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LETTER TO THE EDITOR

Aprotinin’s Effect on ACT is Not an Artifact

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, MD, chogue2{at}jhmi.edu (Hogue) Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA (London)

In Response:

We thank Dr. Lerner (1) for clarifying our terminology regarding the effects of aprotinin on the celite-based activated clotting time (ACT) (2). Aprotinin is known to prolong the celite ACT by multiple mechanisms including inhibition of kalleikrein, contact activation, Factor IX, and possibly via inhibition of tissue factor-mediated activation of Factor X (an anticoagulation effect) (3). Since it binds to celite, aprotinin interferes with celite’s ability to activate blood within the ACT test tube (i.e., similar to the way that a lupus anticoagulant prolongs aPTT without in vivo anticoagulant properties) (3). Therefore, part (but not all) of the effect of aprotinin on the celite ACT is an in vitro "artifact" rather than pharmacologic effect. The more important point is that basing heparin administration on the celite ACT in the presence of aprotinin may risk subtherapeutic anticoagulation during cardiopulmonary bypass using normal ACT thresholds (i.e., 480 s) (3). A previous case involving the development of a left atrial thrombus during cardiac surgery was attributed to lower levels of anticoagulation during cardiopulmonary bypass with a heparin-bonded circuit (4). Inadequate anticoagulation during aprotinin administration could have deleterious prothrombotic consequences since this compound also inhibits plasmin and at higher levels (>250 KIU/mL) potentially protein C (3,5,6). Indeed, thromboembolic complications were reported in the early experience with aprotinin in cardiac surgical patients when heparin administration was based on the celite ACT (7–9). We agree with Dr. Lerner that future work is needed to investigate the clinical importance of the laboratory findings that aprotinin might possess some inherent weak anticoagulation effects. In the meantime, clinicians should heed current manufacturer and FDA recommendation for heparin administration and monitoring when aprotinin is used during cardiac surgery as we point out in our editorial.

REFERENCES

1. Lerner AB. Aprotinin’s effect on ACT is not an artifact. Anesth Analg 2007;104:1302.[Free Full Text]
2. Hogue CW, London MJ. Aprotinin use during cardiac surgery: a new or continuing controversy? Anesth Analg 2006;103:1067–71.[Free Full Text]
3. Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery. A review of current and emerging techniques. Anesthesiology 1999;91:1122–51.[Web of Science][Medline]
4. Cheung AT, Levin SK, Weiss SJ, et al. Intracardiac thrombus: a risk of incomplete anticoagulation for cardiac operations. Ann Thorac Surg 1994;58:541–2.[Abstract]
5. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforschung 1983;33:479–94.[Medline]
6. Espana F, Estelles A, Griffin JH, et al. Aprotinin (trasylol) is a competitive inhibitor of activated protein C. Thromb Res 1989;56:751–6.[Web of Science][Medline]
7. Sundt TM, Kouchoukos NT, Saffitz JE, et al. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418–24.[Abstract]
8. Cosgrove DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization. A placebo-controlled study. Ann Thorac Surg 1992;54:1031–8.[Abstract]
9. Laub GW, Riebman JB, Chen C, et al. The impact of aprotinin on coronary artery bypass graft patency. Chest 1994;106:1370–5.[Web of Science][Medline]

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