RESUMEN
BACKGROUND: Left ventricular assist devices (LVADs) have provided a new therapeutic option for patients with end-stage heart failure. Despite advances in device design, there remains an apparent bleeding diathesis, which leads to increased transfusion requirements and reoperative rates. The purpose of our study was to examine the abnormalities that might contribute to these clinical sequelae. METHODS AND RESULTS: To separate the effects of cardiopulmonary bypass (CPB), eight patients undergoing coronary revascularization (CABG) were compared with seven LVAD (TCI HeartMate) recipients intraoperatively and 2 hours postoperatively. We evaluated several well-characterized indexes of platelet activation: platelet count, platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), and thromboxane B2 (TXB2). We also measured activation of thrombin: thrombin-antithrombin III (TAT), prothrombin fragment 1 + 2 (F1 + 2), and fibrinopeptide A (FPA) as well as markers of fibrinolysis: plasmin-alpha 2-antiplasmin (PAP) and D-dimer. Patterns of intraoperative platelet adhesion and activation were not statistically different in the CABG control and LVAD groups. In the immediate postoperative period, however, there was significant release of PF4 and beta-TG and generation of TXB2. Compared with the CABG controls (TAT, 26 +/- 8 micrograms/L; F1 + 2, 4 +/- 1 nmol/L; mean +/- SEM), there was a significant increase in TAT (380 +/- 112 micrograms/L) and F1 + 2 (23 +/- 4 nmol/L) in LVAD patients 2 hours after surgery. Furthermore, a sharp rise in FPA was noted 20 minutes after LVAD initiation (CABG, 8 +/- 4 ng/mL; LVAD, 235 +/- 63 ng/mL; P < .05). A concomitant increase in both PAP (CABG, 987 +/- 129 micrograms/L; LVAD 3456 +/- 721 micrograms/L; P < .05) and D-dimer (CABG, 1678 +/- 416 ng/mL; LVAD, 15243 +/- 4682 ng/mL; P < .05) was observed. CONCLUSIONS: The additive effects of CPB and LVAD lead to platelet activation as well as elevation of markers of in vivo thrombin generation, fibrinogen cleavage, and fibrinolytic activity. The etiology of these findings may be secondary to the LVAD surface, flow characteristics, and/or operative procedure. Nevertheless, platelet alterations and exaggerated activation of the coagulation and fibrinolytic systems may contribute to the clinically observed hemostatic defect.
Asunto(s)
Coagulación Sanguínea , Fibrinólisis , Corazón Auxiliar/efectos adversos , Hemorragia/etiología , Adolescente , Adulto , Anciano , Puente Cardiopulmonar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria , Recuento de Plaquetas , Factor Plaquetario 4/análisis , Trombina/metabolismo , Tromboxano B2/sangreRESUMEN
Postoperative morbidity after cardiopulmonary bypass most commonly manifests as bleeding diatheses or pulmonary dysfunction. The pathophysiology has been attributed to the activation of cellular and humoral components of blood after contact with an artificial surface. Development of a surface that would be nonthrombogenic and also would constitute a less potent inflammatory stimulus would therefore be beneficial. In the following experiments, we evaluated the heparin-bonded Carmeda Bioactive Surface (Medtronics Cardiopulmonary, Anaheim, Calif.) in an in vitro model of extracorporeal circulation at standard-dose heparin (5 U/ml), to examine the effects of the surface treatment on activation of blood elements, and at reduced-dose heparin (1 U/ml), to determine whether surface-bound heparin would serve as an effective anticoagulant. During the initial recirculation period, platelet counts in the Carmeda (n = 12) circuits were preserved at both doses of heparin and compared with control values (n = 12): At 5 U/ml, control 36% +/- 4% (mean +/- standard error of the mean) versus Carmeda 81% +/- 5%; at 1 U/ml, 43% +/- 3% versus 61% +/- 10%, expressed as a percent of baseline at 30 minutes, p < 0.05. Furthermore, plasma levels of platelet factor 4 and beta-thromboglobulin were significantly reduced in the Carmeda circuits throughout the experiment: At heparin 5 U/ml, 2500 +/- 340 ng/ml versus 604 +/- 191 ng/ml; at 1 U/ml, 2933 +/- 275 ng/ml versus 577 +/- 164 ng/ml of platelet factor 4 at 2 hours (p < 0.05). The pattern of beta-thromboglobulin release was similar, with effects more pronounced at the lower dose of heparin. Surface modification also reduced leukocyte depletion (p < 0.05) and release of elastase at both concentrations of heparin (5 U/ml, 0.72 +/- 0.29 ng/ml versus 0.33 +/- 0.23 ng/ml; 1 U/ml, 0.85 +/- 0.08 ng/ml versus 0.20 +/- 0.05 ng/ml, at 2 hours, p < 0.05). Moreover, as heparin concentration was reduced, Carmeda surface treatment significantly decreased generation of C3a des Arg (1 U/ml, 14,410 +/- 3558 ng/ml versus 3053 +/- 1039 ng/ml at 2 hours, p < 0.05). Although heparin bonding was originally intended to obviate the need for systemic heparinization, Carmeda treatment did not reduce fibrinopeptide A generation at the lower dose of heparin. In summary, Carmeda treatment failed to exhibit anticoagulant efficacy in this model; however, the data suggest that surface modification may have a role in ameliorating the typical inflammatory response initiated by blood contact with an artificial surface.