In vivo rabbit acute model tests of polyurethane catheters coated with a novel antithrombin-heparin covalent complex

Summary

Catheter use has been associated with an incresed risk of thrombotic complications. The objective was to make catheters less thrombogenic with the use of antithrombin-heparin covalent complex (ATH). The antithrombotic activity of ATH-coated catheters was compared to uncoated (control) and heparincoated catheters in an acute rabbit model of accelerated occluding clot formation. Anaesthetized rabbits were pre-injected with rabbit 125I-fibrinogen,followed by insertion of test catheters into the jugular vein. Blood was drawn and held in a syringe, reinjected, then flushed with saline. The experiment was terminated when blood could no longer be withdrawn (occluding clot). Efficacy was defined as the ability of catheters to remain unoccluded. Clot formation, determined by measuring deposition of radiolabeled fibrin, was a secondary endpoint. ATH-coated catheters were resistant to clotting for the full 240-minute duration, while uncoated and heparin-coated catheters had an average clotting time of 78 and 56 minutes, respectively. The patency ofATH coating was dependant on intact heparin pentasaccharide sequences, rather than the chemistries of the basecoat, the PEO spacer arm, or the antithrombin (AT) protein. The ATH coating was stable to ethylene oxide sterilization, modest abrasion, protease attack, and the coating did not appear to leach off the catheter. Surface tension measurements showed that the ATH modified surface was more hydrophilic than uncoated control catheters or heparin-coated catheters. Thus, ATH-coated catheters are better at preventing clots than uncoated or heparin-coated catheters and show promise as an alternative to the currently available catheters in reducing thrombotic complications associated with its use.

Keywords

Anticoagulant - ATH - polyurethane - modified catheters - surface grafting

• References

• 1 Andrew M, Marzinotto V, Pencharz P. et al. A crosssectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home. J Pediatr 1995; 126: 358-63.
• 2 Joffe HV, Goldhaber SZ. Upper-extremity deep vein thrombosis. Circulation 2002; 106: 1874-80.
• 3 Randolph AG, Cook DJ, Gonzales CA. et al. Benefit of heparin in central venous and pulmonary artery catheters: a meta-analysis of randomized control trials. Chest 1998; 113: 165-71.
• 4 Monreal M, Alastrue A, Rull M. et al. Upper extremity deep venous thrombosis in cancer patients with venous access devices-prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 1996; 75: 251-3.
• 5 Spijker HT, Graaff R, Boonstra PW. et al. On the influence of flow conditions and wettability on blood material interactions. Biomaterials 2003; 24: 4717-27.
• 6 Chan A, Berry L, Mitchell L. et al. Evaluation of antithrombin-heparin covalent complex coated endoluminal grafts in rabbits. Transactions Soc Biomat 1999; 22: 102.
• 7 Chan AKC, Berry L, Andrew M, Klement P. Antithrombin- heparin covalent complex: a novel approach for improving thromboresistance of cardiovascular devices. International Biomaterials Congress. 2000
• 8 Klement P, Du YJ, Berry L. et al. Blood-compatible biomaterials by surface coating with a novel antithrombin- heparin covalent complex. Biomaterials 2002; 23: 527-35.
• 9 Chan A, Berry L, Klement P. et al. A novel antithrombin- heparin covalent complex: antithrombotic and bleeding studies in rabbits. Blood Coagul Fibrinolysis 1998; 9: 587-95.
• 10 Klement P, Liao P, Bajzar L. A novel approach to arterial thrombolysis. Blood 1999; 94: 2735-43.
• 11 Klement P, Liao P, Hirsh J. et al. Hirudin causes more bleeding than heparin in a rabbit ear bleeding model. J Lab Clin Med 1998; 132: 181-5.
• 12 Green D, Klement P, Liao P. et al. Interaction of low molecular weight heparin with ketorolac. J Lab Clin Med 1996; 127: 583-7.
• 13 Chan A, Berry L, O’Brodovich H. et al. Covalent antithrombin-heparin complexes with high anticoagulant activity. Intravenous, subcutaneous, and intratracheal administration. J Biol Chem 1997; 272: 22111-7.
• 14 Paredes N, Wang A, Berry L. et al. Mechanisms responsible for catalysis of the inhibition of factor Xa or thrombin by antithrombin using a covalent antithrombin- heparin complex. J Biol Chem 2003; 278: 23398-409.
• 15 Berry L, Andrew M, Chan A. Antithrombin-heparin complexes. Dumitriu S. Polymeric Biomaterials. Part II: Medical and Pharmaceutical Applications of Polymers.. New York: Marcel Dekker Inc.; 2001: 669-702.
• 16 Berry L, Stafford A, Fredenburgh J. et al. Investigation of the anticoagulant mechanisms of a covalent antithrombin-heparin complex. J Biol Chem 1998; 273: 34730-6.
• 17 Chan AKC, Paredes N, Thong B. et al. Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin. Thromb Haemost 2004; 91: 1009-18.