Mitigation of device-associated thrombosis and thromboembolism using combinations of heparin and tirofiban

Combined anti-platelet-anticoagulant therapy is increasingly being used to reduce the risk of device-induced thrombosis and thromboembolism. However, direct quantitative confirmation of the effectiveness of this combination approach is lacking. This study was undertaken to quantify the effects of various combinations of heparin (anticoagulant) and tirofiban (antiplatelet agent) on device-induced thrombosis and thromboembolism using a coronary stent as a prototype device. Adult sheep were implanted with ex vivo carotid-carotid shunts containing replaceable tubing segments in which nitinol stents were deployed. Nine combinations of heparin (average activated clot time = 129, 199, and 355 seconds) and tirofiban (0%, 50%, and 100% platelet inhibition) were tested at random with three replicates per animal. Thrombus weight on the stent at the end of each experiment (1 hour) was measured, and emboli released from the stent were continuously monitored during the experiment using a light scattering microemboli detector. With no tirofiban, increasing the heparin concentration was associated with a decreased endpoint thrombus weight (p < .05) but with a slight (non-significant) increase in the number of downstream thromboemboli. However, the presence of tirofiban decreased both thrombus weight and thromboemboli numbers (p < .05), regardless of the heparin concentration. In the presence of medium or high tirofiban, an increase of heparin from low to medium levels also decreased both thrombus weight and thromboemboli numbers (p < .05). Heparin alone does not provide adequate protection against thromboembolism (and may actually increase it by reducing thrombus cohesive strength). However, the combination of heparin and tirofiban is effective in reducing both thrombus and thromboemboli, and an optimal combination may exist.