the veins and arteries, with individual platelets and their adhesive dynamics included explicitly in the models. Further, we include the biochemistry of coagulation cascade, which is essential to modeling thrombus formation, and couple that to our platelet aggregation model. The simulation results—tested against three different experiments—demonstrate that the proposed model is effective in capturing the in vivo and in vitro experimental observations.

          Related collections

          Most cited references 46

          • Record: found
          • Abstract: found
          • Article: not found

          A shear gradient-dependent platelet aggregation mechanism drives thrombus formation.

          Platelet aggregation at sites of vascular injury is essential for hemostasis and arterial thrombosis. It has long been assumed that platelet aggregation and thrombus growth are initiated by soluble agonists generated at sites of vascular injury. By using high-resolution intravital imaging techniques and hydrodynamic analyses, we show that platelet aggregation is primarily driven by changes in blood flow parameters (rheology), with soluble agonists having a secondary role, stabilizing formed aggregates. We find that in response to vascular injury, thrombi initially develop through the progressive stabilization of discoid platelet aggregates. Analysis of blood flow dynamics revealed that discoid platelets preferentially adhere in low-shear zones at the downstream face of forming thrombi, with stabilization of aggregates dependent on the dynamic restructuring of membrane tethers. These findings provide insight into the prothrombotic effects of disturbed blood flow parameters and suggest a fundamental reinterpretation of the mechanisms driving platelet aggregation and thrombus growth.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Adhesion mechanisms in platelet function.

            Platelet adhesion is an essential function in response to vascular injury and is generally viewed as the first step during which single platelets bind through specific membrane receptors to cellular and extracellular matrix constituents of the vessel wall and tissues. This response initiates thrombus formation that arrests hemorrhage and permits wound healing. Pathological conditions that cause vascular alterations and blood flow disturbances may turn this beneficial process into a disease mechanism that results in arterial occlusion, most frequently in atherosclerotic vessels of the heart and brain. Besides their relevant role in hemostasis and thrombosis, platelet adhesive properties are central to a variety of pathophysiological processes that extend from inflammation to immune-mediated host defense and pathogenic mechanisms as well as cancer metastasis. All of these activities depend on the ability of platelets to circulate in blood as sentinels of vascular integrity, adhere where alterations are detected, and signal the abnormality to other platelets and blood cells. In this respect, therefore, platelet adhesion to vascular wall structures, to one another (aggregation), or to other blood cells, represent different aspects of the same fundamental biological process. Detailed studies by many investigators over the past several years have been aimed to dissect the complexity of these functions, and the results obtained now permit an attempt to integrate all the available information into a picture that highlights the balanced diversity and synergy of distinct platelet adhesive interactions.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Shear-induced unfolding triggers adhesion of von Willebrand factor fibers.

              von Willebrand factor (VWF), a protein present in our circulatory system, is necessary to stop bleeding under high shear-stress conditions as found in small blood vessels. The results presented here help unravel how an increase in hydrodynamic shear stress activates VWF's adhesion potential, leading to the counterintuitive phenomena of enhanced adsorption rate under strong shear conditions. Using a microfluidic device, we were able to mimic a wide range of bloodflow conditions and directly visualize the conformational dynamics of this protein under shear flow. In particular, we find that VWF displays a reversible globule-stretch transition at a critical shear rate gamma(crit) in the absence of any adsorbing surface. Computer simulations reproduce this sharp transition and identify the large size of VWF's repeating units as one of the keys for this unique hydrodynamic activation. In the presence of an adsorbing collagen substrate, we find a large increase in the protein adsorption at the same critical shear rate, suggesting that the globule unfolding in bulk triggers the surface adsorption in the case of a collagen substrate, which provides a sufficient density of binding sites. Monitoring the adsorption process of multiple VWF fibers, we were able to follow the formation of an immobilized network that constitutes a "sticky" grid necessary for blood platelet adhesion under high shear flow. Because areas of high shear stress coincide with a higher chance for vessel wall damage by mechanical forces, we identified the shear-induced increase in the binding probability of VWF as an effective self-regulating repair mechanism of our microvascular system.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                PLoS Comput. Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, CA USA )
                1553-734X
                1553-7358
                January 2017
                17 January 2017
                : 13
                : 1
                Affiliations
                [1 ]Division of Applied Mathematics, Brown University, Providence, Rhode Island, United States of America
                [2 ]Department of Biomedical Engineering, Yale University, New Haven, Connecticut, United States of America
                University of Pennsylvania, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: AY JDH GEK.

                • Performed the experiments: HL AY.

                • Analyzed the data: HL AY.

                • Contributed reagents/materials/analysis tools: HL AY.

                • Wrote the paper: HL AY.

                Article
                PCOMPBIOL-D-16-01057
                10.1371/journal.pcbi.1005291
                5240924
                28095402
                © 2017 Yazdani et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 10, Tables: 0, Pages: 24
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: U01HL116323
                Award Recipient :
                This work was supported by National Institute of Health Grant No. U01HL116323. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Platelets
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Platelets
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Platelets
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Platelets
                Medicine and Health Sciences
                Hematology
                Blood
                Platelets
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                Platelets
                Medicine and Health Sciences
                Hematology
                Blood Coagulation
                Platelet Aggregation
                Medicine and Health Sciences
                Hematology
                Blood Coagulation
                Platelet Activation
                Physical Sciences
                Physics
                Classical Mechanics
                Continuum Mechanics
                Fluid Mechanics
                Fluid Dynamics
                Flow Rate
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Stenosis
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Stenosis
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Flow
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Flow
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Flow
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Flow
                Medicine and Health Sciences
                Hematology
                Blood
                Blood Flow
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Hematology
                Blood
                Physical Sciences
                Materials Science
                Materials by Attribute
                Adhesives
                Custom metadata
                All relevant data are within the paper.

                Quantitative & Systems biology

                Comments

                Comment on this article