Thrombosis Modulates Arterial Drug Distribution for Drug-Eluting Stents

Abstract

Background-Drug-eluting stents deliver potent compounds directly to arterial segments but can become clot laden when deployed. The question arises as to whether thrombi affect drug elution and arterial uptake. Methods and Results-Paclitaxel transport and retention were assessed in clots of different blood components. Diffusivity, affected by clot organization, is fastest in fibrin (Ϸ347 m 2 /s), slower in fibrin-red blood cell clots (34.98 m 2 /s), and slowest in whole-blood clots (3.55 m 2 /s). Blood cells bind and retain paclitaxel such that levels in clot increase linearly with red cell fraction. At physiological hematocrit, clot retains 3 times the amount of paclitaxel in surrounding solutions. Computational models predict that the potential of thrombus to absorb, retain, and release drug or to act as a barrier to drug delivery depends on clot geometry and strut position in clot relative to the vessel wall. Clot between artery and stent can reduce uptake 10-fold, whereas clot overlying the stent can shield drug from washout, increasing uptake. Model assumptions were confirmed and predictions were validated in a novel rat model that introduces thrombosis within stented aortas where nonocclusive thrombus acts as capacitive space for drug and shifts drug levels to decrease tissue uptake 2-fold. Conclusions-Thrombus apposed on stents creates large variations in drug uptake and can act to either increase or decrease wall deposition according to the clot and stent geometry. Arterial deposition of drug from stents deployed in clots will be highly variable and unpredictable unless the clot can be adequately controlled or removed.

Arterial Mass Transport Behaviour of Drugs from Drug Eluting Stents

“…The greater the volume of clot covering the strut, and the closer the strut is to the wall, creates improved conditions for greater drug delivery. Hwang et al (2005) discovered that in this configuration concentration distribution in the wall can be 30 fold higher than situations where no clot is present. Similarly thrombus or plaque between the strut and the artery wall act as a buffer layer and reduce wall concentrations.…”

“…Illustration of the cross-sectional structure of a healthy artery wall. Hwang et al (2005) were among the first to explore the influence of thrombus height, width and type on the arterial drug uptake. Stents can be deployed at sites of thrombus and after implantation a clot will inevitably develop once the struts become covered with plasma proteins.…”

“…They concluded that the proximity of the device does not necessarily ensure adequate targeting because transport forces can cause local concentrations to deviate from the mean concentration. In a later paper Hwang et al (2005) evaluated the paclitaxel uptake in stented abdominal aortas of adult male Sprague-Dawley rats in the presence and absence of controlled mural thrombus. The in vivo clot dimensions were determined and used as boundary conditions and input parameters for the computational model.…”

“…The computational analysis predicted an arterial drug ratio of 0.56 which correlates with the 50% decrease in arterial uptake ascertained from the animal experiments. Hwang et al (2005) discovered that by varying clot size and location, large variations in arterial uptake were witnessed. In 2007, Balakrishnan et al deployed a Cypher sirolimus eluting stents in porcine arteries.…”

Early restenosis after drug-eluting stent implantation: A putative role for platelet activation

“…In addition, stent thrombosis with DES may be linked to a decreased efficacy of DES in preventing restenosis. In an animal model, Hwang et al (11) have shown that thrombus apposition within a DES creates large variations in drug elution, rendering drug delivery to the vessel wall unpredictable. The presence of a thrombus may therefore create a situation specific to DES, compared with bare metal stents, eventually being linked to the occurrence of neointimal hyperplasia and restenosis.…”