Prevention of arterial thrombosis using a novel heparin with enhanced antiplatelet activity and reduced anticoagulant activity

Purpose: Thrombosis after arterial injury is often initiated by von Willebrand factor (vWF)-dependent. platelet accumulation. A promising antithrombotic strategy is the interruption of platelet/vWF interactions, Previously, Rie demonstrated Iron chemical and affinity modification can entrance heparin's anti-vWF activity while reducing conventional anticoagulation, Here, we investigated whether a modified heparin can block platelet-dominated arterial thrombosis. Methods: Standard heparin Nas oxidized with periodate, refined to have high affinity and inhibitory potency, and tested in a guinea pig model of platelet-dependent arterial thrombosis. In this model, a controlled mechanical arterial injury yields cyclic flow variations (CFVs) caused by recurrent accumulation of platelet thrombi, Results: All six control animals developed CFVs (mean, 10.4 +/- 2.6 CFVs), and six of seven animals treated with standard heparin also developed CFVs (mean, 7.6 +/- 4.6), Only one of six animals treated with the anti-vWF heparin and one of six treated with AJvW-2 (an anti-vWF antibody) developed CFVs (mean, 2.0 +/- 4.9 and 0.5 +/- 1.2, respectively). Thus both the modified heparin and AJvW-2 were more effective than standard heparin (p < 0.03). Bleeding rimes and platelet counts were unaffected. A modified activated partial thromboplastin time tvas less prolonged by the modified high-affinity heparin (91 +/- 17 seconds) than by standard heparin (144 +/- 30 seconds; p < 0.01). Conclusions: The modified heparin with high vWF affinity was a more effective arterial antithrombotic agent, with fewer conventional anticoagulant effects than standard hepa rin, Interruption of the vWF/platelet interaction is a promising antithrombotic strategy that may be net by novel heparin-based antithrombotic drugs.