LIVER TRANSPLANTATION 21:1231–1232, 2015

LETTERS TO THE EDITOR

Thrombolytic Protocol Minimizes Ischemic-Type Biliary Complications in Liver Transplantation From Donation After Circulatory Death Donors Received May 6, 2015; accepted May 13, 2015.

TO THE EDITOR: TABLE 1. Presence of Thrombi in the Peribiliary

With interest, we have read the article by Seal et al.1 recently published in Liver Transplantation. The authors proposed that injection of tissue plasminogen activator, a potent thrombolytic agent, into the hepatic artery of donation after circulatory death (DCD) donor livers before transplantation reduces the incidence of biliary strictures after liver transplantation. We would like to challenge the basis for this potentially harmful therapy and wonder whether there is any evidence for the presence of thrombi in the biliary microcirculation of livers from DCD donors. At first sight, it seems reasonable to assume that clot formation may occur in the vasculature of a DCD donor because there is an inevitable period of circulatory arrest before cold flush out with preservation solution. However, in the study described by Seal et al.,1 all DCD donors received a therapeutic dose of heparin intravenously before withdrawal of life support, making it unlikely that clot formation may have occurred. Moreover, several studies have indicated that hypoxia due to circulatory arrest (as occurs in a dying person) is associated with a pronounced stimulation of the fibrinolytic system because of the release of endogenous plasminogen activators.2,3 In accordance with this, Vendrell et al.4 recently reported evidence of clinically relevant endogenous hyperfibrinolysis in DCD donors (Maastricht type II). These investigators, therefore, argued against the need for additional fibrinolytic therapy in DCD donors. Is there any evidence that despite full heparinization and the endogenous hyperfibrinolysis in DCD donors, relevant clot formation still occurs in the biliary microcirculation? To answer this question, we recently performed a histological study of biopsies taken from the extrahepatic bile duct of 128 donor livers at the time of transplantation.5 In 73 cases (23 DCD livers and 50 livers of donation after brain death [DBD] donors), bile duct biopsies were taken at the end of cold storage. In contrast to the study by Seal

Vascular Plexus (PVP) of Liver Grafts at the End of Cold Storage

Presence of thrombi in the PVP

DBD Livers

DCD Livers

Total

(n 5 50)

(n 5 23)

(n 5 73)

P Value

1 (2.0%)

1 (4.3%)

2 (2.7%)

0.57

et al.,1 local legislation did not allow the administration of heparin to the donor before withdrawal of life support. Nevertheless, we found a very low (2.7%) incidence of thrombi in the peribiliary vascular plexus, and there was no difference between DCD and DBD livers (Table 1). This study, therefore, did not support the application of thrombolytic therapy in DCD donor livers. Altogether, we believe that other factors, such as increasing experience, may explain the observed differences in this retrospective study and that there is no proven scientific justification for the use of a thrombolytic agent in DCD liver transplantation.

Laura C. Burlage, BS.c.1,2 Shanice A. Karangwa, BS.c.1,2 Ton Lisman, Ph.D.1,2 Paulo N. A. Martins, M.D., Ph.D.3 Robert J. Porte, M.D., Ph.D.1,2 1 Surgical Research Laboratory Department of Surgery University Medical Center Groningen University of Groningen Groningen, the Netherlands

Address reprint requests to Robert J. Porte, M.D., Ph.D., Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands. Telephone: 131-503612896; FAX: 131-50-3614873; E-mail: [email protected] DOI 10.1002/lt.24185 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION. DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases C 2015 American Association for the Study of Liver Diseases. V

1232 BURLAGE ET AL.

LIVER TRANSPLANTATION, September 2015

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Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation Department of Surgery University Medical Center Groningen, University of Groningen Groningen, the Netherlands 3 Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation Department of Surgery University of Massachusetts Medical School University of Massachusetts Medical Center University of Massachusetts Worcester, MA

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REFERENCES 1. Seal JB, Bohorquez H, Reichman T, Kressel A, Ghanekar A, Cohen A, et al. Thrombolytic protocol minimizes

ischemic-type biliary complications in liver transplantation from donation after circulatory death donors. Liver Transpl 2015;21:321-328. Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg 2011;254: 10-19. Porte RJ, Clavien PA. Preflush with plasminogen activator in non–heart-beating donors: Is it worth it? Transplantation 2000;69:1769-1771. Vendrell M, Hessheimer AJ, Ruiz A, de Sousa E, Paredes D, Rodrıguez C, et al. Coagulation profiles of unexpected DCDD donors do not indicate a role for exogenous fibrinolysis. Am J Transplant 2015;15:764771. op den Dries S, Westerkamp AC, Karimian N, Gouw AS, Bruinsma BG, Markmann JF, et al. Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures. J Hepatol 2014;60:1172-1179.

Thrombolytic protocol minimizes ischemic-type biliary complications in liver transplantation from donation after circulatory death donors.

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