Aprotinin, cardiac surgery, and factor V Leiden.
BACKGROUND
Aprotinin has been shown to reduce blood transfusion in cardiac surgery. Aprotinin inhibits activated protein C (APC). Patients with factor V (FV) Leiden have an inherited resistance to APC proteolysis. If the inhibition of APC by aprotinin contributes to its beneficial effect in cardiac surgery, then patients with FV Leiden undergoing cardiac surgery might be expected to require less transfusion than patients without FV Leiden. However, the use of aprotinin in such patients also could compromise the protein C regulatory pathway and precipitate a clinical thrombotic event.


METHODS
Patients undergoing cardiac surgery were studied for the presence of the FV Leiden defect by the use of a Russell's viper venom clot-based assay and polymerase chain reaction. The total amount of blood transfused was recorded for each patient. The effect of aprotinin on the plasma of normal and FV Leiden patients was studied. Further studies were performed on the direct inhibition of APC by aprotinin.


RESULTS
Over an 18-month period, 162 patients were studied, of whom 13 (8%; 95% CI, 4.3-13.3%) were positive for FV Leiden. These 13 had a smaller requirement for blood transfusion than the to 13 matched controls. In vitro, aprotinin induced a FV Leiden defect in normal plasma and exacerbated the defect in the plasma of FV Leiden patients. Aprotinin inhibited APC in a dose-dependent manner, and kinetic analysis showed competitive inhibition with an inhibition constant of 4.5 microM (250 Kallikrein inhibitor units/mL).


CONCLUSIONS
The inhibition of APC by aprotinin may contribute to its hemostatic effect. The use of aprotinin in patients with FV Leiden could cause extreme dysfunction of the protein C regulatory pathway, which could result in clinical thrombosis.
Sweeney
J D
JD
Herbert C. Lichtman Blood Bank and Transfusion Medicine Research Unit, Miriam Hospital, Providence, Rhode Island, USA.
Blair
A J
AJ
Dupuis
M P
MP
King
T C
TC
Moulton
A L
AL
D000368:Aged; D000369:Aged, 80 and over; D007611:Aprotinin / Q000008:administration & dosage / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D001803:Blood Transfusion / Q000706:statistics & numerical data; D006348:Cardiac Surgical Procedures; D004305:Dose-Response Relationship, Drug; D005165:Factor V / Q000032:analysis* / Q000235:genetics; D005260:Female; D006490:Hemostatics / Q000008:administration & dosage / Q000494:pharmacology*; D006579:Heterozygote; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010949:Plasma / Q000187:drug effects; D011486:Protein C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011517:Prothrombin Time
D006490:Hemostatics; D011486:Protein C; C095381:factor V Leiden; D005165:Factor V; D007611:Aprotinin