Abstract-Biocompatible stent coatings may alleviate problems of increased (sub)acute thrombosis after stent implantation. Hyaluronic acid (HA), a ubiquitous, nonsulfated glycosaminoglycan, inhibits platelet adhesion and aggregation and prolongs bleeding when administered systemically. However, the effects of immobilized HA for reducing stent platelet deposition in vivo are unknown. We therefore quantified the antithrombotic effects of coating stainless steel stents and tubes with HA using an established baboon thrombosis model under physiologically relevant blood flow conditions. HA-coated and uncoated (control) stents (3.5 mm in diameter, nϭ32) and stainless steel tubes (4.0 mm in diameter, nϭ18) were deployed into exteriorized arteriovenous shunts of conscious, nonanticoagulated baboons. Accumulation of 111In-radiolabeled platelets was quantified by continuous gamma-camera imaging during a 2-hour blood exposure period. HA coating resulted in a significant reduction in platelet deposition in long (4 cm) tubes (0.24Ϯ0.15ϫ10 9 versus 6.12Ϯ0.49ϫ10 9 platelets; PϽ0.03), short (2 cm) stainless steel tubes (0.18Ϯ0.06ϫ10 9 versus 3.03Ϯ0.56ϫ10 9 platelets; PϽ0.008), and stents (0.82Ϯ0.20ϫ10 9 versus 1.83Ϯ0.23ϫ10 9 platelets; PϽ0.02) compared with uncoated control devices. Thus, HA coating reduces platelet thrombus formation on stainless steel stents and tubes in primate thrombosis models. These results indicate that immobilized HA may represent an attractive strategy for improving the thromboresistance of endovascular devices. Key Words: thrombosis Ⅲ stents Ⅲ hyaluronic acid Ⅲ baboon S tent thrombosis results from a series of complex interactions involving the presence of a thrombogenic surface, the damaged vascular wall, altered blood flow, and the activation of platelets and coagulation proteins. 1 The effectiveness of antiplatelet agents in reducing thrombosis in atherosclerotic disease has been demonstrated with aspirin and clopidogrel. 2,3 Ticlopidine has been shown to reduce periprocedural thrombotic events in coronary stenting to 1% to 2% in low-and intermediate-risk groups. 4,5 However, the incidence of stent thrombosis is substantially increased in higher-risk patients. 6 In addition, aspirin and ticlopidine may produce significant side effects. 7 These findings suggest a need for further improvements in antithrombotic strategies associated with coronary stenting.Coating stents with biocompatible and nonthrombogenic materials is an attractive alternative for further reducing (sub)acute stent thrombosis. A number of different stent coatings have been evaluated previously. 8 -13 Results with these coatings, including antithrombotic agents and components of cell membranes (biomimicry), appear promising, although larger studies and more cost-effective coatings are needed. 14,15 Hyaluronic acid (HA) is a ubiquitous, nonsulfated glycosaminoglycan component of the extracellular matrix. Both HA and immobilized sulfated HA have been shown to inhibit platelet aggregation and platelet adhesion, as well as to prolong ble...
Thrombosis on an atherosclerotic lesion can cause heart attack or stroke. Thrombosis may be triggered by plaque rupture or erosion, creating a thrombogenic stenosis. To measure and model this situation, collagen-coated stenoses have been exposed to nonanticoagulated blood in a baboon ex vivo shunt. The maximum rate of platelet accumulation, measured using a gamma camera, was highest in the throat region of moderate and severe stenoses, and increased with increasing stenosis severity. A species transport model of platelet accumulation was developed, which included mechanisms of convection, shear-enhanced diffusion, near-wall platelet concentration, and a kinetic model of platelet activation and aggregation. The model accurately reproduced the average spatial pattern and time rate of platelet accumulation in the upstream and throat regions of the stenosis, where shear-enhanced diffusivity increased platelet transport in the stenosis throat. Downstream of the throat where flow is complicated by recirculation, the model computed a transport-limited region with lower than measured platelet accumulation, suggesting that fluid-phase platelet activation may significantly affect both transport and adhesion rates in the poststenotic region. This model may provide an initial quantitative estimate of the likelihood of occlusive thrombus in individual patients due to plaque erosion, artery spasm, incomplete angioplasty, or plaque rupture.
This study suggests that MRI could be used as a complete diagnostic tool for accurate evaluation of aortic coarctation, by determining stenosis location and severity and by accurately estimating pressure gradients.
Atherosclerosis of the human arterial system produces major clinical symptoms when the plaque advances to create a high-grade stenosis. The hemodynamic shear rates produced in high-grade stenoses are important in the understanding of atheromatous plaque rupture and thrombosis. This study was designed to quantify the physiologic stress levels experienced by endothelial cells and platelets in the region of vascular stenoses. The steady hemodynamic flow field was solved for stenoses with percent area reductions of 50, 75, and 90 percent over a range of physiologic Reynolds numbers (100-400). The maximum wall shear rate in the throat region can be shown to vary by the square root of the Reynolds number. The shear rate results can be generalized to apply to a range of stenosis lengths and flow rates. Using dimensions typical for a human carotid or coronary artery, wall shear rates were found to vary from a maximum of 20,000 s-1 upstream of the throat to a minimum of -630 s-1 in the recirculation zone for a 90 percent stenosis. An example is given which illustrates how these values can be used to understand the relationship between hemodynamic shear and platelet deposition.
Local delivery of anti-thrombotic and anti-restenotic drugs is desired to achieve high concentrations of agents which may be rapidly degraded systemically or which exhibit very short half-lives in vivo. In this article, the operating characteristics of a novel local drug delivery method are described and its effectiveness demonstrated computationally and experimentally. Computational models used a finite volume method to determine the concentration field. Optical dye density measurements of Evans blue in saline were performed in an in vitro steady flow system. Modeling parameters were kept in the physiologic range. Experimental flow visualization studies demonstrated high concentrations of infusate near the vessel wall. Computational studies predicted high, clinically significant drug concentrations along the wall downstream of the infusion device. When the radial infusion velocity is large (infusion flow rate, Qinf>0.5% of the main flow rate, Q), the wall concentration of the infused drug remains high, e.g., levels are greater than 80% of the infusate concentration 5 cm downstream of the infusion device. At lower infusion rates (Qinf<0.001Q), the drug concentration at the wall decreases exponentially with axial distance to less than 25% of the infusate concentration 5 cm downstream of the infusion device, although therapeutic drug levels are still readily maintained. The near wall drug concentration is a function of flow conditions, infusion rate, and the drug diffusivity. Good agreement was obtained between computational and experimental concentration measurements. Flow simulation and experimental results indicate that the technique can effectively sustain high local drug concentrations for inhibition of thrombosis and vascular lesion formation.
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