969-99 Biocompatible Mechanical Left Ventricular Support: Potential Alternative to Transplantation

Use of mechanical circulatory support has been limited by its associated bleeding and thrombotic complications. Blood contact with an artificial surface results in a well-deined pattern of hematologic alterations. The TCI HeartMate® left ventricular assist device (LVAD) is an implantable circulatory support pump currently used as a bridge to transplantation. Its textured blood contacting surfaces result in a formation of an adherent pseudoneointimal lining which eliminates the direct interaction of blood elements with the artificial surface. To determine if this biological lining could mitigate the stereotypical blood-synthetic surface interactions, we studied eight patients who underwent implantation at our institution over a 10 month period from 5/93 to 3/94. Seven of the 8 patients were bridged to transplantation. Three patients were transplanted within 10 days and one month data could not be obtained. Hemodynamic and hemostatic parameters (mean±sd) were studied as follows:Pre-implantPOD 7POD 28Cardiac index (I/min/m2)1.8±0.73.2±0.43.1±0.5Systolic BP (mmHg)759±6.8125.8±9.7130.4±8.1Hemoglobin (mg/dl)7.4±1.88.2±1.69.6±2.0Plasma free hemoglobin (mg/dl)15.4±1.76.4±2.36.8±1.9Prothrombin time (sec)14.2±1.113.4±0.713.3±0.7Partial thromboplastin time (sec)56.7±15.931.8±4.837.6±11.9Platelet count (× 103lcu mm)250±81269±63325±37In vitro platelet reactivity to the agonist ADP remained normal pre and post implantation. Average perioperative blood requirements included PRBC, 3.3±1.3 units; platelets, 2.3±4.5 units; fresh frozen plasma, 2±1.9 units. No blood products were required after postoperative day 2.We conclude that TCI LVAD support improves hemodynamics and can bridge patients in pre-implant cardiogenic shock to transplantation. Furthermore, no red cell destruction or hemostatic and thrombotic complications were observed despite one month of support without anticoagulation therapy. Therefore, as the donor shortage continues, LVADs with biocompatible surfaces may provide an alternative to cardiac transplantation

The Effects of Heparin Bound Surface Modification (Carmeda

To determine if treatment with covalently bound heparin (Carmeda Bioactive Surface (CBAS))a to the synthetic surface of the extracorporeal circuit (ECC) would alter the stereotypic pattern of adverse platelet alterations, 450 ml of heparinized blood (lU/ml) was recirculated at a flow rate of twice the circulating volume (L/min) for 2 hrs at 37°C through either untreated (CONT,n=7) or treated (CBAS,n=7)circuits constructed of identical components including a pediatric (0.8m2) reversed hollow fiber membrane oxygenator. In CONT circuits, platelet count maintained 88+1% (x±SEM) of its initial level in the circuit prime sample, dropped to 36±6% after 5 min, and returned to 56±2% following 2 hrs of ECC. In CBAS circuits, platelet count in the circuit prime sample demonstrated 90±4%, decreased to 68±10% after 5 min (p<0.05) and declined further to 45±5% after 2 hrs (NS). Although platelets from both groups retained reactivity to ADP after priming the circuit, only at 5 min of recirculation did CBAS circuits significantly preserve this responsiveness. In CONT circuits, baseline plasma levels of platelet factor 4 rose from 24±3 to 581±82 ng/ml in the primed circuit and continued to rise to 2933±27 6 ng/ml by 2 hrs of ECC. In contrast, CBAS circuits markedly reduced this release after 2 hrs (577±165 ng/ml). Furthermore, by 2 hrs of ECC, plasma levels of thromboxane B2 in the CBAS circuits were significantly reduced when compared to CONT circuits (3035±1529 vs 29916±16293 pg/ml, respectively). We conclude that CBAS modification of the simulated extracorporeal circuit preserved the initial circulating platelet count with retained ADP reactivity and markedly decreased release of platelet factor 4 and thromboxane B2

Hollow Fiber Membrane Oxygenator Reduces Platelet Loss During Simulated Extracorporeal Circulation

Contact between blood and the extracorporeal circuit results in adverse alterations in platelet number and function. To determine the effects of surface composition and flow on these changes, 450 ml of heparinized (5 U/ml) blood from random, aspirin-free volunteers was recirculated at a flow rate of twice the circulating volume for 2 hrs at 37°C through circuits with an identical surface area (1.0m2). These circuits contained either a spiral coil, silicon rubber, membrane oxygenator (SC) or a hollow fiber, polypropylene membrane oxygenator (HF). In SC circuits (n=5), platelet counts fell to 10±3% (±SEM p .05) at 2 hrs. Plasma levels of the platelet-specific protein platelet factor (PF) 4 rose to 2780 ± 222 ng/ml (p <.05) by 5 minutes, reaching 6338 ±.767 ng/ml (p < .05) at 2 hours in SC circuits. In contrast, PF4 in HF circuits rose to 836±73 ng/ml and 2640 ± 410 ng/ml (p < .05), respectively. Although platelets in the SC circuits became insensitive to ADP ≥ 50 uM) within 5 min, platelets from HF circuits aggregated to ADP (17 uM) despite 2 hrs of ECC. We conclude that the hollow fiber membrane oxygenator not only reduces adhesion, maintaining the circulating platelet count, but also reduces platelet protein release and preserves platelet function as well

Platelet Preservation During Simulated Cardiopulmonary Bypass Via Phosphodiesterase Inhibition

Inhibition of platelet function reduces adverse platelet alterations during cardiopulmonary bypass (CPB) but agents most efficacious must be given intravenously. Consequently, we evaluated a new type III phosphodiesterase inhibitor (PDEI), CK2130 (100 uM), comparing it with the most commonly prescribed oral PDEI, dipyridamole (100 uM). 450 ml of fresh heparinized (5U/ml) blood, drawn from aspirin-free volunteers, was recirculated for 2 hrs at 37°C in a polypropylene circuit (1.0m2) containing a spiral-coil membrane oxygenator. In control saline circuits (N=5), platelet counts fell to 10±3% (mean + standard error of the mean) of initial levels within 5 min and sensitivity to ADP disappeared. Plasma levels of a platelet-specific protein platelet factor 4 (PF4) rose from 2780±222 ng/ml at five minutes to 6338±767 ng/ml after 2 hrs (p < .05), indicating extensive platelet release. In contrast, with CK2130 (N=3), although platelets were similarly insensitive to ADP, platelet counts dropped to only 63±11% at five minutes and PF4 rose from 1012±510 ng/ml at five minutes to only 3689± 898 ng/ml after 2 hrs (p < .05). With dipyridamole (N=4) platelet counts fell to 66±7% and PF4 rose from 861±122 ng/ml at five minutes to only 2157±346 ng/ml after 2 hrs (p <.05) but platelets remained responsive to ADP. In conclusion, both CK2130 and dipyridamole significantly preserved the initial circulating platelet count and reduced release of PF4 with CK2130 producing more pronounced inhibition of function as well. Thus, PDEIs may play a promising role as platelet inhibitors during CPB

Preservation of Platelets during Cardiopulmonary Bypass with ZK36374: A New Prostacyclin Analogue

Extracorporeal circulation is associated with extensive alterations in platelet number and function. In certain individuals these adverse platelet changes are exacerbated by heparin. ZK36374 (ZK), a stable analogue of prostacyclin, reversibly inhibits all phases of platelet activation. A patient was presented with heparin induced platelet activation and paradoxical thrombosis who required cardiopulmonary bypass to correct severe tricuspid stenosis and ASD. We employed full heparinization and ZK to prevent surface and heparin induced thrombocytopenia. Prior to heparinization, a constant infusion of ZK was begun at 10 nanograms/kilogram/minute, tapered to 2 nanograms/kilogram/minute during bypass, and maintained until heparin was reversed with protamine. Prior to bypass, platelets demonstrated 50% reactivity and 2% reactivity when challenged by ADP and epinephrine, respectively, indicating inhibition of platelet function by ZK. Two hours after arrival in recovery 92% prebypass circulating platelet count, 90% preservation of platelet reactivity to ADP, and a template bleeding time near control were achieved. ZK was used safely to prevent both heparin and surface induced platelet changes during cardiopulmonary bypass in this patient

Preservation of Canine Platelets with Iloprost (ZK 36374) during Extracorporeal Circulation

(J. Extra-Corpor. Technol. 19[3] p. 258-264 Fall 1987, 23 ref.) Contact between blood and synthetic/air interfaces during extracorporeal circulation (ECC) results in adverse platelet alterations. We tested the efficacy of a new reversible potent prostacyclin analogue, iloprost (ZK 36374), in preventing these untoward conseguences in fifteen mongrel dogs undergoing extracorporeal circulation using either a membrane or bubble oxygenator. In treated groups, infusion of iloprost was incrementally increased to 150 ng/kg/min at least 15 minutes prior to incision. Equal infusion volumes of saline were administered to the control group. Platelet counts in control dogs (n = 6, membrane/control) decreased to 57 ± 10% (mean ± standard error of the mean) of initial levels by 30 minutes of ECC; in contrast, dogs infused with iloprost demonstrated consistently stable platelet counts despite perfusion with either membrane (1 07 ± 1 0%, n = 6) or bubble (81 ± 13%, n = 3) oxygenators. At 30 minutes of ECC, the iloprost infusion was discontinued. Although the platelet counts in the membrane iloprost-treated group continued to remain stable (99 ± 7%), platelet counts in the bubble iloprost-treated group droppped precipitously to 49 ± 1 0% within 60 minutesof discontinuance of infusion. Furthermore, by 90 minutes of ECC, platelets continued to demonstrate reduced sensitivity to ADP as measured by percent light transmission in both control (53 ± 15%) and bubble iloprost-treated (20 ± 16%) groups. In contrast, the membrane iloprost-treated group regained normal reactivity (80 ± 15%). We conclude that iloprost effectively prevents adverse platelet alterations during ECC. Furthermore, its salutary effects in membrane oxygenator systems persist long after platelet functional inhibition is reversed