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LETTERS TO THE EDITOR

Aprotinin and Thromboembolism in Liver Transplantation: Is There Really a Causal Effect?

Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, University Hospital Groningen, Groningen, The Netherlands

To the Editor:

We have read the article by Fitzsimons et al. (1) on thrombus formation in the central circulation in two patients receiving aprotinin during orthotopic liver transplantation (OLT) with interest. The authors conclude that aprotinin may have been responsible for these unfortunate thrombotic complications. The occurrence of thromboembolic events in OLT associated with the use of aprotinin has been described before (2). However, there are also several reports on thromboembolic complications in patients undergoing OLT who did not receive aprotinin or any other antifibrinolytic drug (3–7). In addition to this, it is conceivable that thrombotic complications in patients undergoing OLT who did not receive aprotinin are underreported. Many factors may predispose for thrombotic complications during OLT. Although hard data are lacking, the incidence of pulmonary embolism during OLT is estimated to be around 1%–1.5% (AM De Wolf, personal communication 2001). Until now, convincing evidence of a causal relationship between aprotinin and thromboembolic complications has not been provided in any of the reported cases. Therefore, we question the scientific value of these isolated case reports. Scientific evidence should come from large prospective randomized trials. None of the present randomized trials showed a significant difference in thromboembolic complications (8,9).

At this point we would like to stress that aprotinin has no known intrinsic procoagulant effect. As a serine-protease inhibitor, it even has an inhibiting effect on the intrinsic (10) and the extrinsic clotting systems (11) and on thrombin-induced platelet aggregation (12). In this respect, aprotinin is also considered a mild anticoagulant. In a recent analysis of coagulation variables in patients enrolled in a placebo-controlled study, we found a significant prolongation of APTT and TEG r-values in patients who received large-dose aprotinin, compared with placebo, confirming this mild anticoagulant effect (13). These findings are in line with studies in patients undergoing cardiac surgery, which showed a lower rate of thromboembolic neurological complications in aprotinin-treated patients (14,15). In addition to this, a recent meta-analysis of all randomized controlled trials with aprotinin in cardiac surgery also showed no higher incidence of myocardial infarction in the aprotinin-treated patients (16). We therefore conclude that great care should be taken to draw conclusions from incidental case reports.

References

1. Fitzsimons MG, Peterfreund RA, Raines DE. Aprotinin administration and pulmonary thromboembolism during orthotopic liver transplantation: report of two cases. Anesth Analg 2001; 92: 1418–21.[Free Full Text]
2. Baubillier E, Cherqui D, Dominique C, et al. A fatal thrombotic complication during liver transplantation after aprotinin administration. Transplantation 1994; 57: 1664–6.[Web of Science][Medline]
3. Navalgund AA, Kang Y, Sarner JB, et al. Massive pulmonary thromboembolism during liver transplantation. Anesth Analg 1988; 67: 400–2.[Free Full Text]
4. Ellis JE, Lichtor JL, Feinstein SB, et al. Right heart dysfunction, pulmonary embolism, and paradoxical embolization during liver transplantation: a transesophageal two-dimensional echocardiographic study. Anesth Analg 1989; 68: 777–82.[Abstract/Free Full Text]
5. Farrell FJ, Nguyen M, Woodley S, et al. Outcome of liver transplantation in patients with hemochromatosis. Hepatology 1994; 20: 404–10.[Web of Science][Medline]
6. Sankey EA, Crow J, Mallett SV, et al. Pulmonary platelet aggregates: possible cause of sudden peroperative death in adults undergoing liver transplantation. J Clin Pathol 1993; 46: 222–7.[Abstract/Free Full Text]
7. Gologorsky E, De Wolf AM, Scott V, et al. Intracardiac thrombus formation and pulmonary thromboembolism immediately after graft reperfusion in seven patients undergoing liver transplantation. Liver Transpl 2001; 7: 783–9.[Web of Science][Medline]
8. Garcia-Huete L, Domenech P, Sabate A, et al. The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 1997; 26: 1143–8.[Medline]
9. Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. EMSALT Study Group Lancet 2000; 355: 1303–9.
10. Despotis GJ, Alsoufiev A, Goodnough LT, Lappas DG. Aprotinin prolongs whole blood activated partial thromboplastin time but not whole blood prothrombin time in patients undergoing cardiac surgery. Anesth Analg 1995; 81: 919–24.[Abstract]
11. Chabbat J, Porte P, Tellier M, Steinbuch M. Aprotinin is a competitive inhibitor of the factor VIIa-tissue factor complex. Thromb Res 1993; 71: 205–15.[Web of Science][Medline]
12. Poullis M, Manning R, Laffan M, et al. The antithrombotic effect of aprotinin: actions mediated via the proteaseactivated receptor 1. J Thorac Cardiovasc Surg 2000; 120: 370–8.[Abstract/Free Full Text]
13. Molenaar IQ, Legnani C, Groenland TH, et al. Aprotinin in orthotopic liver transplantation: evidence for a prohemostatic, but not a pro-thrombotic effect. Liver Transpl 2001; 7: 896–903.[Web of Science][Medline]
14. Levy JH, Pifarre R, Schaff HV, et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995; 92: 2236–44.[Abstract/Free Full Text]
15. Smith PK, Muhlbaier LH. Aprotinin: safe and effective only with the full-dose regimen. Ann Thorac Surg 1996; 62: 1575–7.[Free Full Text]
16. Levi M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354: 1940–7.[Web of Science][Medline]

Response

Department of Anesthesia and Critical Care, Harvard Medical School/MA General Hospital, Boston, Massachusetts

In Response:

We would like to thank Drs. Molenaar and Porte for their response to our case report. They cite one case report (1) as suggesting aprotinin administration may be related to pulmonary thromboembolism. In fact, there are four case reports in which seven patients suffered pulmonary thromboemboli in the setting of aprotinin (1–4). They also state that many factors may predispose patients undergoing orthotopic liver transplant to pulmonary thromboemboli. We agree. A review of the prior case reports indicates that veno-venous bypass was used in five cases of thromboemboli (2–4) and not used in one (3), and the last case did not mention technique (1). Certainly venous stasis with infrahepatic inferior vena cava occlusion would seem to increase the risk of thrombus formation. In fact it may be that this subpopulation needs further study.

Drs. Molenaar and Porte cite Garcia-Huete et al. (5) and Porte et al. (6) as studies that did not show any difference in thromboembolic complications between patients treated with and without aprotinin. They also cite a personal communication with Dr. Wolf indicating a 1%–1.5% incidence of thromboemboli in OLT. Garcia-Huete et al.’s (5) study group only had 40 patients; a larger population would be required to establish a true difference in the incidence of thromboemboli. Porte et al.’s (6) study did not control for surgical technique, which may be a significant factor. The treatment groups in this study were also too small to detect differences in the incidence of thromboemboli.

Many differences exist between liver transplant surgery and cardiac surgery. Indeed, we believe that clinical outcome data generated during studies of cardiac surgery to which Drs. Molenaar and Porte refer may not apply to liver transplant recipients.

Drs. Molenaar and Porte question the value of isolated case reports. A case report is by no means intended to provide definite evidence of a causal relationship between an intervention and an outcome. The goal of a case report is to provide communication between individual clinicians to raise awareness of phenomena that may require further formal study.

References

1. Baubillier E, Cherqui D, Khalil M, et al. A fatal thrombotic complication during liver transplantation after aprotinin administration. Transplantation 1994; 57: 1664–6.
2. Sopher M, Braunfeld M, Shackleton C, et al. Fatal pulmonary embolism during liver transplantation. Anesthesiology 1997; 87: 429–32.[Web of Science][Medline]
3. O’Connor CJ, Roozeboom D, Brown C, Tuman KJ. Pulmonary thromboembolism during liver transplantation: possible association with antifibrinolytic drugs and novel treatment options. Anesth Analg 2000; 91: 296–9.[Abstract/Free Full Text]
4. Fitzsimons MG, Peterfreund RA, Raines DE. Aprotinin administration and pulmonary thromboembolism during orthotopic liver transplantation: report of two cases. Anesth Analg 2001; 92: 1418–21.
5. Garcia-Huete L, Domenech P, Sabate A, et al. The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 1997; 26: 1143–8.
6. Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicenter randomised double-blind study. Lancet 2000; 355: 1303–9.[Web of Science][Medline]

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