Reduced Thrombus Formation by Hyaluronic Acid Coating of Endovascular Devices

Abstract

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...

Attachment of hyaluronan to metallic surfaces

“…These results are consistent with other research groups that have shown that polymer surfaces coated with HA are relatively passive toward platelet adhesion and activation, 18,19,59 while stainless steel promotes platelet adhesion and activation. 19 On the RGD-HA surface [ Fig. 4(d)] rounded and partially spread platelets were observed, but very few (if any) spread platelets were present.…”

“…As mentioned, the lack of platelet adhesion on the HA-coated surface is consistent with other reports, 18,19,59 and indicates that the HA is adequately coating the sample and is masking the underlying aldehyde, silane, and steel. Presumably, platelets sedimented onto the HA surface during the 30 min of incubation, but they may not have adhered sufficiently to resist removal during the mild rinsing procedure.…”

“…This technique precludes the use of a carbodiimide that is required for many types of attachment syntheses 9,18,19,58 Because aldehyde silanes are not available, the aldehyde group was created from an epoxy silane after the epoxy was firmly attached to a clean metal surface. Our results show that we were successful in creating an aldehyde-functionalized metal surface.…”

“…16 However, in general, platelet adhesion and activation, and thrombus formation are greatly reduced or nearly absent on surfaces coated with HA and some of its derivatives. [17][18][19] For example, Abatangelo et al have shown that sulfated derivatives of HA are noncytotoxic, resistant to enzymatic degradation, and retain antithrombogenic properties. 20 Further research on sulfated HA has shown that when photoimmobilized on a poly(ethylene terephthalate) surface, HA retained these same antithrombogenic properties.…”

Thromboembolic Disease and Antithrombotic Therapy in Newborns

“…163 New catheter materials in the clinical and preclinical stage of development, such as Hyaluronic Acid coated catheters and AT-heparin covalent complex coated catheters may prove to be useful in the future. 204,205 The latter is of particular interest in newborns who have decreased levels of AT.…”