Covalently-bound heparin makes collagen thromboresistant

Objective - Blood compatibility of artificial surfaces depends on their immunogenic and thrombogenic properties. Collagen's weak antigenicity makes it an attractive candidate for stent coatings or fabrication of vascular grafts. However, the thrombogenic nature of collagen limits its application. We examined whether heparinization can make collagen more thromboresistant. Methods and Results - Collagen was heparinized by crosslinking collagen with extensively periodate oxidized heparin and/or by covalently bonding of mildly periodate oxidized heparin. Both ways of heparinization have no effect on platelet adhesion and could not abolish induction of platelet procoagulant activity. However, thrombin generation was completely prevented under static and flow conditions. The functionality of immobilized heparin was confirmed by specific uptake of antithrombin, 13.5 +/- 4.7 pmol/cm(2) and 1.95 +/- 0.21 pmol/cm(2) for mildly and heavily periodated heparin, respectively. Conclusions - These results indicate that immobilization of heparin on collagen, even as a crosslinker, is a very effective way to prevent surface thrombus formation. These data encourage the application of heparinized collagen as stent-graft material in animal and eventually human studies.