Suppression mechanisms for thrombus formation on heparin-immobilized segmented polyurethane-ureas

Heparin-immobilized segmented polyurethane-ureas (Biomer, Ethicon Co., Somerville, NJ) containing long poly(ethylene oxide) spacers (Mn = 4,000) have shown excellent nonthrombogenic properties through enhanced heparin bioactivity in vitro. In this study, three different surfaces, Biomer (B), PEO-grafted Biomer (B-PEO) and heparin-immobilized Biomer with PEO spacers (B-PEO-Hep), were investigated, using a rabbit A-A shunt model. Occlusion times, at various flow rates (2.5, 5.0, 7.5, and 15.0 ml/min) were measured using surface modified tubings (1.5 mm ID, 30 cm length) inserted into rabbit carotid arteries. Platelet count, aggregability, and activated partial thromboplastin time (aPTT) were measured with whole blood to observe systemic effects in ex vivo experiments. For Biomer and B-PEO, occlusion times were prolonged with an increasing flow rate, while platelet count and aggregability decreased. B-PEO showed prominent prolongation of occlusion time at flow rates over 5.0 ml/min with decreased platelet count and aggregability, indicating surface-induced platelet activation and systemic thromboembolization possibly caused by the presence of PEO. In contrast, B-PEO-Hep surfaces showed the longest and relatively flow-rate-independent occlusion times without detectable platelet activation. We concluded that the improved ex vivo blood compatibility of B-PEO-Hep, compared with Biomer and B-PEO, is due to the prevention of fibrin net formation by immobilized heparin, resulting in a reduction in fibrin related platelet aggregation and subsequent thrombus formation.