A mathematical model of post-canalization thrombolysis

During the initial phase of lysis of an occlusive thrombus using lytic agents such as tissue plasminogen activator, blood flow through the centre of the clot is established (the process of recanalization). Following canalization, the clot remains on the vessel wall and further lysis is required. This paper develops a multi-species mathematical model to describe the bulk chemical reactions in the bloodstream and the convective and diffusive transport of chemical species to and from the clot surface in conditions following canalization. For the steady state case, the model indicates that the process of clot lysis following initial recanalization is dominated by surface chemical reactions and the bulk reactions play little role in the lytic process. Lytic rate is dependent on the clot geometry and flow conditions. The rate of clot dissolution is greatest at the upstream end of the clot and decreases steadily downstream due to lytic agent being removed from the flowing blood as it binds to the clot surface. This model may be further developed and used to simulate and compare different lytic regimes.     

Effect of blood gases and pH on thromboembolic reactions in rabbit mesenteric microvessels

The influence of changes in systemic blood gas and pH values on the thromboembolic reaction following wall puncture was studied in rabbit mesenteric arterioles and venules (diameter 20–40 m), using intravital videomicroscopy. Under normal circumstances the number of emboli produced was higher in arterioles than in venules (6 and 1, respectively). The initial thrombus growth, the number of emboli produced per vessel and the total duration of the embolisation period were not significantly influenced by changes in blood gas and pH values in both arterioles and venules. Therefore, the observed difference in thromboembolic reaction between arterioles and venules cannot be explained by differences in blood gas and pH values in these microvessels. Since reduced velocity, as a measure of wall shear rate, did not correlate with the thromboembolic reaction in arterioles or venules, fluid dynamics can also not explain the difference, indicating that the thrombogenic or anuthrombogenic activity of arteriolar and venular walls differs following injury. A combination of hypercapnia and hypoxia was found to result in a prolongation of the average time period needed to produce a new embolus in both vessel types. This prolongation in embolus production time was largely due to the occurrence of periods, in which the thrombus did not grow, reflecting hampering of the adhesion and aggregation of blood platelets to a growing thrombus under hypereapnic/hypoxic conditions.     

Numerical Modeling of the Flow in Intracranial Aneurysms: Prediction of Regions Prone to Thrombus Formation

The deposition of intralumenal thrombus in intracranial aneurysms adds a risk of thrombo-embolism over and above that posed by mass effect and rupture. In addition to biochemical factors, hemodynamic factors that are governed by lumenal geometry and blood flow rates likely play an important role in the thrombus formation and deposition process. In this study, patient-specific computational fluid dynamics (CFD) models of blood flow were constructed from MRA data for three patients who had fusiform basilar aneurysms that were thrombus free and then proceeded to develop intralumenal thrombus. In order to determine whether features of the flow fields could suggest which regions had an elevated potential for thrombus deposition, the flow was modeled in the baseline, thrombus-free geometries. Pulsatile flow simulations were carried out using patient-specific inlet flow conditions measured with MR velocimetry. Newtonian and non-Newtonian blood behavior was considered. A strong similarity was found between the intra-aneurysmal regions with CFD-predicted slow, recirculating flows and the regions of thrombus deposition observed in vivo in the follow-up MR studies. In two cases with larger aneurysms, the agreement between the low velocity zones and clotted-off regions improved when non-Newtonian blood behavior was taken into account. A similarity was also found between the calculated low shear stress regions and the regions that were later observed to clot.     

T型分叉血管中血液流动对动脉血栓形成的影响

目的 从血流动力学角度研究T型血管分叉处血液流动的改变对血栓形成的影响。主要从血流速度、分支直径、T型分叉角度及血液粘度方面研究血液流动对血栓形成的影响。同时结合相关医学病例,从多学科角度分析并验证医学研究中的有关血栓形成机理的猜测。方法 建立T-型动脉血管的几何模型,采用计算流体动力学方法对血管内流场进行数值分析研究,分析不同条件的流动对血栓形成影响。结果 在分叉血管附近的支血管和主血管中分别形成了两处较大区域的涡流区域,另外,在分叉交接处的下游位置也出现了一处较小的区域,这些区域速度较低,剪应力出现突然增大趋势,符合血栓形成,因此成为“最适成栓位置”。结论 血栓在“最适成栓位置”的形成还与分支血管直径、血管中血流速度、分叉角度以及血液粘度等有密切关系。     

In vivo dynamic light scattering imaging of blood coagulation

Physiological blood coagulation/clotting is an essential biological process that is initiated by vessel injury and includes a cascade of enzymatic reactions finalized by fibrin polymerization and clot formation. We utilize dynamic light scattering (DLS) imaging to monitor in vivo red cell mobility as an indicator of blood coagulation. In the course of the experiments, blood flow is arrested using mechanical occlusion, and then laser injury is applied. We demonstrate that the combination of laser injury with DLS imaging on occluded blood vessels (i.e., under static conditions) is suitable to detect even subtle changes of plasma viscosity in the circulatory system, which reflects the process of clot development. This approach is noninvasive and has a relatively simple and easy-to-use technical design. Thus, the proposed methodology provides a promising tool for investigating blood clotting within the vasculature.     

A Novel Plasma-Based Fluid for Particle Image Velocimetry (PIV): <Emphasis Type="Italic">In-Vitro</Emphasis> Feasibility Study of Flow Diverter Effects in Aneurysm Model

Particle image velocimetry (PIV) is a commonly used method for in vitro investigation of fluid dynamics in biomedical devices, such as flow diverters for intracranial aneurysm treatment. Since it is limited to transparent blood substituting fluids like water-glycerol mixture, the influence of coagulation and platelet aggregation is neglected. We aimed at the development and the application of a modified platelet rich plasma as a new PIV fluid with blood-like rheological and coagulation properties. In standardized intracranial aneurysm silicone models, the effect of this new PIV plasma on the fluid dynamics before and after flow diverter implantation was evaluated and compared with water-glycerol measurements. The flow diverting effect was strongly dependent on the used fluid, with considerably lower velocities achieved using PIV plasma, despite the same starting viscosity of both fluids. Moreover, triggering coagulation of PIV plasma allowed for intra-aneurysmal clot formation. We presented the first in vitro PIV investigation using a non-Newtonian, clottable PIV plasma, demonstrating a mismatch to a standard PIV fluid and allowing for thrombus formation.     

Underlying mechanisms of thrombus formation/growth in atherothrombosis and deep vein thrombosis

Thrombosis remains a leading cause of death worldwide despite technological advances in prevention, diagnosis, and treatment. The traditional view of arterial thrombus formation is that it is a platelet-dependent process, whereas that of venous thrombus formation is a coagulation-dependent process. Current pathological and basic studies on atherothrombosis and venous thrombosis have revealed the diverse participation of platelet and coagulation activation mechanisms in both thrombus initiation and growth processes during clinical thrombotic events. Atherosclerotic plaque cell-derived tissue factor contributes to fibrin formation and platelet aggregation. The degree of plaque disruption and a blood flow alteration promote atherothrombotic occlusion. While blood stasis/turbulent flow due to luminal stenosis itself initiates venous thrombus formation. The coagulation factor XI-driven propagation phase of blood coagulation plays a major role in venous thrombus growth, but a minor role in hemostasis. These lines of evidence indicate that atherothrombosis onset is affected by the thrombogenic potential of atherosclerotic plaques, the plaque disruption size, and an alteration in blood flow. Upon onset of venous thrombosis, enhancement of the propagation phase of blood coagulation under blood stasis and a hypercoagulable state contribute to large thrombus formation.     

Visualization study of the transient flow in the centrifugal blood pump impeller

Rotary blood pumps as a left ventricular assist device have several advantages over the use of existing pulsatile devices used for this purpose. The relative velocity distribution to the rotating impeller was observed by high-speed videography and particle image velocimetry (PIV) with the purpose of characterizing the unsteady fluid motion in the impeller and assessing antithrombogenicity based on the fluid dynamic properties within the flow path. Flow visualization in the present study has clearly shown the existence of drastic transient motion of flows in the impeller. The secondary flows developed in the passage, which are adverse in terms of hydrodynamic efficiency, contributed to the washout conditions on the blood contacting surface.     

Effect of carryover of clot activators on coagulation tests during phlebotomy

We investigated the effect of clot activators carried over from the serum tube on major coagulation tests during phlebotomy. First, blood specimens from 30 normal subjects were mixed with small amounts of fluid containing clot activators, and their effects on various coagulation tests were determined. Only the value of fibrin monomer complex displayed a remarkable change when thrombin-containing fluid was added to the blood specimens. Subsequently, 100 paired blood specimens (taken from 75 healthy volunteers and 25 patients taking warfarin) were collected in coagulation tubes before and after the serum tube using standard phlebotomy procedures. Various coagulation tests were performed to determine the effect of contamination of thrombin-containing blood on coagulation parameters. Differences between the 2 tubes were minimal but significant for some of the coagulation tests. Therefore, we conclude that the effect of clot activators in the serum tube on coagulation tests is minimal when standard phlebotomy procedures are used.     

Computational Model of Device-Induced Thrombosis and Thromboembolism

A numerical model of thrombosis/thromboembolism (T/TE) is presented that predicts the progression of thrombus growth and thromboembolization in low-shear devices (hemodialyzers, oxygenators, etc.). Coupled convection–diffusion-reaction equations were solved to predict velocities, platelet agonist (ADP, thromboxane A2, and thrombin) concentrations, agonist-induced and shear-induced platelet activation, and platelet transport and adhesion to biomaterial surfaces and adherent platelets (hence, thrombus growth). Single-platelet and thrombus embolization were predicted from shear forces and surface adhesion strengths. Values for the platelet-biomaterial reaction constant and the platelet adhesion strength were measured in specific experiments, but all other parameter values were obtained from published sources. The model generated solutions for sequential time steps, while adjusting velocity patterns to accommodate growing surface thrombi.Heparinized human blood was perfused (0.75 ml/min) through 580 μm-ID polyethylene flow cells with flow contractions (280 μm-ID). Thrombus initiation, growth, and embolization were observed with videomicroscopy, while embolization was confirmed by light scattering, and platelet adhesion was determined by scanning electron microscopy.Numerical predictions and experimental observations were similar in indicating: 1) the same three thrombotic locations in the flow cell and the relative order of thrombus development in those locations, 2) equal thrombus growth rates on polyethylene and silicon rubber (in spite of differing overall T/TE), and 3) similar effects of flow rate (1.5 ml/min versus 0.75 ml/min) on platelet adhesion and thrombosis patterns.     

Spatio-temporal Flow Analysis in Bileaflet Heart Valve Hinge Regions: Potential Analysis for Blood Element Damage

Point-wise velocity measurements have been traditionally acquired to estimate blood damage potential induced by prosthetic heart valves with emphasis on peak values of velocity magnitude and Reynolds stresses. However, the inherently Lagrangian nature of platelet activation and hemolysis makes such measurements of limited predictive value. This study provides a refined fluid mechanical analysis, including blood element paths and stress exposure times, of the hinge flows of a CarboMedics bileaflet mechanical heart valve placed under both mitral and aortic conditions and a St Jude Medical bileaflet valve placed under aortic conditions. The hinge area was partitioned into characteristic regions based on dominant flow structures and spatio-temporal averaging was performed on the measured velocities and Reynolds shear stresses to estimate the average bulk stresses acting on blood elements transiting through the hinge. A first-order estimate of viscous stress levels and exposure times were computed. Both forward and leakage flow phases were characterized in each partition by dynamic flows dependent on subtle leaflet movements and transvalvular pressure fluctuations. Blood elements trapped in recirculation regions may experience exposure times as long as the entire forward flow phase duration. Most calculated stresses were below the accepted blood damage threshold. Estimates of the stress levels indicate that the flow conditions within the boundary layers near the hinge and leaflet walls may be more detrimental to blood cells than bulk flow conditions, while recirculation regions may promote thrombus buildup.     

The vascular prosthesis without pseudointima prepared by antithrombogenic phospholipid polymer

On the luminal surface of the common synthetic vascular prostheses, blood coagulation can occur and a thrombus membrane is formed when blood flow passes through it. The thrombus membrane should be organized according to the wound healing process and it becomes a pseudointima which could serve as a blood conduit. However, the small-diameter vascular prosthesis may be quickly occluded by the initial thrombus. Therefore, no clinically applicable small-diameter prostheses have been developed to date. 2-Methacrylovloxyethyl phosphoryleholine (MPC) polymers resemble the structure of an outer cell membrane similar to the fluid mosaic model and demonstrate excellent antithrombogenicity. The purpose of this study is to develop a clinically applicable small-diameter prosthesis based on the new concept of the MPC polymer. We prepared vascular prostheses (2mm ID) from polymer blend composed of segmented polyurethane and the MPC polymer. The prostheses were placed in rabbit carotid arteries. The luminal surface retrieved at eight weeks after implantation was clear without thrombus and pseudointima. We now realize that the vascular prosthesis having the MPC polymer can be applied as a small-diameter prosthesis because it functions without thrombus and pseudointima formation.     

Blood coagulation and propagation of autowaves in flow

This study analyses the effect of flow and boundary reactions on spatial propagation of waves of blood coagulation. A simple model of coagulation in plasma consisting of three differential reaction-diffusion equations was used for numerical simulations. The vessel was simulated as a two-dimensional channel of constant width, and the anticoagulant influence of thrombomodulin present on the undamaged vessel wall was taken into account. The results of the simulations showed that this inhibition could stop the coagulation process in the absence of flow in narrow channels. For the used mathematical model of coagulation this was the case if the width was below 0.2 mm. In wider vessels, the process could be stopped by the rapid blood flow. The required flow rate increased with the increase of the damage region size. For example, in a 0.5-mm wide channel with 1-mm long damage region, the propagation of coagulation may be terminated at the flow rate of more than 20 mm/min.     

Multiscale Systems Biology and Physics of Thrombosis Under Flow

Blood clotting under hemodynamic conditions involves numerous multiscale interactions from the molecular scale to macroscopic vessel and systemic circulation scales. Transmission of shear forces to platelet receptors such as GPIbα, P-selectin, α(2)β(1), and α(2b)β(3) controls adhesion dynamics. These forces also drive membrane tether formation, cellular deformation, and mechanosignaling in blood cells. Blood flow results in red blood cell (RBC) drift towards the center of the vessel along with a near-wall plasma layer enriched with platelets. RBC motions also dramatically enhance platelet dispersion. Trajectories of individual platelets near a thrombotic deposit dictate capture-activation-arrest dynamics as these newly arriving platelets are exposed to chemical gradients of ADP, thromboxane, and thrombin within a micron-scale boundary layer formed around the deposit. If shear forces are sufficiently elevated (>50?dyne/cm(2)), the largest polymers of von Willebrand Factor may elongate with concomitant shear-induced platelet activation. Finally, thrombin generation enhances platelet recruitment and clot strength via fibrin polymerization. By combination of coarse-graining, continuum, and stochastic algorithms, the numerical simulation of the growth rate, composition, and occlusive/embolic potential of a thrombus now spans multiscale phenomena. These simulations accommodate particular flow geometries, blood phenotype, pharmacological regimen, and reactive surfaces to help predict disease risk or response to therapy.     

Tuning a lattice-Boltzmann model for applications in computational hemodynamics

The interest in lattice-Boltzmann models in the computational hemodynamics realm has increased in recent years. In this context, the correct choice of numerical parameters for the appropriate simulation of blood flows in major arteries is a crucial aspect. For this reason, we present three parameter-tuning strategies that allow us to reproduce correctly the pulsatile time-dependent flow of an incompressible fluid under physiological regimes. These strategies are studied for a model based on a single-relaxation-time approach in combination with second order boundary conditions for both velocity and pressure, and proper equilibrium distributions that take care of the incompressible behavior exhibited by the fluid. The implementation is validated with the three-dimensional Womersley flow benchmark. As well, the simulation of blood flows in a curved artery, in an anastomosed vessel, in a patient specific vertebral artery and in an aneurysmal region are presented in order to show how the method and the setting of the numerical parameters are applied to different realistic hemodynamics problems.     

一种血管内支架的有限元模型及计算流体动力学分析

支架植入所造成的血栓、血管损伤及其对血流动力学的影响是造成支架内再狭窄的主要原因。我们利用有限元模型与计算流体动力学的方法,分析了一种支架在植入过程中与斑块、血管的相互作用及其对血流情况的影响。结果发现：支架植入后端部发生翘起,这容易损伤血管壁;支架植入模型所对应的即刻回缩率明显高于支架自身的回缩率,其结果分别为12.3%、3.1%;支架壁厚与连接筋设计能够引起血管壁面剪应力的明显变化。这对于血管内支架的设计具有一定的指导意义。     

Simulation of Intrathrombus Fluid and Solute Transport Using In Vivo Clot Structures with Single Platelet Resolution

The mouse laser injury thrombosis model provides up to 0.22 μm-resolved voxel information about the pore architecture of the dense inner core and loose outer shell regions of an in vivo arterial thrombus. Computational studies were conducted on this 3D structure to quantify transport within and around the clot: Lattice Boltzmann method defined vessel hemodynamics, while passive Lagrangian Scalar Tracking with Brownian motion contribution simulated diffusive-convective transport of various inert solutes (released from lumen or the injured wall). For an input average lumen blood velocity of 0.478 cm/s (measured by Doppler velocimetry), a 0.2 mm/s mean flow rate was obtained within the thrombus structure, most of which occurred in the 100-fold more permeable outer shell region (calculated permeability of the inner core was 10^?11 cm²). Average wall shear stresses were 80–100 dyne/cm² (peak values >200 dyne/cm²) on the outer rough surface of the thrombus. Within the thrombus, small molecule tracers (0.1 kDa) experienced ~70,000 collisions/s and penetrated/exited it in about 1 s, whereas proteins (~50 kDa) had ~9000 collisions/s and required about 10 s (tortuosity ~2–2.5). These simulations help define physical processes during thrombosis and constraints for drug delivery to the thrombus.     

龙津对体外血栓形成、凝血及纤维蛋白溶解作用的实验研究

在正常和DIC家兔或大鼠中证明,口服龙津后,体外血栓长度缩短,血栓重量减轻,全血凝块和纤维蛋白凝块溶解加速,KPTT延长,ELT缩短,t-PA活性增强(P<0.05)。以上资料提示龙津有抗凝和溶栓的双重作用。     

Micro-scale Dynamic Simulation of Erythrocyte–Platelet Interaction in Blood Flow

Platelet activation, adhesion, and aggregation on the blood vessel and implants result in the formation of mural thrombi. Platelet dynamics in blood flow is influenced by the far more numerous erythrocytes (RBCs). This is particularly the case in the smaller blood vessels (arterioles) and in constricted regions of blood flow (such as in valve leakage and hinge regions) where the dimensions of formed elements of blood become comparable with that of the flow geometry. In such regions, models to predict platelet motion, activation, aggregation and adhesion must account for platelet–RBC interactions. This paper studies platelet–RBC interactions in shear flows by performing simulations of micro-scale dynamics using a computational fluid dynamics (CFD) model. A level-set sharp-interface immersed boundary method is employed in the computations in which RBC and platelet boundaries are tracked on a two-dimensional Cartesian grid. The RBCs are assumed to have an elliptical shape and to deform elastically under fluid forces while the platelets are assumed to behave as rigid particles of circular shape. Forces and torques between colliding blood cells are modeled using an extension of the soft-sphere model for elliptical particles. RBCs and platelets are transported under the forces and torques induced by fluid flow and cell–cell and cell–platelet collisions. The simulations show that platelet migration toward the wall is enhanced with increasing hematocrit, in agreement with past experimental observations. This margination is seen to occur due to hydrodynamic forces rather than collisional forces or volumetric exclusion effects. The effect of fluid shear forces on the platelets increases exponentially as a function of hematocrit for the range of parameters covered in this study. The micro-scale analysis can be potentially employed to obtain a deterministic relationship between fluid forces and platelet activation and aggregation in blood flow past cardiovascular implants.     

轴流血泵入口管道流场的数值模拟与实验研究

目的研究轴流血泵入口管道内血流流场分布情况及血栓形成风险。方法利用计算流体力学(computational fluid dynamics,CFD)模拟血泵及入口管道内流动情况,获取血流速度及其分布;用二维粒子成像测速(particle image velocimetry,PIV)系统测试轴流血泵入口管道中心截面内的血液流动情况及三维粒子成像测速系统测试整个管道内的血液流动情况。CFD计算和PIV实验中血泵的转速为8000 r/min,流量为5.0 L/min。通过分析入口管道内的流场分布评价血泵入口管道内的血栓形成风险。结果整个入口管道内不存在回流、涡流和低速流动区域,血液沿管道的流动速度在管壁边界层外由0 m/s迅速增大到0.8 m/s以上。管道内的血液流速集中分布于1.2~1.5 m/s范围,管道内的平均紊流度为0.17。结论由于管道内的流动平稳且不存在回流、涡流和低速流动,因此不易形成血栓。入口管道使血流平稳,有助于改善轴流血泵内的流场。