Anesth Analg 2003;96:1231-1232
© 2003 International Anesthesia Research Society
LETTERS TO THE EDITOR
Liver Transplantation, Solvent-Detergent Treated Plasma and Antifibrinolytics
Yves Ozier, MD, and
Claire Rieux, MD
Department of Anesthesia and Intensive Care, Hopital Cochin, Paris, France
Comite de Securite Transfusionnelle et d’Hemovigilance, Assistance Publique-Hopitaux de Paris, Paris, France
To the Editor:
We read with great interest the article by de Jonge et al regarding the enhanced fibrinolysis observed in liver transplant (LT) recipients when solvent-detergent treated plasma (SDP) is used (1). They have drawn to our attention that the solvent-detergent treatment process used for virus inactivation of pooled plasma induces alterations in several serine proteases that are relevant to the treatment of acquired fibrinolytic states (2). They have made important observations suggesting that SDP transfusion may lead to insufficient levels of alpha-2-antiplasmin and subsequently to failure to prevent the increased fibrinolysis that is well-recognized during LT.
However, we cannot comply with the authors last suggestion regarding "routine administration of antifibrinolytic drugs when using SDP" during LT. Some SDP preparations, including the one used in this study, have a reduced protein S activity (3,4) . Cases of deep vein thromboses in patients with thrombotic thrombocytopenic purpura following repetitive plasma exchange with SDP have been reported and the role of a reduced protein S activity has been questioned (5). Moreover, a surprisingly high incidence of intraoperative deaths from pulmonary embolism during LT has been related to the use of SDP in one US center (6). Consequently, the FDA has advised healthcare professionals not to use SDP in patients undergoing LT. As antifibrinolytic therapy will induce a shift of the hemostatic balance toward coagulation, thrombotic complications may be feared at the outset in patients with thrombotic risk factors. This consideration supports the view that the decision to use antifibrinolytics should be taken on an individual basis and that it should not be routine. Several SDP preparations are currently in use around the world, that differ in the industrial process. Whether such differences have an influence on the activity of coagulation proteins is unclear and warrants further investigation.
References
- de Jonge J, Groenland TH, Metselaar HJ, et al. Fibrinolysis during liver transplantation is enhanced by using solvent/detergent virus-inactivated plasma (ESDEP). Anesth Analg 2002; 94: 1127–31,table of contents.[Abstract/Free Full Text]
- Mast AE, Stadanlick JE, Lockett JM, Dietzen DJ. Solvent/detergent-treated plasma has decreased antitrypsin activity and absent antiplasmin activity. Blood 1999; 94: 3922–7.[Abstract/Free Full Text]
- Beeck H, Hellstern P. In vitro characterization of solvent/detergent-treated human plasma and of quarantine fresh frozen plasma. Vox Sang 1998; 74 Suppl 1: 219–23.
- Leebeek FW, Schipperus MR, van Vliet HH. Coagulation factor levels in solvent/detergent-treated plasma. Transfusion 1999; 39: 1150–1.[Medline]
- Flamholz R, Jeon HR, Baron JM, Baron BW. Study of three patients with thrombotic thrombocytopenic purpura exchanged with solvent/detergent-treated plasma: is its decreased protein S activity clinically related to their development of deep venous thromboses? J Clin Apheresis 2000; 15: 169–72.[Web of Science][Medline]
- Coignard B, Nguyen GT, Tokars J, et al. A cluster of intra-operative deaths in a liver transplant center associated with the use of solvent/detergent plasma. Proceedings of the 11th Annual Meeting of the Society for Healthcare Epidemiology of America 2001.
Response
Jeroen de Jonge, MD PhD,
Theo H. Groenland, MD,
Herold J. Metselaar, MD PhD,
Jan N. IJzermans, MD PhD,
Huub H. van Vliet, PhD,
Loes Visser, MD, and
Hugo W. Tilanus, MD PhD
Department of Surgery, St. Franciscus Gasthuis, Rotterdam, The Netherlands
In Response:
We thank Solheim and his colleagues and Ozier and Rieux for their accurate reading and comments on our article regarding the enhanced fibrinolysis after introduction of solvent-detergent (SD) treated plasma in liver transplantation (ESDEP®). Solheim et al. shared their experience with 208 liver transplant patients, treated with ESDEP in the Oslo University Hospital since 1993. They do not support the routine administration of antifibrinolytic therapy during liver transplantation, because of the absence of problems with hyperfibrinolysis.
During the study period, we experienced serious hemostatic problems with substantial blood loss. This may partly be attributed to the limited number of transplantations performed per year in our center at that time, the seriousness of pre-operative coagulation disorders in our patient population and the use of a standard liver transplantation technique without piggyback anastomosis. In patients with normal pre-operative coagulation tests and little blood loss, no fibrinolysis was seen using ESDEP plasma. The appearance of hyperfibrinolysis seemed related to the amount of blood loss. Calculation reveals that with each blood loss and replacement of half of the circulating volume according to the followed transfusion protocol, the  2-antiplasmine activity in the circulating plasma will be reduced by about 10%. With an average patient and a starting activity of 0.7 IU/L this means that after a blood loss of about 8,0 L the 2-antiplasmine activity will reach the hemostatic level of 0.4 IU/L, which is associated with prolonged bleeding after surgery (1). This hemostatic level is probably reached much earlier due to consumption of 2-antiplasmine during surgery and by the release of considerable amounts of t-PA from the reperfused liver graft.
Therefore we are curious if Solheim et al had little blood loss during their procedures, which may account for the absence of hyperfibrinolysis and if they have actually measured (subclinical) fibrinolytic activity during the transplantation.
Ozier and Rieux rightly indicate the risk of standard antifibrinolytic drugs, as also other coagulation proteins in the ESDEP plasma are influenced by the SD process (2) which may lead to a shift towards pro-coagulation.
Since the introduction of a piggyback anastomosis technique without the need for retroperitoneal dissection, blood loss decreased importantly in our transplant center. As hemorrhage is no longer a main issue, attention must be paid to avoid thrombotic complications. The beneficial effect of routine use of a low dose Aprotinin regime using normal fresh frozen plasma was confirmed by Porte et al. in a multicenter study (3). In this study no differences in thrombotic complications between the placebo group and the Aprotinin groups were seen. We now have used the low dose Aprotinin scheme with ESDEP on a routine base in 120 patients, without thrombotic complications so far. We agree however with Ozier and Rieux that with a further decrease of importance of blood loss as a clinical issue in liver transplantation, the use of antifibrinolytics should be individualized.
References
- Lijnen HR, Collen D. Congenital and acquired deficiency of components of the fibrinolytic system and their relation to bleeding or thrombosis. Fibrinolysis 1989; 3: 67–77.
- Leebeek FW, Schipperus MR, van Vliet HH. Coagulation factor levels in solvent/detergent-treated plasma. Transfusion 1999; 39: 1150–1151.
- Porte RJ, Molenaar IQ, Begliomini B, Groenland THN, Januskiewicz A, Lindgren L, Palareti G, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. Lancet 2000; 355: 1303–1309.[Web of Science][Medline]
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