Contributions of Platelet Activation and Collision to Thrombus Formation in Tortuous Venules

2012 ◽  
Author(s):  
Jennifer K. W. Chesnutt ◽  
Hai-Chao Han
Keyword(s):  
Cardiovascular Disease ◽  
Shear Stress ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Treatment Strategies ◽  
Major Contributor ◽  
Physical Mechanisms ◽  
Vessel Tortuosity ◽  
New Treatment ◽  
The U.S

Vessel tortuosity is often seen in humans in association with various conditions, including thrombosis.1–3 Thrombosis is a major contributor to cardiovascular disease, which is the leading cause of death in the U.S. Tortuosity can increase shear stress that can activate platelets, which can lead to thrombosis.4 A fundamental gap exists in understanding how vessel tortuosity regulates thrombosis through such microscale physical mechanisms. Solving this problem is essential to assess the risk of thrombosis and to develop new treatment strategies.

scholarly journals LDL-Cholesterol and Platelets: Insights into Their Interactions in Atherosclerosis

Life ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 39
Author(s):  
Aleksandra Gąsecka ◽  
Sylwester Rogula ◽  
Łukasz Szarpak ◽  
Krzysztof J. Filipiak
Keyword(s):  
Platelet Activation ◽  
Ldl Cholesterol ◽  
Thrombus Formation ◽  
Treatment Strategies ◽  
Activated Platelets ◽  
Coronary Syndromes ◽  
Ldl Binding ◽  
New Treatment ◽  
Atherosclerosis Prevention

Atherosclerosis and its complications, including acute coronary syndromes, are the major cause of death worldwide. The two most important pathophysiological mechanisms underlying atherosclerosis include increased platelet activation and increased low-density lipoproteins (LDL) concentration. In contrast to LDL, oxidized (ox)-LDL have direct pro-thrombotic properties by functional interactions with platelets, leading to platelet activation and favoring thrombus formation. In this review, we summarize the currently available evidence on the interactions between LDL-cholesterol and platelets, which are based on (i) the presence of ox-LDL-binding sites on platelets, (ii) generation of ox-LDL by platelets and (iii) the role of activated platelets and ox-LDL in atherosclerosis. In addition, we elaborate on the clinical implications of these interactions, including development of the new therapeutic possibilities. The ability to understand and modulate mechanisms governing interactions between LDL-cholesterol and platelets may offer new treatment strategies for atherosclerosis prevention.

scholarly journals Numerical modelling of blood rheology and platelet activation through a stenosed left coronary artery bifurcation

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259196
Author(s):  
David G. Owen ◽  
Diana C. de Oliveira ◽  
Emma K. Neale ◽  
Duncan E. T. Shepherd ◽  
Daniel M. Espino
Keyword(s):  
Shear Stress ◽  
Platelet Activation ◽  
Residence Time ◽  
Thrombus Formation ◽  
Blood Rheology ◽  
Cell Aggregation ◽  
Red Blood Cell Aggregation ◽  
History Of ◽  
Tracking Model ◽  
Low Shear

Coronary bifurcations are prone to atherosclerotic plaque growth, experiencing regions of reduced wall shear stress (WSS) and increased platelet adhesion. This study compares effects across different rheological approaches on hemodynamics, combined with a shear stress exposure history model of platelets within a stenosed porcine bifurcation. Simulations used both single/multiphase blood models to determine which approach best predicts phenomena associated with atherosclerosis and atherothrombosis. A novel Lagrangian platelet tracking model was used to evaluate residence time and shear history of platelets indicating likely regions of thrombus formation. Results show a decrease in area of regions with pathologically low time-averaged WSS with the use of multiphase models, particularly in a stenotic bifurcation. Significant non-Newtonian effects were observed due to low-shear and varying hematocrit levels found on the outer walls of the bifurcation and distal to the stenosis. Platelet residence time increased 11% in the stenosed artery, with exposure times to low-shear sufficient for red blood cell aggregation (>1.5 s). increasing the risk of thrombosis. This shows stenotic artery hemodynamics are inherently non-Newtonian and multiphase, with variations in hematocrit (0.163–0.617) and elevated vorticity distal to stenosis (+15%) impairing the function of the endothelium via reduced time-averaged WSS regions, rheological properties and platelet activation/adhesion.

scholarly journals Catalytic dysregulation of SHP2 leading to Noonan syndromes affects platelet signaling and functions

Blood ◽  
2019 ◽  
Vol 134 (25) ◽  
pp. 2304-2317 ◽  
Author(s):  
Marie Bellio ◽  
Cédric Garcia ◽  
Thomas Edouard ◽  
Sophie Voisin ◽  
Benjamin G. Neel ◽  
...  
Keyword(s):  
Shear Stress ◽  
Platelet Activation ◽  
Germ Line ◽  
Thrombus Formation ◽  
Tyrosine Phosphatase ◽  
Collagen Matrix ◽  
Loss Of Function ◽  
Ptpn11 Gene ◽  
Platelet Signaling ◽  
Stress Dependent

Abstract Src homology 2 domain–containing phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a ubiquitous protein tyrosine phosphatase that is a critical regulator of signal transduction. Germ line mutations in the PTPN11 gene responsible for catalytic gain or loss of function of SHP2 cause 2 disorders with multiple organ defects: Noonan syndrome (NS) and NS with multiple lentigines (NSML), respectively. Bleeding anomalies have been frequently reported in NS, but causes remain unclear. This study investigates platelet activation in patients with NS and NSML and in 2 mouse models carrying PTPN11 mutations responsible for these 2 syndromes. Platelets from NS mice and patients displayed a significant reduction in aggregation induced by low concentrations of GPVI and CLEC-2 agonists and a decrease in thrombus growth on a collagen surface under arterial shear stress. This was associated with deficiencies in GPVI and αIIbβ3 integrin signaling, platelet secretion, and thromboxane A2 generation. Similarly, arterial thrombus formation was significantly reduced in response to a local carotid injury in NS mice, associated with a significant increase in tail bleeding time. In contrast, NSML mouse platelets exhibited increased platelet activation after GPVI and CLEC-2 stimulation and enhanced platelet thrombotic phenotype on collagen matrix under shear stress. Blood samples from NSML patients also showed a shear stress–dependent elevation of platelet responses on collagen matrix. This study brings new insights into the understanding of SHP2 function in platelets, points to new thrombopathies linked to platelet signaling defects, and provides important information for the medical care of patients with NS in situations involving risk of bleeding.

Models of Shear-Induced Platelet Activation and Numerical Implementation with Computational Fluid Dynamics Approaches

2021 ◽  
Author(s):  
Dong Han ◽  
Jiafeng Zhang ◽  
Bartley Griffith ◽  
Zhongjun Wu
Keyword(s):  
Shear Stress ◽  
Platelet Activation ◽  
Large Scale ◽  
Numerical Models ◽  
Thrombus Formation ◽  
Underlying Mechanism ◽  
Serious Adverse Events ◽  
Large Scale Analysis ◽  
Shear Stress Level ◽  
Dynamic Shape

Abstract Shear-induced platelet activation is one of the critical outcomes when blood is exposed to elevated shear stress. Excessively activated platelets in the circulation can lead to thrombus formation and platelet consumption, resulting in serious adverse events such as thromboembolism and bleeding. While experimental observations reveal that it is related to the shear stress level and exposure time, the underlying mechanism of shear-induced platelet activation is not fully understood. Various models have been proposed to relate shear stress levels to platelet activation, yet most are modified from the empirically calibrated power-law model. Newly developed multiscale platelet models are tested as a promising approach to capture a single platelet's dynamic shape during activation, but it would be computationally expensive to employ it for a large-scale analysis. This paper summarizes the current numerical models used to study the shear-induced platelet activation and their computational applications in the risk assessment of a particular flow pattern and clot formation prediction.

scholarly journals Platelet Aggregation and Fibrin Deposition: The Yin and Yang of Thrombin Activity Regulation By Platelet Glycoprotein Ibα

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 114-114
Author(s):  
Alessandro Zarpellon ◽  
Patrizia Marchese ◽  
Antonella Zampolli ◽  
Grazia Loredana Mendolicchio ◽  
Zaverio M. Ruggeri
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Shear Stress ◽  
Carotid Artery ◽  
Platelet Activation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Type I ◽  
Scanning Electron

Abstract Generation of α-thrombin (FIIa) in response to vascular injury is a key mechanism influencing thrombus formation. Platelet activation by FIIa is mediated by different protease activated receptors (PARs), although the most abundant FIIa binding site on platelets, but not a substrate for proteolysis, is glycoprotein (GP) Ibα in the GPIb-IX-V complex. The functional role of GPIbα in mediating/regulation thrombin functions relative to that of different PARs remains unclear. The goal of these studies was to define how binding to GPIbα can modulate FIIa functions. In mouse platelets we replaced endogenous GPIbα with either its human wild type counterpart (huGPIbα-WT) or with huGPIbα mutated at key residues involved in thrombin binding (D277N, Y276-8-9/F). Because these two mutations resulted in an undistinguishable phenotype, they are designated collectively as huGPIbα-Mut hereon. Mice expressing huGPIbα, WT or Mut, were evaluated in intravital models of arterial thrombosis induced by a ferric chloride-induced carotid artery lesion and venous thromboembolism induced by intravenous α-thrombin injection. Moreover, the blood of huGPIbα WT or Mut mice was also tested in an ex vivo model of thrombus formation upon perfusion over a thrombogenic surface under controlled flow conditions and platelets were evaluated for their responses to FIIa-induced activation. Mice expressing huGPIbα - WT or Mut - have comparable platelet counts and GPIbα surface density. Moreover, huGPIbα-WT platelets bind FIIa similarly than their normal human control counterpart, while huGPIbα-Mut platelets have essentially no detectable FIIa binding. Upon FIIa stimulation, which on mouse platelets is mediated by PAR4, aggregation and Ca2+ transients were significantly enhanced in huGPIbα-Mut as compared to huGPIbα-WT. In contrast, blocking FIIa binding to GPIbα on human platelets essentially abolished FIIa mediated activation, which in human occurs predominantly through PAR1. These results are compatible with the conclusion that, in mice, GPIbα is a competitive inhibitor of FIIa for PAR4-mediated functions. In the presence of metabolically inactive (PGE1 treated) huGPIbα-Mut washed platelets, the clotting time of a purified fibrinogen solution was significantly shorter when triggered by relative high concentration of FIIa (4 nM), but pronouncedly prolonged at a lower FIIa concentration (0.5 nM). Clot visualization showed a much more structured fibrin mesh in the presence of huGPIbα-WT platelets, which was lost with in the presence of huGPIbα-Mut platelets. Mutant mice tested in a model of carotid artery injury exhibited a pronounced prothrombotic phenotype, with a shorter time to occlusion. However they were protected from death induced by I.V. injection of α-thrombin. In ex vivo perfusion studies, the total volume of platelet aggregates formed in huGPIbα-Mut mouse blood exposed to acid-insoluble fibrillar collagen type I was slightly bigger than in huGPIbα-WT mice, but the number of thrombi was increased and their individual size smaller. These huGPIbα-Mut platelets exhibited clear signs of increased activation, as visualized by scanning electron microscopy (SEM). Strikingly, fibrin was almost totally absent in the huGPIbα-Mut thrombi. This was in striking contrast with what observed in huGPIbα-WT mice, in which the surface of platelet thrombi with directly and tightly connected with thick fibrin fibers as visualized by scanning electron microscopy. Possibly because of the reduced platelet membrane-fibrin fibril connection in huGPIbα-Mut platelets, these mice were significantly less susceptible to death when injected with an α-thrombin dose that caused 80% mortality plus in huGPIbα-WT mice. Thus, mice whose platelets have defective α-thrombin binding to GPIbα have a prothrombotic phenotype in high shear stress flow arteries and are protected from thromboembolic death in the low shear stress venous circulation. Our findings identify GPIbα as a relevant FIIa activity modulator in hemostasis and thrombosis through distinct and opposite mechanisms affecting platelet activation (The Yin) and fibrin formation (The Yang). Disclosures No relevant conflicts of interest to declare.

scholarly journals A primer on metabolic memory: why existing diabesity treatments fail

2020 ◽  
Author(s):  
Sidar Copur ◽  
Peter Rossing ◽  
Baris Afsar ◽  
Alan A Sag ◽  
Dimitrie Siriopol ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cardiovascular Disease ◽  
Paradigm Shift ◽  
Treatment Strategies ◽  
Tissue Level ◽  
Metabolic Memory ◽  
New Paradigm ◽  
Long Time ◽  
New Treatment ◽  
Prevention Of Cardiovascular Disease

Abstract Despite massive government and private sector investments into prevention of cardiovascular disease, diabetes mellitus and obesity, efforts have largely failed, and the burden of cost remains in the treatment of downstream morbidity and mortality, with overall stagnating outcomes. A new paradigm shift in the approach to these patients may explain why existing treatment strategies fail, and offer new treatment targets. This review aims to provide a clinician-centred primer on metabolic memory, defined as the sum of irreversible genetic, epigenetic, cellular and tissue-level alterations that occur with long-time exposure to metabolic derangements.

scholarly journals Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex

2005 ◽  
Vol 289 (4) ◽  
pp. E695-E702 ◽  
Author(s):  
Hisham S. Elbatarny ◽  
Donald H. Maurice
Keyword(s):  
Cardiovascular Disease ◽  
Platelet Activation ◽  
Leptin Receptor ◽  
Thrombus Formation ◽  
Human Platelets ◽  
Janus Kinase ◽  
Camp Phosphodiesterase ◽  
Signaling Complex ◽  
Coronary Events ◽  
Mechanistic Basis

An elevated circulating level of the adipocyte-derived satiety hormone leptin is an independent risk factor for cardiovascular disease. Because thrombus formation is a major cause of acute coronary events and leptin was shown previously to facilitate ADP-induced platelet aggregation, we chose to define the signaling events involved in leptin-mediated platelet activation. Using pharmacological, biochemical, and cell biological approaches, we show that leptin-induced platelet activation required activation of a signaling cascade that included the long form of the leptin receptor, three kinases [Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt)], the insulin receptor substrate-1 (IRS-1), and the major human platelet cAMP phosphodiesterase phosphodiesterase 3A (PDE3A). Moreover, we identify a role for an intraplatelet LEPR/JAK2/IRS-1/PI3K/PKB/PDE3A molecular complex that allows for the selective leptin-mediated activation of platelets. Our data demonstrate that leptin promotes platelet activation, provides a mechanistic basis for the prothrombotic effect of this hormone, and identifies a potentially novel therapeutic avenue to limit obesity-associated cardiovascular disease.

scholarly journals Tortuosity Triggers Platelet Activation and Thrombus Formation in Microvessels

2011 ◽  
Vol 133 (12) ◽  
Author(s):  
Jennifer K. W. Chesnutt ◽  
Hai-Chao Han
Keyword(s):  
Shear Stress ◽  
Platelet Activation ◽  
Fluid Shear Stress ◽  
Thrombus Formation ◽  
Fluid Velocity ◽  
Experimental Studies ◽  
Critical Shear Stress ◽  
Mean Flow ◽  
Mean Velocity ◽  
Activation Rate

Tortuous blood vessels are often seen in humans in association with thrombosis, atherosclerosis, hypertension, and aging. Vessel tortuosity can cause high fluid shear stress, likely promoting thrombosis. However, the underlying physical mechanisms and microscale processes are poorly understood. Accordingly, the objectives of this study were to develop and use a new computational approach to determine the effects of venule tortuosity and fluid velocity on thrombus initiation. The transport, collision, shear-induced activation, and receptor-ligand adhesion of individual platelets in thrombus formation were simulated using discrete element method. The shear-induced activation model assumed that a platelet became activated if it experienced a shear stress above a relative critical shear stress or if it contacted an activated platelet. Venules of various levels of tortuosity were simulated for a mean flow velocity of 0.10 cm s−1, and a tortuous arteriole was simulated for a mean velocity of 0.47 cm s−1. Our results showed that thrombus was initiated at inner walls in curved regions due to platelet activation in agreement with experimental studies. Increased venule tortuosity modified fluid flow to hasten thrombus initiation. Compared to the same sized venule, flow in the arteriole generated a higher amount of mural thrombi and platelet activation rate. The results suggest that the extent of tortuosity is an important factor in thrombus initiation in microvessels.

Naturally Produced Extracellular Matrix Is an Excellent Substrate for Canine Endothelial Cell Proliferation and Resistance to Shear Stress on PTFE Vascular Grafts

1997 ◽  
Vol 78 (05) ◽  
pp. 1392-1398 ◽  
Author(s):  
A Schneider ◽  
M Chandra ◽  
G Lazarovici ◽  
I Vlodavsky ◽  
G Merin ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Cell ◽  
Cell Attachment ◽  
Thrombus Formation ◽  
Endothelial Cell Proliferation ◽  
Ptfe Graft ◽  
Vascular Prostheses ◽  
Endothelial Cell Attachment

SummaryPurpose: Successful development of a vascular prosthesis lined with endothelial cells (EC) may depend on the ability of the attached cells to resist shear forces after implantation. The present study was designed to investigate EC detachment from extracellular matrix (ECM) precoated vascular prostheses, caused by shear stress in vitro and to test the performance of these grafts in vivo. Methods: Bovine aortic endothelial cells were seeded inside untreated polytetrafluoro-ethylene (PTFE) vascular graft (10 X 0.6 cm), PTFE graft precoated with fibronectin (FN), or PTFE precoated with FN and a naturally produced ECM (106 cells/graft). Sixteen hours after seeding the medium was replaced and unattached cells counted. The strength of endothelial cell attachment was evaluated by subjecting the grafts to a physiologic shear stress of 15 dynes/cm2 for 1 h. The detached cells were collected and quantitated. PTFE or EC preseeded ECM coated grafts were implanted in the common carotid arteries of dogs. Results: While little or no differences were found in the extent of endothelial cell attachment to the various grafts (79%, 87% and 94% of the cells attached to PTFE, FN precoated PTFE, or FN+ECM precoated PTFE, respectively), the number of cells retained after a shear stress was significanly increased on ECM coated PTFE (20%, 54% and 85% on PTFE, FN coated PTFE, and FN+ECM coated PTFE, respectively, p <0.01). Implantation experiments in dogs revealed a significant increase in EC coverage and a reduced incidence of thrombus formation on ECM coated grafts that were seeded with autologous saphenous vein endothelial cells prior to implantation. Conclusion: ECM coating significantly increased the strength of endothelial cell attachment to vascular prostheses subjected to shear stress. The presence of adhesive macromolecules and potent endothelial cell growth promoting factors may render the ECM a promising substrate for vascular prostheses.

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