Saratin,an Inhibitor of Collagen-Platelet Interaction,Decreases Venous Anastomotic Intimal Hyperplasia in a Canine Dialysis Access Model

Abstract

Prosthetic dialysis access thrombosis and/or stenosis is the most common cause of graft impairment or loss and is primarily attributed to venous outflow stenosis due to intimal hyperplasia. Intimal hyperplasia is thought to result from interactions between areas of exposed subendothelial collagen in an injured vessel and platelets, resulting in platelet adhesion. Saratin, an inhibitor of the WF-dependent binding of platelet to collagen interaction, has been shown in vitro to reduce the adhesion of platelets to collagen. In the current study, the authors inves-tigated the effects of topical saratin administration in a canine dialysis access model in regard to intimal hyperplasia development at the venous anastomosis. Fourteen female mongrel dogs underwent placement of a femoral polytetrafluoroethylene (PTFE) dialysis access graft and were placed into 1 of 2 groups: 1) control or 2) experimental with topical saratin application. The experimental group had 600,μg of saratin (1 μg/,μL) applied for 5 minutes directly onto the venous anastomosis before restoration of blood flow; control groups received vehicle control. At 4 weeks postoperative, a portion of the graft was removed along with a segment of the outflow vein. Veins were subsequently processed, sectioned, and analyzed along the length of the excised segment and divided into blocks that included the area of the graft toe, midanastomotic region and heel, and blocks A-E. Intimal hyperplasia was assessed by a computerassisted morphometric analysis. Platelet counts and bleeding times were also measured. Vein segments in the control group (n= 7) showed pronounced intimal hyperplasia in blocks B, C, and D as compared to the saratin group (n = 6). Distribution of intimal hyperplasia by blocks between control and saratin groups were as follows: block [A] 8.6 ±1.9 vs 9.7 ±3.0% (p = NS), [B] 32.7 ±6.3 vs 10.7 ±3.5% (p=0.01), [C] 44.8 ±6.2% vs 10.3 ±1.5% (p=0.0004), [DI 40.8 ±1 1.0 vs 9.1 ±4.2% (p = 0.02), [E] 7.5 ±5.5 vs 2.7 ±0.4% (p = NS). Intimal hyperplasia normalized to vein wall thickness also showed a significant reduction with saratin application. Bleeding times and platelet counts obtained at different time points during the experiment showed no difference between control and saratin groups. In a canine dialysis access model using PTFE grafts, topical application of saratin at the venous anastomosis decreased intimal hyperplasia development by as much as 77% when compared with control animals. Saratin provides for a method of substantially reducing intimal hyperplasia by direct local application without systemic side effects.

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