Detailed examination of the mode of action and fate of surface bound heparin is important to the assessment of the oft-stated but never proven concerns regarding the use of heparin in long term implants: 1) the necessity for a heparin microenvironment 2) saturation of bound heparin 3) consumption of blood components 4) enhanced platelet disposition. Work to date has shown that heparin immobilized on polyvinyl alcohol by glutaraldehyde crosslinking (heparin-PVA) need not be lost from the surface to impart thrombo-resistance to the PVA or underlying substrate as measured by various in vitro assays and in a novel AV shunt model in dogs. Furthermore the bound thrombin-antithrombin III inactive complex is readily displaced from the surface by plasma (yielding post-complex antithrombin III and presumably post-complex thrombin) indicating that the surface bound heparin does not become saturated with inactive complex. Platelet interactions appear to be more complex and these are the primary focus of this proposal. The platelet compatibility of heparin-PVA coated polyethylene tubing will be compared with that of control PVA tubing without heparin in a chronic shunt in dogs, by measuring the platelet consumption rate and by measuring the platelet deposition profile as a function of time at low flowrates in our parallel flow shunt. This ex vivo compatibility and the previously determined in vitro response of platelets will be compared with that observed for PVA surfaces which have been modified by immobilization of polyethylene glycol, or PGE1 or PGE2 with the intention of reducing the platelet reactivity of the substrate. Also the potential to """"""""neutralize"""""""" or """"""""bypass"""""""" the immobilized heparin will be studied, the in vitro displacement behaviour of bound thrombin will be subject to further clarification and the dose effect relationship for immobilized heparin will be determined in the parallel flow AV shunt model. The potential thromboresistance of heparinized materials warrants these detailed investigations. With this information it may be possible to use heparinized materials in the cardio-circulatory assist devices and blood handling procedures that await the development of blood compatible materials.
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