Recombinant human transgenic antithrombin in cardiac surgery: a dose-finding study.
BACKGROUND
Acquired antithrombin III (AT) deficiency may render heparin less effective during cardiac surgery and cardiopulmonary bypass (CPB). The authors examined the pharmacodynamics and optimal dose of recombinant human AT (rh-AT) needed to maintain normal AT activity during CPB, optimize the anticoagulant response to heparin, and attenuate excessive activation of the hemostatic system in patients undergoing coronary artery bypass grafting.


METHODS
Thirty-six patients scheduled to undergo elective primary coronary artery bypass grafting and who had received heparin for 12 h or more before surgery were enrolled in the study. Ten cohorts of three patients each received rh-AT in doses of 10, 25, 50, 75, 100, 125, 175, or 200 U/kg, a cohort of six patients received 150 U/kg of rh-AT, and a control group of six patients received placebo.


RESULTS
Antithrombin III activity exceeded 600 U/dl before CPB at the highest dose (200 U/kg). Doses of 75 U/kg rh-AT normalized AT activity to 100 U/dl during CPB. Activated clotting times during CPB were significantly (P < 0.0001) greater in patients who received rh-AT (844 +/- 191 s) compared with placebo patients (531 +/- 180 s). Significant (P = 0.001) inverse relations were observed between rh-AT dose and both fibrin monomer (r = -0.51) and D-dimer (r = -0.51) concentrations. No appreciable adverse events were observed with any rh-AT doses used in the study.


CONCLUSIONS
Supplementation of native AT with transgenically produced protein (rh-AT) in cardiac surgical patients was well tolerated and resulted in higher activated clotting times during CPB and decreased levels of fibrin monomer and D-dimer.
Levy
Jerrold H
JH
Department of Anesthesiology, Emory University School of Medicine and Division of Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Georgia 30322, USA. jerrold_levy@emoryhealthcare.org
Despotis
George J
GJ
Szlam
Fania
F
Olson
Peter
P
Meeker
David
D
Weisinger
Andrew
A
D000368:Aged; D000990:Antithrombin III / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D020152:Antithrombin III Deficiency / Q000150:complications / Q000188:drug therapy*; D001777:Blood Coagulation / Q000187:drug effects; D001803:Blood Transfusion; D006348:Cardiac Surgical Procedures; D015331:Cohort Studies; D001026:Coronary Artery Bypass; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D019076:Transgenes
D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III