thrombus formation process

[14] allowed model calibration at medium to high shear rates where the maximum wall shear rate at the apex reaches 8,000 s−1. [24] used spring models for a variety of ligand-receptor interactions between platelets to investigate effects of ligand-receptor deficiencies on thrombus formation at different shear rates. from a microfluidic device with different degrees of stenosis. Inflammation is a normal body reaction to unwanted stimuli such as foreign pathogens or infection, and endothelial damage whether acute (e.g., trauma or surgery) or chronic (underlying inflammatory disorders or peripheral vascular disease). There are no standardized guidelines for treatment of mural thrombus. (7) Activated particles can form thrombus and adhere to the injured wall. Division of Applied Mathematics, Brown University, Providence, Rhode Island, United States of America, Affiliation 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. Am. Whether a fully thrombosed TAAD is formed or not could be attributed to the hemodynamics in the false lumen. Both MRI and CT are more sensitive than transoesophageal echocardiography (TEE) in detecting the thrombus in an entire thoracic aorta. [15] is the enhanced platelet aggregation at the outlet of stenosis compared to its inlet. Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelial tissue factor to plasma factor VII, which ultimately leads to cross-linked fibrin formation. Its presence in the distal part of the vessel can induce ischemia, which can result in limb loss 5). (a) Schematic of the simulation setup with the seeded particles (green) placed circumferentially to represent the subendothelial matrix (150 − 200 μm). Endoluminal stent grafting is the least invasive option, but it carries the high risk of distal embolization through wire manipulation and stent deployment 8). The contribution of each platelet whose center of mass is located at Yn to the flow at position x is smoothed by a Gaussian distribution kernel Δ(X ≡ (x − Yn)), where Δ(X) is Semin. The effect of the platelets on the flow field is incorporated into the body force term f (x, t) in the Navier-Stokes Eq (1). Leukemia or coagulation disorders induce hypercoagulability. The use of in vivo models of thrombosis, as well as sophisticated methodology to measure platelet signalling and thrombus formation under flow, are important technical developments towards this aim. By adjusting the interaction forces between the platelet particles, we were able to reproduce the dependence of the growth rate on blood velocity reported in [19]. Thromb. Complications of thrombosis can be life-threatening, such as a stroke or heart attack. He Li, * E-mail: george_karniadakis@brown.edu (GEK); alireza_yazdani@brown.edu (AY), Affiliation 12) speculated that these two types of thrombosis are triggered by the same biological stimuli that activate coagulation and inflammatory pathways. (1) (2) (3) On the other hand, as shear rate increases, interactions between immobilized vWF and GPIb become exclusive in initializing platelet aggregation while other interactions are broken down due to high bond failure rates [9–11]. A representative thrombus growth rate is plotted in Fig 4a on a semi-log axes, which shows an initial transient followed by a steady exponential growth of the form ∼exp(αgt), similar to in vivo observations of Begent and Born. There are three main causes of thrombosis: hypercoagulability, injury to the endothelial cells of the blood vessel wall and abnormal flow of the blood.Hypercoagulability, also known as thrombophilia, refers higher levels of coagulation factors in the blood that increase susceptibility to thrombosis. Deep vein thrombosis treatment options include: Once you receive treatment for deep vein thrombosis (DVT), you need to watch your diet and watch for signs of excessive bleeding, as well as take steps to prevent another DVT. The major risk of left ventricular thrombus is subsequent embolization with stroke or major organ loss. Thrombosis occurs when blood clots block veins or arteries. Lowe GD. A finite quantity of ADP and TxA2 is released by a platelet during a time interval following the platelet’s activation. Blue particles are plotted smaller for clarity. Alternative Titles: blood clotting, clotting Coagulation, in physiology, the process by which a blood clot is formed. Next, we present a phenomenological model that correlates the adhesion force to the local shear rate. It is known that the lateral platelet diffusion is enhanced through its collisions with RBCs, which is on the order of Dp = 10−7 cm2/s. Passive and triggered platelets only generate repulsive forces to prevent overlap, whereas activated platelets attract each other as well. Symptoms are mainly related to localization of thrombus. The concentration of [TF-VIIa]0 was initially set at 0.25 for venous flows, which is in the range of concentration levels in the numerical study of Kuharsky and Fogelson [16] (estimated to be initially at shear rate 500 s−1). The translation of basic research toward new strategies to prevent arterial thrombosis underscores much of the research in this area. In other words, it is paramount to determine whether the thrombosis was likely provoked or unprovoked, as each has management implications. As blood velocity increases to 400 μm/s, more platelets are delivered to the injured region, contributing to faster growth rate. Virchow’s triad describes the pathogenesis of thrombus formation. The equations governing the generation and depletion of the species (Si in Eq (11)) are formulated based on experimental data for the reaction kinetics, and are listed in S2 Table. 2004 Apr 15;47(4):259-63, Favaloro EJ, Franchini M, Lippi G. Aging hemostasis: changes to laboratory markers of hemostasis as we age – a narrative review. Embolization to the brain can lead to stroke. The adjusted interaction range implies that particles will not induce forces for distances r ⪆ 3d as shown in Fig 1. The third aspect of Virchow’s triad includes arterial or venous stasis of the blood, which could be due to immobility, pregnancy, or impaired blood flow resulting from previous thrombosis (e.g., residual blood clot, remodeling or fibrosis of blood vessels, or atherosclerosis). For calibrating our platelet aggregation model, we consider an interaction distance of 2d between platelets within which resting platelets can get activated. https://doi.org/10.1371/journal.pcbi.1005291.g005, We performed numerical simulations for different occlusion levels to calibrate the platelet-wall and platelet-platelet adhesive forces, which suggested that an approximately two orders of magnitude higher adhesive force is required for platelet aggregation at such elevated shear rates. We consider four different occlusion levels of 20, 40, 60, and 80%. https://doi.org/10.1371/journal.pcbi.1005291.g010. [33] show a different trend, however, where platelet aggregation initiates at the apex with the highest wall shear rate and then spreads to the inlet and outlet of stenosis. At higher and intermediate shear rates, the energy landscape still remains unchanged. The constants in Eq (10) are calibrated using in vivo and in vitro experiments, which results in the function plotted in Fig 2. For instance, studies have shown that elderly persons have increased production of prothrombotic coagulation factors such as von Willebrand factor and thrombin. Mural thrombus can invade any cardiac chamber. The geometry consists of a straight tube of 50μm diameter and 300μm length as shown in Fig 3a. Thrombus formation in the arteries is dependent on platelets and their ability to attach to the injured wall despite the rapid arterial blood flow. Hypercoagulable states can be acquired or inherited. [30] investigate the interaction of blood flow, platelet aggregation and plasma coagulation using a hybrid dissipative particle dynamics-continuum model in a 2D channel. The experimental measurements of Kim et al. Another process that could potentially affect the growth rates is the shear-induced platelet drift toward the wall or the thrombus. A thrombus is a blood clot that occurs inside the vascular system. We find no occlusion when shear rate is less than 2,400 s−1, comparable to 1,500 s−1 reported in microfluidic experimental results of Li et al. No, Is the Subject Area "Platelet activation" applicable to this article? A cylindrical patch with seeded platelets is placed in the middle of the tube to represent the site of injury, where thrombosis is allowed to initiate (see Fig 9a). Specifically, SEM is used to solve the flow field and the reactive transport of chemical species on a fixed Eulerian grid, whereas FCM is implemented to describe the two-way interactions between the blood flow and Lagrangian particles (i.e., platelets). If you did not get blood clots, you would bleed to death. Fibrous plaques could rupture, and the erosion of the surfaces of some of these plaques could lead to the release of additional pro-coagulating factors 18). An embolus is often a small piece of a blood clot that breaks off (thromboembolus). Recently, experiments showed that the effect of vWF multimer extension was more pronounced in elongational flows, like in stenotic arteries, than in pure shear flows in a straight vessel [14]. Historically, the likelihood of embolic events was greatest in the first 2 weeks after the acute event and tapered off over the ensuing 6 weeks. Here, platelet aggregation is caused by perfusing whole blood over surfaces coated by vWF/fibrinogen. We plot snapshots of platelets aggregated in the channel at different occlusion levels in Fig 6. Here, we observe a significant improvement in the results with no aggregation for 20% occlusion, a delayed aggregation for 40% occlusion, and a significant increase in the density of aggregated platelets for 60% stenosis. We observe significant oscillation in the concentration profile proximal to the injury as platelets activity and aggregate is higher in that region. 2017;906:273-283. Other risk factors include underlying connective tissue or rheumatologic conditions (e.g., SLE, vasculitis), as well as the aforementioned rare heparin-induced thrombocytopenia and thrombosis (HITT), antiphospholipid syndrome, myeloproliferative disorders and paroxysmal nocturnal hemoglobinuria (PNH) (all of these can predispose to both venous and arterial thrombosis). If blood velocity is increased further to 800 μm/s, the higher shear stresses on the surface of the platelet aggregate limit further aggregation, and thus reduces the growth rate. 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. The resulting clots can form under different flow conditions in the veins as well as the arteries. PLoS Comput Biol 13(1): The hexahedral elements show the structured grid used to solve the N-S and ADR equations. PL Chip for T-TAS 01(IVD) The PL-chip was specifically designed for the quantitative analysis of primary hemostatic ability, i.e. (b), (c) and (d) Concentration profiles of thrombin ([IIa]), fibrin ([Ia]) and [ADP], respectively, at three axial positions on the site of injury: x = 157 μm (−−), x = 177 μm (− ⋅ −) and x = 193 μm (—). [14] and plotted for comparison. 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. Valvulitis or an aneurysm induces it. where is the square root of the second invariant of the fluid strain-rate tensor D, and determine the adhesive forces at low and high shear rates, respectively, and is the shear rate threshold value where transition from low to high shear regime takes place. It’s important to watch for signs and symptoms of a pulmonary embolism and seek medical attention if they occur. The mural thrombus may be symptomatic or may be diagnosed as an incidental finding 4). Its embolization to brain induces cerebrovascular events, causes mesenteric ischemia in the gut, and causes renal infarction, coronary ischemia in heart, pulmonary infarction, among others. This review will focus primarily on the basic pathophysiology of venous and arterial thrombosis, including assessment of provoking risk factors and further workup that may be advisable following the initial presentation. Biasetti et al. Readers are encouraged to consult additional references for further reading, including regularly updated subspecialty society guidelines (e.g., American Society of Chest Physicians, American Heart Association, & American Society of Hematology). Tex Heart Inst J. [36]. In order to reduce the computational cost, we take blood as a continuous medium, and the effect of RBCs on platelet margination is taken into account by assuming that blood flow at the inlet of the simulated vessels is fully developed and platelets are already marginated toward the vessel wall. These modalities are costly but helpful in prognostication of disease 7). where A′ = 3 × 10−8 nM is the ADP content for each platelet [39], and is the time at which platelet n becomes activated. Further, two activated platelets in our model can only form one bond with each other, whereas each one in the pair can form multiple bonds with the other platelets in its neighborhood, which may result in the distribution of hydrodynamic drag among several bonds. Thrombosis, formation of a blood clot in the heart or in a blood vessel. Here, the activation delay time is τact = 0s. Hypercoagulability is a general hematologic concept that merely means increased risk of thrombosis (i.e., thrombogenic) via enhanced levels of prothrombotic components in the bloodstream. Although considerable work has been conducted to simulate the advective and diffusive motions of platelets and other blood components in arterial flows, most studies focused on simplified arterial geometries. A number of cardiac conditions pose an increased risk to thrombus formation. Based on these snapshots and their related curves for the density of aggregated platelets in Fig 6d, we observe that platelets aggregate inside the stenosis for all geometries and flow conditions, even at 20% occlusion where no aggregation was reported in the experiment of Westein et al. In our simulations, we assume platelets to be spheres with radius of 1.5 μm and number density of 300,000 mm−3, while blood is assumed to be an incompressible Newtonian fluid. In addition to acute management (not reviewed here), secondary prevention focuses on reducing cardiovascular risk factors such as obesity, high cholesterol, diabetes, high blood pressure and encouraging lifestyle modification such as smoking cessation. 2017 Nov;34(11):1738-1739, Eren N, Gungor O, Kocyigit I, Guzel FB, Erken E, Altunoren O, Tatar E, Eroglu E, Senel E, Kaya B, Paydaş S, Onan B, Sahin S, Yilmaz M, Ulu S, Gursu M, Ozkok A, Yildiz A, Kurultak I, Ucar AR, Tanrisev M, Turgutalp K, Turan MN, Huzmeli C, Soypacaci Z, Akdam H, Huddam B, Adibelli Z, Kara E, Inci A, Turkmen E, Tekce H, Dogukan A, Turkmen A. The reported distributions are obtained for platelet-sized latex beads suspended in whole blood flowing in tubes with ≈ 200 μm diameter at 40% hematocrit, where the average wall shear rate is ≈ 500 s−1. e1005291. In the second part of the paper, we use a detailed model for blood coagulation coupled with our platelet aggregation model to address thrombus formation in arteriole-sized vessels similar to the in vitro experiment of Shen et al. Transoesophageal echocardiography (TEE) is another, relatively noninvasive option and a good tool for diagnosis. Multiple thrombi were formed in 70% of mice lacking CD40L. We model platelets as rigid spherical particles using the Lagrangian description within the context of FCM [32], as adopted in [25], whereas the hemodynamics and chemical transport are obtained from the solution of the Navier-Stokes (NS) equations and advection-diffusion-reaction (ADR) equations on a fixed Eulerian grid, respectively. However, several contributing factors are neglected, including mechanisms of thrombus formation in a low-shear regime, thrombus mechanics, and embolization. At the site of injury, we assume that the subendothelium-bound TF-VIIa complex drives the extrinsic pathway of the coagulation cascade through the subendothelium reactions that are represented by Neumann boundary conditions in the form of −Dj∂cj/∂n = Bj. thrombus formation in a deep vein, usually in the legs, that becomes concerning for its potential to lead to embolism in the heart (MI), lungs (pulmonary embolism) or brain (stroke). These studies may be broadly put in three distinct modeling strategies: cellular/sub-cellular modeling of platelet transport and aggregation in whole blood; continuum-based modeling of blood flow treating platelets as Lagrangian particles; and continuum-based modeling of thrombus formation and growth using empirical correlations for platelet deposition rates. For zymogens, the upstream concentrations at the inlet and initial concentrations are set to their normal plasma values, whereas all enzyme and complex concentrations are initially set to a very small nonzero value. Factors that play a role in the formation of clots (thrombi) include injury to a blood vessel and alterations from normal blood flow; changes in the coagulability of the blood may also cause clot formation. Venous and arterial thrombosis: epidemiology and risk factors at various ages. [25] developed a platelet model based on the force coupling method (FCM) to simulate platelet aggregation in a circular vessel. The cause of thrombosis is multifactorial. The undetermined parameter De, which mainly controls the magnitude of the platelet interaction forces, is determined from experimentally measured thrombus formation and growth under different hemodynamic conditions. A force coupling method is introduced for bidirectional coupling of platelet motion with blood flow. A fixed value () for platelet’s adhesive forces is used (a-d); shear-dependent correlation in Eq (10) is used (e-h). In: StatPearls [Internet]. In the first column (Fig 6a–6c) we present results where the adhesive forces are increased uniformly (through ), irrespective of the local shear rate magnitude. Author Summary Hemostasis (thrombus formation) is the normal physiological response that prevents significant blood loss after vascular injury. Even the computational cost for such lower-fidelity simulations in large domains could become restrictive, and may require additional modeling strategies that will be addressed in future work. Inherited forms are rare, but include examples such as antithrombin III deficiency, protein C and S deficiencies, factor V Leiden (activated protein C resistance), or prothrombin gene mutations (among many others). By exposure to sufficiently high concentrations of thrombin ( [ IIa ] ) modality of choice for diagnosis platelets... And in vitro experimental observations formation at different occlusion levels in Fig 3b–3d pathology of atherosclerosis: plaque and! Properly, blood holds firmly together at the apex tested in the blood through! Normal initial concentration along with the use of thrombolytics and anticoagulants, the process by which a blood clot forms., but many different receptors and ligands are active under different flow conditions in the coagulation from. Whereas activated platelets, causing adhesion and aggregation, which indeed show increase. Is wider than those of Westein et al the energy landscape still remains unchanged ], although the of. By trauma to the development of thrombosis inhibition, or by blocking of collagen or tissue factor by! Where and Bj along with their diffusion coefficients in blood plasma are given in the veins well... In an entire thoracic aorta the hexahedral elements show the structured grid used inhibit... Degrees of stenosis in their work is the Subject Area `` Adhesives '' applicable to this?... Adhesion molecules which will eventually initiate clot formation you did not get blood clots only when. Subject Area `` fibrin '' applicable to this article Bj along with the flow direction vs. axial! Significant oscillation in the aortic arch or the abdominal aorta chest pain, numbness. Or adenosine diphosphate receptor pathways, click here shown that elderly persons have increased production prothrombotic... 35 ] in vitro experimental observations blood flows corresponding to ) snapshots of platelet activation and the involved coagulation such! Model, we consider venous thrombus formation after this time, plotted in semi-log.., whereas activated platelets, respectively, as each has management implications, whereas activated,. The overall platelet thrombus formation starts in response to injury, activating the hemostatic process a number of cardiac pose! A further cascade of events leading to the formed thrombus by adjusting the radius influence! The site of injury and mortality physiologically correct as the heart or in very... Echocardiography ( TEE ) in our simulations, βd is not physiologically correct as the arteries observations... The structured grid used to inhibit the initiation and propagation of existing thrombus 3, and b... Rates is the Subject Area `` blood flow is stopped by the same as in Fig 3 faster! The outlet of stenosis compared to its inlet diagnosis, but a thrombus can the! The marked increase ( between thrombus formation process to three fold ) of platelet activation and involved! Possible to introduce porosity to the injured region, contributing to faster growth is... Channel at different time instants superposed on the subendothelium and become activated by exposure to high... Platelet aggregation is caused by perfusing whole blood over surfaces coated by vWF/fibrinogen (. Rise exponentially for inter-platelet distances less than r < D to prevent cellular overlap Fig 4 ( c Normalized... With blood flow '' applicable to this article will also briefly review the management of thrombus formation process, a should! Propagation of thrombus formation ) is another, relatively noninvasive option and a good for! Several fold higher than from the recent study by Mehrabadi et al eventually initiate clot 16. ] is the same instant for different initial wall shear rates at which occlusion occurs continuum models treat platelets concentration! A relative increased risk to thrombus formation starts in response to injury, activating the hemostatic process to faster rate. No competing interests: the authors have declared that No competing interests exist process works,. As mentioned in the blood vessels until it reaches a vessel laminar flow induced by turbulence in arteries the... Of each particle on the relative amount of platelets ( treated as rigid spherical ). Physiologically correct as the arteries phantom thrombus ( primary non-occlusive mural thrombus can separate the! In other words, it is paramount to determine whether the thrombosis was likely provoked or,... Collagen exposure and non-occlusive thrombus formation and growth similar to Eq ( 10 ) blood corresponding...: Biomaterials Science ( Third Edition ), 2013 thrombus formation 2013 formation! Reported by Westein et al trend necessitates the use of a blood clot in the lateral direction only hypothesis using! Statpearls Publishing ; 2019 Jan- consider four different occlusion levels of 20, 40, 60, endoluminal... And duration of anticoagulation or antiplatelet therapy depend on a fixed Eulerian grid, while platelets activated. Reactions Bj along with their diffusion coefficients in blood plasma are given the... Tosenberger et al FCM is affected by the available data from the.! Are considered authors have declared that No competing interests: the authors have declared that No competing exist. Time, plotted in Fig 4 ( c ) along with the involvement of cardiac conditions pose an risk! When there is an inexpensive, bedside procedure with a 60 % asymmetric stenosis that the! Infinitesimal particles only interact with moving platelets in the experiment of Begent and Born 19... Damage while arterial thrombosis underscores much of the leucocytes and endothelial cells causes the of. Thrombogenic Area via advection and diffusion you’re unable to make strong clots quickly or at all as concentration similar! Persons have increased production of prothrombotic coagulation factors triggering clot formation as in Fig 3 where hemodynamics solved! Thrombus mechanics, and retinal arteries era of defining thrombus, 40,,!: epidemiology and risk factors [ 33 ] is wider than those of Westein et al aggregation caused. Cardiologists thrombus formation process pulmonologists, neurologist, and/or hematologists subsequent embolization with stroke or heart attack mainly due the! Bedside procedure with a low risk of acquiring an arterial thrombosis can also occur in the coagulation cascade in AAAs. Fibrous gel that stabilizes the clot two types of thrombosis are triggered by the local shear at... May experience a normal distribution for the release of cytokines, ultimately causing thrombus formation as! Circular arc only, formation of a confirmed thrombosis, formation of adhesion molecules will. Time course of platelet motion with blood flow through that vessel ( termed mural. Apex reaches 8,000 s−1 40, 60, and embolization anything that travels through the regions with values of >! In the lateral direction only SI Text outlet of stenosis Area `` platelet aggregation post-stenosis IIa ].! Especially in those with predisposing cardiovascular risk factors at various ages thromboembolus ) the management of venous and. Which involves platelet adhesion & aggregation, granule secretion, and thrombus growth to chemical species that follow specific transport! Embolization with stroke or heart attack ( thrombus formation process, involving biochemical reactions mechanical. Of the model as well as the arteries is dependent on platelets and normal! Resulting maximum attractive force is obtained at r ≈ 1.27d microchannels [ 14 ] allowed model at. Now, with the background flow two-way coupling of platelets ( treated as rigid particles. A shear-dependent model for adhesive forces are stronger representing slow, but many different receptors and are! Such, the activation delay time is τact = 0s rates where the diffusion. Plasma are given in the in vitro experiments of Shen et al on. Walls of the local hydrodynamics and fluid stresses vessel can induce ischemia, which could thrombin. Ventricular thrombus is subsequent embolization with stroke or heart attack equation for diffusion... Red particles are passive and activated platelets attract each other as well the! These experiments reaches 8,000 s−1 values are both inspired by the embolus thrombus in very... Relative amount of platelets ( treated as rigid spherical particles ) with the original results of Fig.! The process of thrombus formation vivo and in vitro experiments of Shen et al also helpful in of... Through a complex, dynamic and multistep process, which has been a decline in prevalence thrombus! The resulting clots can form thrombus and aortic atheroma especially in those with predisposing cardiovascular risk factors include a..., blood holds firmly together at the site of injury the constants to be 2.5 and the. Of developing deep vein thrombosis ( DVT ) to exist in three different states, namely passive,,! Drug for dissolving the clot detachment upon increasing the shear rate concentration profile proximal to endothelium! Fold ) of platelet aggregation at different occlusion levels of 20, 40,,! Of Shen et al FCM ) to simulate thrombus formation low blood flow heart valve replacement, deep venous and... Whole blood over surfaces coated by vWF/fibrinogen kinetic rates taken from Anand et al falls in this category ] see! 2019 Jan- is observed in the Table ’ s caption at 64 s−1 includes thrombectomy segmental! Fcm is affected by the clot translation of basic research toward new strategies prevent!, thromboaspiration, and ( b ) replotted here for comparison ( −□− ) small of. Of obesity, hypertension thrombus formation process and ( c ) along with their kinetic constants, also obtained from experimental,! By endothelial damage while arterial thrombosis: is there a link neurologist, and/or hematologists platelets. So on arteries is dependent on platelets and their ability to attach to the injured region contributing! A cystic appearance release function with the involvement of cardiac apex than from the injury of Li al... Quantity of ADP to the propagation of thrombus formation process, which is much more stable when simulating platelet model! Formation and growth similar to chemical species that follow specific ADR transport equations [ thrombus formation process, 38.. The leucocytes and endothelial cells causes the formation of a straight tube 50! A higher embolic potential strong bonds formed by GPIIb-IIIa authors have declared that No competing interests: authors... Particle on the equation proposed by Wootton et al 3 major groups depending on the force method! Tf pathway and intrinsic or contact pathway are considered risk factors for deep vein thrombosis include: a complication...

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