Increase in post-reperfusion sensitivity to tissue plasminogen activator-mediated fibrinolysis during liver transplantation is associated with abnormal metabolic changes and increased blood product utilisation.

BACKGROUND Increased systemic fibrinolytic activity can occur in liver transplant recipients after the donor graft is reperfused. However, it remains unclear whether this is related solely to tissue plasminogen activator (t-PA) levels or whether unique metabolic changes can alter t-PA activity and enhance fibrinolytic activity. We hypothesise that an increase in sensitivity to t-PA-mediated fibrinolysis (StF) following liver reperfusion is associated with specific metabolic abnormalities. MATERIALS AND METHODS Liver transplant recipients had serial blood samples analysed with a modified thrombelastography assay using exogenous t-PA to measure sensitivity/resistance to fibrinolysis with the lysis 30 min after maximum clot strength (tLY30). Paired plasma samples were analysed with mass spectroscopy-based metabolomics. The tLY30 was correlated to metabolites using Spearman's rho. StF was defined as a tLY30 change of >8.5% from the anhepatic phase to 30 min after reperfusion based on the distribution of tLY30 in a healthy control population. RESULTS StF occurred in 53% of patients. Cohorts had similar MELD scores (18 vs 16, p=0.876) and tLY30 at baseline (p=0.867) and anhepatic phase of surgery (p=0.463). Thirty min after reperfusion, the tLY30 was 73% in patient with StF vs 33% in those without StF 33% (p=0.006). StF was associated with increased red blood cell transfusions (p=0.035), during the first 2 hours of reperfusion. Nine metabolites demonstrated a correlation with tLY30 (p<0.05). DISCUSSION StF is a transient event that resolves within 2 hours of graft reperfusion and is associated with increased blood product use. This phenomenon correlates with derangements in citric acid cycle, purine and amino acid metabolism. Future research is needed to determine whether these metabolites are biomarkers or mechanistically linked to increased sensitivity to t-PA-mediated fibrinolytic activity following graft reperfusion.

[1]  Takashi Ito,et al.  Uric acid enhances alteplase-mediated thrombolysis as an antioxidant , 2018, Scientific Reports.

[2]  A. D’Alessandro,et al.  A three-minute method for high-throughput quantitative metabolomics and quantitative tracing experiments of central carbon and nitrogen pathways. , 2017, Rapid communications in mass spectrometry : RCM.

[3]  J. Lindeman,et al.  Succinate Accumulation and Ischemia–Reperfusion Injury: Of Mice but Not Men, a Study in Renal Ischemia–Reperfusion , 2016, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  G. Ercolani,et al.  Post reperfusion syndrome during liver transplantation: From pathophysiology to therapy and preventive strategies. , 2016, World journal of gastroenterology.

[5]  A. Sauaia,et al.  Viscoelastic measurements of platelet function, not fibrinogen function, predicts sensitivity to tissue‐type plasminogen activator in trauma patients , 2015, Journal of thrombosis and haemostasis : JTH.

[6]  José A Fernández,et al.  Acylcarnitines are anticoagulants that inhibit factor Xa and are reduced in venous thrombosis, based on metabolomics data. , 2015, Blood.

[7]  S. Diamond,et al.  Shock releases bile acid inducing platelet inhibition and fibrinolysis. , 2015, The Journal of surgical research.

[8]  A. Sauaia,et al.  Plasma is the physiologic buffer of tissue plasminogen activator-mediated fibrinolysis: rationale for plasma-first resuscitation after life-threatening hemorrhage. , 2015, Journal of the American College of Surgeons.

[9]  David S. Wishart,et al.  MetaboAnalyst 3.0—making metabolomics more meaningful , 2015, Nucleic Acids Res..

[10]  A. Sauaia,et al.  Hemolysis Exacerbates Hyperfibrinolysis, Whereas Platelolysis Shuts Down Fibrinolysis: Evolving Concepts of the Spectrum of Fibrinolysis in Response to Severe Injury , 2015, Shock.

[11]  Edward T Chouchani,et al.  Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS , 2014, Nature.

[12]  A. Singer,et al.  ED bedside point-of-care lactate in patients with suspected sepsis is associated with reduced time to iv fluids and mortality. , 2014, American Journal of Emergency Medicine.

[13]  J. Vishwanatha,et al.  Cell Surface Translocation of Annexin A2 Facilitates Glutamate-induced Extracellular Proteolysis* , 2014, The Journal of Biological Chemistry.

[14]  N. Chandok,et al.  Female donor to male recipient gender discordance results in inferior graft survival: a prospective study of 1,042 liver transplants , 2014, Journal of hepato-biliary-pancreatic sciences.

[15]  R. Porte,et al.  Fibrinolytic Proteins in Human Bile Accelerate Lysis of Plasma Clots and Induce Breakdown of Fibrin Sealants , 2012, Annals of surgery.

[16]  C. Bokemeyer,et al.  Succinate reverses in-vitro platelet inhibition by acetylsalicylic acid and P2Y receptor antagonists , 2012, Platelets.

[17]  E. Pretto,et al.  Body surface area index predicts outcome in orthotopic liver transplantation , 2011, Journal of hepato-biliary-pancreatic sciences.

[18]  B. Olde,et al.  Succinate independently stimulates full platelet activation via cAMP and phosphoinositide 3‐kinase‐β signaling , 2011, Journal of thrombosis and haemostasis : JTH.

[19]  S. Parsa,et al.  Post-reperfusion Syndrome and Outcome Variables after Orthotopic Liver Transplantation , 2010, International journal of organ transplantation medicine.

[20]  I. Grigoraș,et al.  Functional improvement between brain death declaration and organ harvesting. , 2010, Transplantation proceedings.

[21]  A. Marcos,et al.  The impact of postreperfusion syndrome on short‐term patient and liver allograft outcome in patients undergoing orthotopic liver transplantation , 2008, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[22]  E. Mascha,et al.  Association between donor‐recipient serum sodium differences and orthotopic liver transplant graft function , 2008, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[23]  N. Serkova,et al.  Early detection of graft failure using the blood metabolic profile of a liver recipient. , 2007, Transplantation.

[24]  A. Gasbarrini,et al.  Gender Affects Reperfusion Injury in Rat Liver , 2001, Digestive Diseases and Sciences.

[25]  P. Nyckowski,et al.  Biochemical assessment of the early liver graft function in relation to selected donor parameters. , 2003, Transplantation proceedings.

[26]  J. Fung,et al.  Influence of high donor serum sodium levels on early postoperative graft function in human liver transplantation: effect of correction of donor hypernatremia. , 1999, Liver transplantation and surgery : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[27]  M. Layton,et al.  Ischemia/reperfusion alters uric acid and ascorbic acid levels in liver. , 1996, The Journal of surgical research.

[28]  T. Starzl,et al.  Effect of donor age and sex on the outcome of liver transplantation , 1995, Hepatology.

[29]  K. Hajjar.  Cellular Receptors in the Regulation of Plasmin Generation , 1995, Thrombosis and Haemostasis.

[30]  M. Pinsky,et al.  Postreperfusion syndrome: hypotension after reperfusion of the transplanted liver. , 1993, Journal of critical care.

[31]  R. Porte.  Coagulation and Fibrinolysis in Orthotopic Liver Transplantation: Current Views and Insights , 1993, Seminars in thrombosis and hemostasis.

[32]  T. Starzl,et al.  Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation. , 1989, Transplantation.

[33]  F. Molinas,et al.  [Fibrinolysis and thrombosis]. , 1974, Sangre.

[34]  S. C. Chung,et al.  Effect of bile on the blood coagulation. , 1964, Yonsei medical journal.