Clinical trial NCT04246307: Investigation of Systemic and Regional Haemostasis During Liver Transplantation by Comparing ClotPro® and TEG®
Official title: Investigation of Systemic and Regional Haemostasis During Liver Transplantation by Comparing ClotPro® and TEG ® Viscoelastic Tests
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Haemostasis Disorders
Keywords: end-stage liver disease
liver transplantation
bleeding management
coagulopathy
thromboelastography
viscoelastic coagulation monitoring
thromboeleastometry
ClotPro
Lead sponsor: Semmelweis University
Sponsor class: OTHER
Collaborators: name: DiaCare Solution Kft
First posted: 2020-01-29
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients requiring liver transplantation for hepatic failure are to be enrolled at time of their liver transplantation.

Patients ≥18 years of age at the time of liver transplantation.

Brief summary: The purpose of the research is to compare the global and the portal haemostasis during liver transplantation by functional investigations using TEG® and ClotPro® tests. The study aims at revealing important coagulation-associated links affecting the outcome of the liver transplant surgery.

Detailed description: Donor data Liver donor data are investigated following the "Donor Query" used for donor reports of the Organ Coordination Office of the Hungarian National Blood Transfusion Service. (http://www.ovsz.hu/sites/ovsz.hu/files/szervadomanyozas_dokumentum/donacio/donorlekerdezo-2013-06-03.pdf) The donor is identified by the alarm ID and the Eurotransplant number (ETnr). Independently of this study, the "Donor Query" is completed for all donor reports and helps to asses donor suitability.

Recipient preoperative data In case of a liver alarm, age, body metrics, medical history, type and severity of hepatic disease, concomitant diseases, and admission laboratory test results of the recipient are recorded. Independently of this study, these data/procedures are recorded/performed for all liver transplant candidates.

Surgical data In addition to technical data of the surgery, data on intraoperative fluid balance, transfusion need, supportive therapy (vasopressor or inotropic therapy, renal replacement therapy), and number and indication of any reoperation are also recorded.

Intraoperative sampling times and investigations

During a liver transplantation, independently of this study, the following procedures are performed to monitor the patient's haemodynamics, homeostasis, and haemostasis:

* femoral artery catheterisation by pulse index contour cardiac output (PiCCO) catheter - haemodynamic monitoring by PiCCO
* radial artery catheterisation - arterial blood gas and arterial pressure monitoring
* subclavian or internal jugular vein catheterisation - central venous pressure (CVP) and central venous blood gas monitoring, drug administration
* external jugular vein catheterisation - blood sampling for haemostasis tests (TEG® and ClotPro® conventional laboratory tests - international normalized ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen, antithrombin (AT), factor V (FV), factor VII (FVII), factor X (FX), factor XIII (FXIII)
* 2 3 large peripheral veins - fluid resuscitation
* permanent urinary catheter - hourly urine output

During the study, for the analysis of haemostasis (TEG®, ClotPro®) and blood gases, 3.5 ml blood will be sampled per site and time from the external jugular vein catheter representing the systemic sample and from the portal vein representing the regional sample. Before performing the portal vein anastomosis, a small amount of blood is routinely flushed from the portal vein. Regional blood sampling is performed from this blood.

Systemic sampling is performed five times:

* before the surgery (S1)
* during the hepatectomy, 10 minutes before the anhepatic phase (S2)
* in the anhepatic phase, before starting portal vein anastomosis: (S3)
* in the neohepatic phase, 15 minutes after releasing portal vein clamping: (S4)
* in the neohepatic phase, at the end of the surgery: (S5)

Regional sampling from the portal vein is performed once:

• in the anhepatic phase, before starting portal vein anastomosis: (R)

Simultaneously with haemostasis and blood gas analyses, the following investigations will be performed (as the part of the anaesthesia protocol):

* haemodynamic measurements by PiCCO
* arterial blood gas analysis from radial artery catheter
* central venous blood gas analysis from subclavian vein catheter
* blood temperature measurement in the femoral artery by PiCCO catheter
* hourly urinary output Postoperative phase and follow-up In the immediate postoperative phase, postoperative heamodynamic, pulmonary, renal function, liver graft function) and their supportive therapy will be analysed.

Laboratory tests (quantitative and qualitative blood count, INR, aPTT, fibrinogen, AT, FV, FVII, FX, FXIII, C reactive protein (CRP), procalcitonin (PCT), electrolytes, creatinine, urea, bilirubin, liver enzymes, albumin, total protein, immunosuppressive drug levels) will be performed at the end of the surgery, at postoperative hours 12 and 24, on postoperative days 2, 3 and 7. As far as possible these tests will be carried out on day 30 and one year after the surgery as well.

Vasopressor and inotropic therapies will be analysed. The duration of assisted ventilation and the presence of pleural fluid or any sign of postoperative pneumonia will be evaluated. Urinary output as well as need for renal replacement therapy and the modality of that will also be investigated. Liver graft function will be monitored by means of laboratory parameters and graft perfusion with sonography. Initial poor function (IPF) and primary nonfunction (PNF) During the study, one-year graft and patient survival rates, the occurrence of small bile duct complications associated with arterial perfusion disorders, and the recurrence of underlying hepatic disease will be recorded. If a biopsy is taken within one year, histopathological results will also be evaluated.

Methodology and organisation of the study Informing patients on the study will occur during liver alarms by an anaesthesiologist. One copy each of the Patient Information Leaflet and the Informed Consent Form signed by the patient, the consenting physician and the principal investigator will be given to the patient. A copy of each of them will be filed in the medical records of the patient and the original one will be part of the research documentation.

During the study, tests for the investigation of parameters described in the protocol will be performed by the patients' physicians and other health care professionals involved in patient care.

Coagulation tests During the study, viscoelastic tests will be performed by TEG® and ClotPro® instruments.

Blood sampling for systemic TEG® and ClotPro® tests will be performed from the routinely catheterised external jugular vein while blood for regional tests will be taken from the portal vein of the recipient. After obtaining informed consent from the patient, 3.5 mL of blood samples will be collected in citrate tubes designated for the study at surgery phases described above. Investigations will be conducted by a TEG® 5000 thromboelastograph (Haemonetics Corp., Switzerland) and a ClotPro® (enicor GmbH, Germany) analyser. Results will subsequently be analysed by computed statistical tests. Simultaneously with viscoelastic tests, blood gas analyses will also be performed from the collected blood samples to obtain current pH, pCO2, and bicarbonate and calcium levels and their role in coagulation will be considered for the study. Furthermore, central body temperature will also be continuously monitored and recorded during the perioperative phase.

During TEG® and ClotPro® measurements in this study, the following parameters will be compared:

for TEG®, the following parameters will be considered in the study: R (reaction time): fluid phase of coagulation, time to formation of 2 mm clot; K (kinetics): time to formation of 20 mm clot; α: angle between 2 mm and 20 mm clot; MA (maximum amplitude): ultimate size of the clot; Ly30: percent rate of lysis at 30 minutes post MA. During the liver transplantation citrated kaolin test (CK-TEG) will be completed.

for ClotPro®, the following parameters will be considered in the study: CT (clotting time): indicates the fluid phase of coagulation (corresponds to R in TEG®); CFT (clot formation time): coagulation kinetics parameter, time between formation of 2 mm and 20 mm clot (corresponds to K in TEG®); α: angle (slope) of line between CT and CFT; A10 and A20 describe clot size (amplitude) at certain time points; MCF (maximum clot firmness): represents the ultimate size (maximum amplitude) of the clot (corresponds to MA in TEG®); clot lysis index at 30 (CLI30) describes the ratio between the maximum clot firmness and the amplitude 30 minutes after clotting time, LT (lysis time): characterises tPA effect.

During the liver transplantation EX-test, IN-test, FIB-test, TPA-test, RVV-test, and ECA-test tests will be completed.

Blood gas analyses Analyses are currently done by a GEM® PremierTM 3500 instrument. The blood gas analyser measures the following parameters: pH, pCO2, pO2, sodium, potassium, ionised calcium, blood glucose, lactate, bicarbonate, base excess, haemoglobin, haematocrit. Blood gas analyses are performed from the arterial and central vein samples. From the portal vein, blood sample is collected by the surgeon.

Laboratory parameters The following parameters will be measured at the laboratory by Sysmex CS 2000i, Sysmex XN-1000 (Sysmex Europe GmbH, Hungary) and Dimension® RxL Max® Integrated Chemistry System (Siemens Healthcare GmbH, Hungary)

* quantitative and qualitative blood count
* INR, aPTT, fibrinogen, AT, FV, FVII, FX, FXIII, sodium, potassium, magnesium, phosphate, ionised calcium
* creatinine, urea
* CRP, PCT
* total and direct bilirubin
* albumin
* liver enzymes: alkaline phosphatase (ALP), glutamic-oxaloacetic transaminase (GOT), glutamate-pyruvate transaminase (GPT), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), cholinesterase
* pancreatic enzymes: amylase, lipase Time of each laboratory test is determined by the study protocol. Laboratory tests associated with this study do not differ from the current clinical practice and thus, pose no additional interventions over the standard care.

Haemodynamic parameters Haemodynamic monitoring is performed for all patients undergoing liver transplantation in the perioperative period, independently from this study. Monitoring is done by a PiCCO instrument. During thermodilution measurements, cardiac output (CO), cardiac index (CI), intrathoracic blood volume index (ITBI), extravascular lung water index (EVLWI), stroke volume (SV), stroke volume variation (SVV), cardiac function index (CFI), maximum left ventricular contractility (dPmax), and mean arterial pressure (MAP) will be monitored.

CVP will be monitored via the catheterised subclavian vein. Time of each haemodynamic test is determined by the study protocol. Haemodynamic tests associated with this study do not differ from the current clinical practice and thus, pose no additional interventions over the standard care.

Oxygen delivery and consumption Parameters characterising oxygen delivery (oxygen delivery index; DO2I) and consumption (oxygen consumption index; VO2I) are calculated from arterial and central venous blood gas analysis results and from haemodynamic parameters.

Statistical methods Statistical analyses will be performed by Social Sciences software (SPSS; SPSS Inc, Chicago, Illinois, USA).

Continuous and discrete variables will be analysed by independent samples t tests (two categories) and one-way analyses of variance (one-way ANOVA; more categories), respectively. Two continuous variables will be compared by Spearman's rank correlation test. Discrete variables will be tested by Pearson's Chi squared test. Ordinary variables will be compared by Mann-Whitney U test or Kruskal-Wallis test. For multivariate analyses, logistic regression models will be generated.

Significance level will be set to 5% (p ≤ 0.05).

Eligibility criteria: Inclusion criteria:

* Patients requiring liver transplantation for chronic liver failure are to be enrolled at time of their liver transplantation.
* Patients ≥18 years of age at the time of liver transplantation.
* Liver transplantation will be performed between January 1st 2020 and January 1st 2021

Exclusion criteria:

* acute liver failure
* Failure to obtain informed consent from the patient.
* Patients \<18 years of age.
* Patients lacking legal competence.
* Coagulation tests included in the study protocol cannot be performed for any technical reason or samples cannot be collected.
* Combined liver and kidney transplantation.

Primary outcomes:
measure: Correlation between TEG® and ClotPro® parameters
timeFrame: 24 hours
Secondary outcomes:
measure: Difference between systemic and the portal haemostasis
timeFrame: 24 hours
measure: Correlation between the fetures of the intraoperative systemic and regional haemostasis and severity of the liver disease
timeFrame: 24 hours
measure: Correlation between local and systemic haemostasis and any subsequent coagulopathic or thrombotic complications
timeFrame: 24 hours
Other outcomes:
Locations:
city: Budapest
country: Hungary
facility: Semmelweis University
state: Pest Megye
Study officials:
References:
citation: Adams MJ, Irish AB, Watts GF, Oostryck R, Dogra GK. Hypercoagulability in chronic kidney disease is associated with coagulation activation but not endothelial function. Thromb Res. 2008;123(2):374-80. doi: 10.1016/j.thromres.2008.03.024. Epub 2008 May 16.
citation: Agarwal B, Wright G, Gatt A, Riddell A, Vemala V, Mallett S, Chowdary P, Davenport A, Jalan R, Burroughs A. Evaluation of coagulation abnormalities in acute liver failure. J Hepatol. 2012 Oct;57(4):780-6. doi: 10.1016/j.jhep.2012.06.020. Epub 2012 Jun 23.
citation: Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res. 2007 Feb 2;100(2):158-73. doi: 10.1161/01.RES.0000255691.76142.4a.
citation: Aird WC. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res. 2007 Feb 2;100(2):174-90. doi: 10.1161/01.RES.0000255690.03436.ae.
citation: Aird WC. Spatial and temporal dynamics of the endothelium. J Thromb Haemost. 2005 Jul;3(7):1392-406. doi: 10.1111/j.1538-7836.2005.01328.x. Epub 2005 May 9.
citation: Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med. 2001 Jul;29(7 Suppl):S28-34; discussion S34-5. doi: 10.1097/00003246-200107001-00013.
citation: Akkina SK, Asrani SK, Peng Y, Stock P, Kim WR, Israni AK. Development of organ-specific donor risk indices. Liver Transpl. 2012 Apr;18(4):395-404. doi: 10.1002/lt.23398.
citation: American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006 Jul;105(1):198-208. doi: 10.1097/00000542-200607000-00030. No abstract available.
citation: Babik B, Blaskó Gy, Fazakas J, et al.: Az életveszélyes perioperatív vérzések ellátása: szakmai irányelv. Aneszteziológia és Intenzív Terápia. 2013, 43(3): 113-143.
citation: Bischof D, Dalbert S, Zollinger A, Ganter MT, Hofer CK. Thrombelastography in the surgical patient. Minerva Anestesiol. 2010 Feb;76(2):131-7. Epub 2009 Nov 24.
citation: Bolliger D, Gorlinger K, Tanaka KA. Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology. 2010 Nov;113(5):1205-19. doi: 10.1097/ALN.0b013e3181f22b5a.
citation: Scarpelini S, Rhind SG, Nascimento B, Tien H, Shek PN, Peng HT, Huang H, Pinto R, Speers V, Reis M, Rizoli SB. Normal range values for thromboelastography in healthy adult volunteers. Braz J Med Biol Res. 2009 Dec;42(12):1210-7. doi: 10.1590/s0100-879x2009001200015. Epub 2009 Oct 30.
citation: Colomina MJ, Diez Lobo A, Garutti I, Gomez-Luque A, Llau JV, Pita E. Perioperative use of prothrombin complex concentrates. Minerva Anestesiol. 2012 Mar;78(3):358-68.
citation: Dalmau A, Sabate A, Aparicio I. Hemostasis and coagulation monitoring and management during liver transplantation. Curr Opin Organ Transplant. 2009 Jun;14(3):286-90. doi: 10.1097/MOT.0b013e32832a6b7c.
citation: Dirkmann D, Hanke AA, Gorlinger K, Peters J. Hypothermia and acidosis synergistically impair coagulation in human whole blood. Anesth Analg. 2008 Jun;106(6):1627-32. doi: 10.1213/ane.0b013e31817340ad.
citation: Durila M, Malosek M. Rotational thromboelastometry along with thromboelastography plays a critical role in the management of traumatic bleeding. Am J Emerg Med. 2014 Mar;32(3):288.e1-3. doi: 10.1016/j.ajem.2013.09.038. Epub 2013 Oct 2.
citation: Edelberg JM, Christie PD, Rosenberg RD. Regulation of vascular bed-specific prothrombotic potential. Circ Res. 2001 Jul 20;89(2):117-24. doi: 10.1161/hh1401.093954.
citation: Fazakas J, Smudla A: Véralvadás zavarok kritikus állapotú betegekben. In Bogár L, Molnár Zs (szerk.): Az intenzív terápia gyakorlata. Budapest, Medicina, 2013, 432-442.
citation: Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, Greenstein SM, Merion RM. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant. 2006 Apr;6(4):783-90. doi: 10.1111/j.1600-6143.2006.01242.x.
citation: Gando S, Wada H, Thachil J; Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost. 2013 May;11(5):826-35. doi: 10.1111/jth.12190.
citation: Ganter MT, Spahn DR. Perioperative coagulation management. Best Pract Res Clin Anaesthesiol. 2010 Mar;24(1):vii-viii. doi: 10.1016/j.bpa.2009.10.002. No abstract available.
citation: Girardis M, Marietta M. Hemostasis in acute liver and kidney failure: nothing is as it seems. Kidney Int. 2013 Jul;84(1):22-4. doi: 10.1038/ki.2013.121.
citation: Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. 2014 Feb 27;370(9):847-59. doi: 10.1056/NEJMra1208626. No abstract available.
citation: Innerhofer P, Kienast J. Principles of perioperative coagulopathy. Best Pract Res Clin Anaesthesiol. 2010 Mar;24(1):1-14. doi: 10.1016/j.bpa.2009.09.006.
citation: Klein K, Hartman SK, Teruya J, Hui SK. An algorithmic approach to coagulation testing. Dis Mon. 2012 Aug;58(8):431-9. doi: 10.1016/j.disamonth.2012.04.006. No abstract available.
citation: Kozek-Langenecker S, Sorensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care. 2011;15(5):R239. doi: 10.1186/cc10488. Epub 2011 Oct 14.
citation: Kozek-Langenecker SA. Perioperative coagulation monitoring. Best Pract Res Clin Anaesthesiol. 2010 Mar;24(1):27-40. doi: 10.1016/j.bpa.2009.09.009.
citation: Levi M, Schultz M, van der Poll T. Coagulation biomarkers in critically ill patients. Crit Care Clin. 2011 Apr;27(2):281-97. doi: 10.1016/j.ccc.2010.12.009.
citation: Levi M, van der Poll T, Schultz M. Systemic versus localized coagulation activation contributing to organ failure in critically ill patients. Semin Immunopathol. 2012 Jan;34(1):167-79. doi: 10.1007/s00281-011-0283-7. Epub 2011 Jul 30.
citation: Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol. 2010 Mar;52(3):355-61. doi: 10.1016/j.jhep.2009.12.001. Epub 2009 Dec 24.
citation: Lisman T, Caldwell SH, Burroughs AK, Northup PG, Senzolo M, Stravitz RT, Tripodi A, Trotter JF, Valla DC, Porte RJ; Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol. 2010 Aug;53(2):362-71. doi: 10.1016/j.jhep.2010.01.042. Epub 2010 May 12.
citation: Meybohm P, Zacharowski K, Weber CF. Point-of-care coagulation management in intensive care medicine. Crit Care. 2013 Mar 19;17(2):218. doi: 10.1186/cc12527. No abstract available.
citation: Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013 Sep;11(9):1064-74. doi: 10.1016/j.cgh.2013.02.026. Epub 2013 Mar 16.
citation: Perner F, Petrányi Gy (szerk.): Szervátültetés. Budapest, Medicina, 2013.
citation: Piangatelli C, Faloia L, Cristiani C, Valentini I, Vivarelli M. Point of care perioperative coagulation management in liver transplantation and complete portal vein thrombosis. Case Rep Transplant. 2014;2014:487364. doi: 10.1155/2014/487364. Epub 2014 Feb 6.
citation: Regan ER, Aird WC. Dynamical systems approach to endothelial heterogeneity. Circ Res. 2012 Jun 22;111(1):110-30. doi: 10.1161/CIRCRESAHA.111.261701.
citation: Rice TW, Wheeler AP. Coagulopathy in critically ill patients: part 1: platelet disorders. Chest. 2009 Dec;136(6):1622-1630. doi: 10.1378/chest.08-2534.
citation: Schaden E, Saner FH, Goerlinger K. Coagulation pattern in critical liver dysfunction. Curr Opin Crit Care. 2013 Apr;19(2):142-8. doi: 10.1097/MCC.0b013e32835ebb52.
citation: Sohal AS, Gangji AS, Crowther MA, Treleaven D. Uremic bleeding: pathophysiology and clinical risk factors. Thromb Res. 2006;118(3):417-22. doi: 10.1016/j.thromres.2005.03.032. Epub 2005 Jul 1.
citation: Solomon C, Sorensen B, Hochleitner G, Kashuk J, Ranucci M, Schochl H. Comparison of whole blood fibrin-based clot tests in thrombelastography and thromboelastometry. Anesth Analg. 2012 Apr;114(4):721-30. doi: 10.1213/ANE.0b013e31824724c8. Epub 2012 Feb 7.
citation: Tahlan A, Ahluwalia J. Factor XIII: congenital deficiency factor XIII, acquired deficiency, factor XIII A-subunit, and factor XIII B-subunit. Arch Pathol Lab Med. 2014 Feb;138(2):278-81. doi: 10.5858/arpa.2012-0639-RS.
citation: Thakur M, Ahmed AB. A Review of Thromboelastography. Int J Periop Ultrasound Appl Technol. 2012; 1 (1):25-29.
citation: Thorsen K, Ringdal KG, Strand K, Soreide E, Hagemo J, Soreide K. Clinical and cellular effects of hypothermia, acidosis and coagulopathy in major injury. Br J Surg. 2011 Jul;98(7):894-907. doi: 10.1002/bjs.7497. Epub 2011 Apr 20.
citation: Tripodi A, Chantarangkul V, Primignani M, Fabris F, Dell'Era A, Sei C, Mannucci PM. The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology. 2007 Aug;46(2):520-7. doi: 10.1002/hep.21732.
citation: van Meurs M, Wulfert FM, Knol AJ, De Haes A, Houwertjes M, Aarts LP, Molema G. Early organ-specific endothelial activation during hemorrhagic shock and resuscitation. Shock. 2008 Feb;29(2):291-9. doi: 10.1097/SHK.0b013e318145a7c1.
citation: Warnaar N, Lisman T, Porte RJ. The two tales of coagulation in liver transplantation. Curr Opin Organ Transplant. 2008 Jun;13(3):298-303. doi: 10.1097/MOT.0b013e3282fce79d.
citation: Wheeler AP, Rice TW. Coagulopathy in critically ill patients: part 2-soluble clotting factors and hemostatic testing. Chest. 2010 Jan;137(1):185-94. doi: 10.1378/chest.08-2535.