Effect of varying nitric oxide release to prevent platelet consumption and preserve platelet function in an in vivo model of extracorporeal circulation

Abstract

The gold standard for anticoagulation during extracorporeal circulation (ECC) remains systemic heparinization and the concomitant risk of bleeding in an already critically ill patient could lead to death. Normal endothelium is a unique surface that prevents thrombosis by the release of antiplatelet and antithrombin agents. Nitric oxide (NO) is one of the most potent, reversible antiplatelet agents released from the endothelium. Nitric oxide released from within a polymer matrix has been proven effective for preventing platelet activation and adhesion onto extracorporeal circuits. However, the critical NO release (NO flux) threshold for thrombus prevention during ECC has not yet been determined. Using a 4-hour arteriovenous (AV) rabbit model of ECC, we sought to find this threshold value for ECC circuits, using an improved NO-releasing coating (Norel-b). Four groups of animals were tested at variable NO flux levels. Hourly blood samples were obtained for measurement of arterial blood gases, platelet counts, fibrinogen levels and platelet function (via aggregometry). A custom-built AV circuit was constructed with 36 cm of poly(vinyl)chloride (PVC) tubing, a 14 gauge (GA) angiocatheter for arterial access and a modified 10 French (Fr) thoracic catheter for venous access. The Norel-b coating reduced platelet activation and thrombus formation, and preserved platelet function - in all circuits that exhibited an NO flux of 13.65 x 10(10) mol x cm(-2) x min(-1). These results were significant when compared with the controls. With the Norel-b coating, the NO flux from the extracorporeal circuit surface can be precisely controlled by the composition of the polymer coating used, and such coatings are shown to prevent platelet consumption and thrombus formation while preserving platelet function in the animal.

Nitric oxide based strategies for applications of biomedical devices

“…Norel-b coating with a top coating of PVC/DOS was used as an ECC circuit of a rabbit arteriovenous shunt model. Compared to bradykinin-stimulated endothelial NO flux (1.6-4.0 Â 10 À 10 mol cm À 2 min À 1 ) and basal endothelial NO flux (0.5 Â 10 À 10 mol cm À 2 min À 1 ) [145], the Norel-b coating had NO fluxes of 2.3, 13.7, 20.6 and 39.1 Â 10 À 10 mol cm À 2 min À 1 of 2, 10, 25, and 50 wt% of DBHD/N 2 O 2 , respectively [144]. All Norel-b coatings except 2 wt% were able to maintain activated clotting time within the baseline and protect the platelet count over the course of 4 h. SEM images showed a significant amount of platelet adhesion and activation for the control groups while few platelets adhered to Norel-b coatings.…”

“…The results showed that NO-releasing circuits greatly suppress platelet adhesion and activation and did not exhibit apparent thrombus formation compared to controls. Annich and co-workers prepared another polymer coating called Norel-b that contains DBHD/N 2 O 2 , PVC/DOS and KTpClPB, to explore the critical flux necessary to protect platelet count and function and to inhibit platelet activation [143,144]. Norel-b coating with a top coating of PVC/DOS was used as an ECC circuit of a rabbit arteriovenous shunt model.…”

ECMO Biocompatibility: Surface Coatings, Anticoagulation, and Coagulation Monitoring

“…Recently, efforts have begun to be explored in the laboratory to incorporate NO-releasing polymers in the ECMO circuit [98] and to provide NO in the sweep gas [99,100,101]. The reasoning for its use in the setting of extracorporeal life support is that the half-life is so short (2-6 sec) that only a local effect occurs [102]. This is the goal of the coated circuits where the anticoagulation activity is sequestered to the artificial surfaces and does not act systemically.…”

“…This is the goal of the coated circuits where the anticoagulation activity is sequestered to the artificial surfaces and does not act systemically. In vitro and animal studies of the use of NO on ECMO circuits have demonstrated a significant improvement in platelet functionality and retention of platelets with minimal generation of the undesirable side effects of nitric oxide infusion, specifically methemoglobin [100,101,102]. The primary downsides to this type of therapy are the lack of current devices, which can accurately dose nitric oxide through the membrane, and the high cost of nitric oxide therapy.…”

The evolution of patient selection criteria and indications for extracorporeal life support in pediatric cardiopulmonary failure

“…23,24 Polymers that release nitric oxide are an extremely promising solution to the problem. 25,26 Although Gibbons's pump and Kolobow's spiral coil silicone membrane oxygenator remain in use today, the centrifugal pump has emerged as an alternative. The centrifugal pump can be miniaturized and is the pump of choice for emergency deployment in resuscitations and for patient transport.…”