Comparison of Diazeniumdiolated Dialkylhexanediamines as Nitric Oxide Release Agents on Nonthrombogenicity in an...

When blood from a patient is circulated through extracorporeal circuits (ECCs), such as in cardiopulmonary bypass or extracorporeal life support, platelets in the blood are activated and form a thrombus. This is prevented clinically with a range of different systemic anticoagulation agents (e.g., heparin); however, this increases a patient's risk of hemorrhage. Previous work with nitric oxide (NO) releasing materials using the combined diazeniumdiolated diamine, N-N-di-N'-butyl-1,6-hexanediamine (DBHD), and a polymer-linked thrombin inhibitor, argatroban (AG), showed significant nonthrombogenicity in ECCs using a 4 h rabbit model. Herein, we evaluated if diazeniumdiolated N-N-di-N'-propyl-1,6-hexanediamine (DPHDN₂O₂), which has a slightly lower degree of lipophilicity compared to DBHDN₂O₂, would provide similar nonthrombogenicity as the AG/DBHDN₂O₂-polymer-coated circuits. While DPHDN₂O₂ releases NO at a higher flux rate than DBHDN₂O₂ when coated (within CarboSil polymer) on the inner wall of polyvinyl chloride tubing, neither coated circuit significantly affected animal hemodynamics. Both diazeniumdiolated diamines, in combination with immobilized AG or alone, significantly reduced thrombus formation similarly in the 4 h rabbit model (vs uncoated control): AG/DBHDN₂O₂: 0.12 ± 0.03 cm²; DBHDN₂O₂: 2.57 ± 0.82 cm²; AG/DPHDN₂O₂: 0.68 ± 0.22 cm²; DPHDN₂O₂: 1.87 + 1.26 cm²; uncoated control: 6.95 ± 0.82 cm². AG/DPHDN₂O₂ was no different than AG/DBHDN₂O in preserving platelet count and function. In addition, AG did not leach into the systemic circulation as the total clotting times were insignificantly different from the baseline values (AG/DPHDN₂O₂: 12.7 + 0.5 s (n = 3); AG/DBHDN₂O₂: 12.3 + 0.7 s (n = 3); baseline: 13.9 + 0.3 s (n = 13)). Based on these results, both DPHDN₂O₂ and DPHDN₂O₂ are good candidates as NO donor molecules for creating nonthrombogenic polymer coatings for ECCs.