Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypass.
BACKGROUND
The pharmacological inhibition of blood-foreign surface interactions is an attractive strategy for reducing the morbidity associated with cardiopulmonary bypass. We compared the inhibitory effects of nafamostat mesilate (a broad-spectrum synthetic protease inhibitor) and minimal-dose aprotinin on blood-surface interactions in clinical cardiopulmonary bypass.


METHODS
Eighteen patients undergoing coronary surgery were divided into three groups: (1) the control group (heparin, 4 mg/kg; n = 6), (2) the nafamostat mesilate group (heparin plus nafamostat, 0.2 mg/kg bolus followed by 2.0 mg/kg/h during cardiopulmonary bypass; n = 6), and (3) the aprotinin group (heparin plus aprotinin, 2.0 x 10(4) KIU/kg; n = 6). Platelet count, platelet aggregation, beta-thromboglobulin, prothrombin fragment F1.2, thrombin-antithrombin complex, plasminogen activator inhibitor-1, alpha2-plasmin inhibitor-plasmin complex, D-dimer, neutrophil elastase, and interleukin-6 were measured before, during, and after bypass. Bleeding times and blood loss were recorded.


RESULTS
There were no significant differences between groups in platelet count, beta-thromboglobulin, plasminogen activator inhibitor-1, interleukin-6, bleeding times, or blood loss. Platelet aggregation was better preserved at 12 hours after surgery in the nafamostat and aprotinin groups than in the control group. Prothrombin fragment F1.2, thrombin-antithrombin complex and neutrophil elastase levels were significantly reduced by aprotinin, but not by nafamostat as compared with the control group. The alpha2-plasmin inhibitor-plasmin complex and D-dimer were significantly lower with either of the drugs. Aprotinin showed better control of D-dimer than did nafamostat.


CONCLUSIONS
Nafamostat mesilate fails to reduce thrombin formation and neutrophil elastase release, whereas minimal-dose aprotinin inhibits both. Neither nafamostat nor aprotinin inhibits platelet activation. Nafamostat reduces fibrinolysis during cardiopulmonary bypass, although its effect is not as potent as aprotinin.
Kaminishi
Yuichiro
Y
Division of Cardiovascular Surgery, Jichi Medical School, Tochigi, Japan.
Hiramatsu
Yuji
Y
Watanabe
Yasunori
Y
Yoshimura
Yukihiro
Y
Sakakibara
Yuzuru
Y
D000368:Aged; D007611:Aprotinin / Q000008:administration & dosage* / Q000009:adverse effects; D001550:Benzamidines; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006146:Guanidines / Q000008:administration & dosage* / Q000009:adverse effects; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007564:Japan; D019272:Leukocyte Elastase / Q000097:blood; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000517:prevention & control*; D019106:Postoperative Hemorrhage / Q000517:prevention & control*; D011292:Premedication; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors; D018746:Systemic Inflammatory Response Syndrome / Q000517:prevention & control*; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000517:prevention & control*
D001550:Benzamidines; D005338:Fibrin Fibrinogen Degradation Products; D006146:Guanidines; D011480:Protease Inhibitors; C036309:fibrin fragment D; D006493:Heparin; D007611:Aprotinin; D019272:Leukocyte Elastase; D013917:Thrombin; C032855:nafamostat