Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures

Pietersen, Lars; Dulk, A. Claire den; Braat, Andries E.; Putter, Hein; Korkmaz, Kerem Sebib; Barański, Andrzej; Schaapherder, Alexander F.; Dubbeld, Jeroen; Hoek, Bart van; Ringers, J.

doi:10.1002/lt.24370

Cited by 13 publications

(15 citation statements)

References 27 publications

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“…The control group had lower body mass index but longer cold ischemia times, but rates of ITBL were exactly the same in both groups (11% and 39% among DBD and cDCD recipients, respectively, in the control group versus 10% and 41% among DBD and cDCD recipients, respectively, in the study group). (51) In summary, this experimental study suggests that fibrinolytic therapy does not play a role in improving liver grafts arising through the DCD process due to lack of fibrin clot deposition during CA. Although it may not be needed for its anticoagulant properties, heparin does offer anti-inflammatory and other cytoprotective effects that may be useful to help improve liver graft quality when administered prior to withdrawal of life support/CA in the context of cDCD.…”

Section: Discussionmentioning

confidence: 77%

“…In contrast, a study from Leiden compared recipients of livers treated with urokinase during back‐table surgery (n = 63: 46 DBD and 17 cDCD) with a group of controls from an earlier era (n = 122: 94 DBD and 28 cDCD). The control group had lower body mass index but longer cold ischemia times, but rates of ITBL were exactly the same in both groups (11% and 39% among DBD and cDCD recipients, respectively, in the control group versus 10% and 41% among DBD and cDCD recipients, respectively, in the study group) …”

Section: Discussionmentioning

confidence: 82%

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Heparin but not tissue plasminogen activator improves outcomes in donation after circulatory death liver transplantation in a porcine model

et al. 2018

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Ischemic-type biliary lesions (ITBLs) arise most frequently after donation after circulatory death (DCD) liver transplantation and result in high morbidity and graft loss. Many DCD grafts are discarded out of fear for this complication. In theory, microvascular thrombi deposited during donor warm ischemia might be implicated in ITBL pathogenesis. Herein, we aim to evaluate the effects of the administration of either heparin or the fibrinolytic drug tissue plasminogen activator (TPA) as means to improve DCD liver graft quality and potentially avoid ITBL. Donor pigs were subjected to 1 hour of cardiac arrest (CA) and divided among 3 groups: no pre-arrest heparinization nor TPA during postmortem regional perfusion; no pre-arrest heparinization but TPA given during regional perfusion; and pre-arrest heparinization but no TPA during regional perfusion. In liver tissue sampled 1 hour after CA, fibrin deposition was not detected, even when heparin was not given prior to arrest. Although it was not useful to prevent microvascular clot formation, pre-arrest heparin did offer cytoprotective effects during CA and beyond, reflected in improved flows during regional perfusion and better biochemical, functional, and histological parameters during posttransplantation follow-up. In conclusion, this study demonstrates the lack of impact of TPA use in porcine DCD liver transplantation and adds to the controversy over whether the use of TPA in human DCD liver transplantation really offers any protective effect. On the other hand, when it is administered prior to CA, heparin does offer anti-inflammatory and other cytoprotective effects that help improve DCD liver graft quality. Liver Transplantation 24 665-676 2018 AASLD.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 82%

Heparin but not tissue plasminogen activator improves outcomes in donation after circulatory death liver transplantation in a porcine model

et al. 2018

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“…On the basis of the results of 4 clinical studies that have investigated the administration of tissue plasminogen activator (tPA) and urokinase during LT, it still remains inconclusive whether such treatment prevents the development of NAS in recipients. (25,27,28,30) The first and largest study by Lang et al (27) performed a double flush of the hepatic artery with urokinase in DCD grafts during the benching procedure. They found a significantly decreased incidence of intrahepatic NAS (1.4%) in grafts pretreated with urokinase (n 5 140) compared with untreated grafts (5.9%, n 5 220).…”

Section: Discussionmentioning

confidence: 99%

Liver grafts procured from donors after circulatory death have no increased risk of microthrombi formation

Verhoeven¹,

Simon²,

Jonge³

et al. 2016

Liver Transpl

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Microthrombi formation provoked by warm ischemia and vascular stasis is thought to increase the risk of nonanastomotic strictures (NAS) in liver grafts obtained by donation after circulatory death (DCD). Therefore, potentially harmful intraoperative thrombolytic therapy has been suggested as a preventive strategy against NAS. Here, we investigated whether there is histological evidence of microthrombi formation during graft preservation or directly after reperfusion in DCD livers and the development of NAS. Liver biopsies collected at different time points during graft preservation and after reperfusion were triple-stained with hematoxylin-eosin (H & E), von Willebrand factor VIII (VWF), and Fibrin Lendrum (FL) to evaluate the presence of microthrombi. In a first series of 282 sections obtained from multiple liver segments of discarded DCD grafts, microthrombi were only present in 1%-3% of the VWF stainings, without evidence of thrombus formation in paired H & E and FL stainings. Additionally, analysis of 132 sections obtained from matched, transplanted donation after brain death and DCD grafts showed no difference in microthrombi formation (11.3% versus 3.3% respectively; P = 0.082), and no relation to the development of NAS (P = 0.73). Furthermore, no microthrombi were present in perioperative biopsies in recipients who developed early hepatic artery thrombosis. Finally, the presence of microthrombi did not differ before or after additional flushing of the graft with preservation solution. In conclusion, the results of our study derogate from the hypothesis that DCD livers have an increased tendency to form microthrombi. It weakens the explanation that microthrombi formation is a main causal factor in the development of NAS in DCD and that recipients could benefit from intraoperative thrombolytic therapy to prevent NAS following liver transplantation. Liver Transplantation 22 1676-1687 2016 AASLD.

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“…5 In summary, we remain critical regarding the suggested effect of thrombolytic agents in reducing ITBL, and think that other factors, like the reported short ischemia times, may be the main explanation for the observed extremely low ITBL rates. However, only one patient in the early DCD group received a retransplantation for ITBL.…”

Section: Bohorquez Et Al Justly Recalls That Ischemic-type Biliary Lementioning

confidence: 93%

Use of thrombolytic therapy in DCD liver transplantation does not seem to improve outcome

Pietersen

Hoek

Braat

2018

American Journal of Transplantation

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The authors compared 100 consecutive donation after circulatory death (DCD) liver transplantations (LT) using a protocol that includes thrombolytic therapy (late DCD group) to a historical DCD group (early DCD group) and a cohort of donation after brain death (DBD) LT. The primary objective of the study was to "present the experience with 100 consecutive DCD LT using a protocol that includes tissue plasminogen activator (tPA) administration."While the team at Ochsner Clinic Foundation, New Orleans, deserves to be congratulated for their excellent results, we do have remarks about the added value of tPA, and we believe its advantages may have been overstated. Bohorquez et al justly recalls that Ischemic-type biliary lesions (ITBL)is the most feared and frequent cause of DCD allograft failure. However, they report a low ITBL rate in the late DCD LT. Noticeable is that the frequency of ITBL in the early versus late DCD LT does not statistically differ (5% vs. 3%, P = .63), and was extremely low in both groups. This makes it likely a result of other improvements, such as the reported short cold ischemia times, also explaining the low peak AST and thus less ITBL, 2 rather than a result of the usage of tPA.Interestingly, a significantly decreased number of retransplantations was shown (1% vs. 18.4%, P = .001). However, only one patient in the early DCD group received a retransplantation for ITBL. Other Lastly, although the clinical safety of using thrombolytic agents in DCD liver transplantation has been supported earlier by our study, in which urokinase (uPA) was used, we could not detect any benefit from the use of uPA, with an unchanged high rate of ITBL in our series (18% in control group vs. 17.5% in urokinase group; P = .68), accompanied by a longer cold ischemia time (572 minutes in control group vs. 535 minutes in study group; P = .09). 5In summary, we remain critical regarding the suggested effect of thrombolytic agents in reducing ITBL, and think that other factors, like the reported short ischemia times, may be the main explanation for the observed extremely low ITBL rates. DISCLOSUREThe authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Keywordsclinical research/practice, donors and donation: donation after brain death (DBD), donors and donation: donation after circulatory death (DCD), liver transplantation/hepatology, surgical technique, thrombosis and thromboembolism

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Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures

Cited by 13 publications

References 27 publications

Heparin but not tissue plasminogen activator improves outcomes in donation after circulatory death liver transplantation in a porcine model

Heparin but not tissue plasminogen activator improves outcomes in donation after circulatory death liver transplantation in a porcine model

Liver grafts procured from donors after circulatory death have no increased risk of microthrombi formation

Use of thrombolytic therapy in DCD liver transplantation does not seem to improve outcome

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