Microvascular obstructions in portal bile duct capillaries and hepatic sinusoids during normothermic machine perfusion of marginal human livers

Tingle, Samuel J; Thompson, ER; Bates, Lucy; Ibrahim, Ibrahim Khider; Figueiredo, Rodrigo; Bury, Yvonne

doi:10.1111/ajt.16337

Cited by 4 publications

(6 citation statements)

References 5 publications

(7 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fibrin deposition in the sinusoids of livers undergoing NESLiP has been noted by others, 12,18 although our interpretation of its presence differs from these previous reports with the additional insight gained from our effluent and alteplase data. Our study provides supporting evidence that fibrin microthrombi may have a causative role in the occurrence of bile duct complications, including NAS, in both DCD and DBD livers and shows, for the first time, an association with transplant outcome.…”

Section: Discussioncontrasting

confidence: 58%

“…11 We also showed that a combination of alteplase rTPA (Actilyse, Boehringer Ingelheim, Germany), given with fresh frozen plasma (FFP) as a source of plasminogen, was associated with an absence of fibrin in the intrahepatic peribiliary vessels, but this was not seen when alteplase was given alone without a plasminogen source. Others have noted microthrombi in the hepatic sinusoids, 12 an observation that probably explains the improvement in hemodynamics, which has been observed when fibrinolytic therapy is given during NESLiP. 13 D-dimers are a product of fibrin breakdown.…”

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

D-dimer Release From Livers During Ex Situ Normothermic Perfusion and After In Situ Normothermic Regional Perfusion: Evidence for Occult Fibrin Burden Associated With Adverse Transplant Outcomes and Cholangiopathy

et al. 2023

View full text Add to dashboard Cite

Background. Deceased donor livers are prone to biliary complications, which may necessitate retransplantation, and we, and others, have suggested that these complications are because of peribiliary vascular fibrin microthrombi. We sought to determine the prevalence and consequence of occult fibrin within deceased donor livers undergoing normothermic ex situ perfusion (NESLiP) and evaluate a role for fibrinolysis. Methods. D-dimer concentrations, products of fibrin degradation, were assayed in the perfusate of 163 livers taken after 2 h of NESLiP, including 91 that were transplanted. These were related to posttransplant outcomes. Five different fibrinolytic protocols during NESLiP using alteplase were evaluated, and the transplant outcomes of these alteplase-treated livers were reviewed. Results. Perfusate D-dimer concentrations were lowest in livers recovered using in situ normothermic regional perfusion and highest in alteplase-treated livers. D-dimer release from donation after brain death livers was significantly correlated with the duration of cold ischemia. In non-alteplase-treated livers, Cox proportional hazards regression analysis showed that D-dimer levels were associated with transplant survival (P = 0.005). Treatment with alteplase and fresh frozen plasma during NESLiP was associated with significantly more D-dimer release into the perfusate and was not associated with excess bleeding postimplantation; 8 of the 9 treated livers were free of cholangiopathy, whereas the ninth had a proximal duct stricture. Conclusions. Fibrin is present in many livers during cold storage and is associated with poor posttransplant outcomes. The amount of D-dimer released after fibrinolytic treatment indicates a significant occult fibrin burden and suggests that fibrinolytic therapy during NESLiP may be a promising therapeutic intervention.

show abstract

Section: Discussioncontrasting

confidence: 58%

Section: Introductionmentioning

confidence: 98%

D-dimer Release From Livers During Ex Situ Normothermic Perfusion and After In Situ Normothermic Regional Perfusion: Evidence for Occult Fibrin Burden Associated With Adverse Transplant Outcomes and Cholangiopathy

et al. 2023

View full text Add to dashboard Cite

show abstract

“…11 In addition, when the liver produces hemostatic proteins during perfusion, the perfusion fluid can start to resemble normal plasma, and undesired activation of the coagulation cascade may lead to the formation of fibrin (micro)thrombi. 12,13 In this study, we measured the concentrations and activity of hemostatic proteins during NMP to better characterize the hemostatic composition of perfusion fluid. In addition to proteins synthesized by hepatocytes, we measured perfusate levels of VWF and tissue plasminogen activator (tPA) that are produced in endothelial cells rather than hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Normothermic Machine-perfused Human Donor Livers Produce Functional Hemostatic Proteins

et al. 2023

View full text Add to dashboard Cite

Background. Normothermic machine perfusion (NMP) is used for the viability assessment of high-risk donor livers before transplantation. The production of hemostatic proteins is one of the major synthetic functions of the liver. The objective of this study was to measure the concentration and functionality of hemostatic proteins concentration in the NMP perfusate of human donor livers. Methods. Thirty-six livers that underwent NMP for viability assessment were included in this study. Perfusate samples taken during NMP (start, 150 min, and 300 min) were used for the measurement of antigen and activity levels of hemostatic proteins (factors II, VII, and X; fibrinogen; plasminogen; antithrombin; tissue plasminogen activator; von Willebrand factor; and proteins induced by vitamin K absence). The antigen levels were correlated with hepatocellular function according to previously proposed individual hepatocellular viability criteria: lactate clearance and perfusate pH. Results. Antigen levels of hemostatic proteins reached subphysiological levels in the NMP perfusate. Hemostatic proteins that were produced during NMP were at least partially active. All livers produced all hemostatic proteins tested within 150 min of NMP. Hemostatic protein concentrations did not significantly correlate with perfusate lactate and perfusate pH after 150 min of NMP. Conclusions. All livers produce functional hemostatic proteins during NMP. The generation of a functional hemostatic system in NMP perfusate confirms the need for adequate anticoagulation of the perfusate to avoid generation of (micro)thrombi that may harm the graft.

show abstract

“…Intravascular deposition of fibrin has been noted to occur de novo after NMP in peripheral biopsies of DCD livers and kidneys. 2,3 These observations, coupled with observations from our small series of perfusions, need further and more detailed investigation, with clinical evaluation, but have prompted us to suggest the following hypotheses/observations: 1. Bile duct stromal infarcts occur secondary to occlusion of peribiliary vessels with fibrin/erythrocyte plugs.…”

mentioning

confidence: 96%

Peribiliary Intravascular Fibrin Occlusions and Bile Duct Necrosis in DCD Livers During Ex Situ Perfusion: Prevention With Tissue Plasminogen Activator and Fresh Frozen Plasma

et al. 2021

View full text Add to dashboard Cite

Microvascular obstructions in portal bile duct capillaries and hepatic sinusoids during normothermic machine perfusion of marginal human livers

Cited by 4 publications

References 5 publications

D-dimer Release From Livers During Ex Situ Normothermic Perfusion and After In Situ Normothermic Regional Perfusion: Evidence for Occult Fibrin Burden Associated With Adverse Transplant Outcomes and Cholangiopathy

D-dimer Release From Livers During Ex Situ Normothermic Perfusion and After In Situ Normothermic Regional Perfusion: Evidence for Occult Fibrin Burden Associated With Adverse Transplant Outcomes and Cholangiopathy

Normothermic Machine-perfused Human Donor Livers Produce Functional Hemostatic Proteins

Peribiliary Intravascular Fibrin Occlusions and Bile Duct Necrosis in DCD Livers During Ex Situ Perfusion: Prevention With Tissue Plasminogen Activator and Fresh Frozen Plasma

Contact Info

Product

Resources

About