Thrombin Generation in Liver Transplant Surgery

Diagnosis and Management of Impaired Thrombin Generation in Liver Transplant Surgery

This is a prospective observational study of 100 patients undergoing liver transplantation at a single centre. Thrombin generation and kinetics will be assessed using a novel point-of-care device, and compared to conventional measures of hemostasis as well as viscoelastic tests to pinpoint specific coagulation deficits and identify potential therapeutic targets. The clinical course of patients will be followed for major bleeding and transfusion outcomes.

Study Overview

• Status: Unknown
• Conditions: Liver Transplantation; Blood Coagulation Disorders; Thrombin; Hemostasis, Surgical; Blood Coagulation Disorder Due to Liver Disease

Detailed Description

Liver transplantation is the only curative option for end stage liver disease, but is associated with high morbidity and mortality. End stage liver disease is known to be accompanied by dysregulated coagulation, which is further exacerbated in the immediate perioperative period by transplantation, leading to both coagulopathic bleeding and thrombosis. Altered thrombin generation is thought to play a key role in the predisposition of these patients for both severe coagulopathic hemorrhage and life-threatening thromboembolic complications. Despite this, thrombin generation during the immediate transplant period in patients with end-stage liver disease is poorly characterized, in part because it is not well reflected by conventional measures of coagulation. This study aims to characterize changes in thrombin generation capacity pre, intra- and post-transplant utilizing a novel point-of-care thrombin generation assay. Other specific aims of the study are to identify risk factors for patients with impaired thrombin generation and will assess the association of impaired thrombin generation with overall clinical bleeding risk. The overarching goal of this work is to develop a point-of-care-testing guided algorithm addressing dysregulated thrombin formation that improves coagulation management without increasing the risk of thromboembolic complications. Ultimately, this line of research will improve the outcomes of liver transplantation.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Recruiting
      • Toronto General Hospital - University Health Network
      • Contact: Justyna Bartoszko, MD MSc FRCPC; Phone Number: 416-340-3567; Email: justyna.bartoszko@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All consenting adults undergoing liver transplantation surgery at Toronto General Hospital

Description

Inclusion Criteria:

• All adult patients (> 18 years of age) proceeding to imminent (within 24 hours) liver transplantation surgery at Toronto General Hospital will be offered participation.
• Patients should have end stage liver disease necessitating transplantation. All etiologies of end stage liver disease will be accepted.

Exclusion Criteria:

- Patients who are unable to consent to the study or who refuse participation will be excluded.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Patients undergoing Liver Transplantation; This is a prospective observational study that intends to offer participation to all patients undergoing liver transplantation at Toronto General Hospital. Parameters that will be measured include Thrombin generation, viscoelastic testing utilizing ROTEM, and conventional laboratory testing (INR, aPTT and Fibrinogen level) at five time points: (a) Prior to cross-clamp application; (b) within the first 30 minutes of venous cross clamp removal; (c) after 30 minutes of reperfusion; (d) On arrival in the intensive care unit (ICU) or post-anesthesia recovery unit; and (5) 12 hours post-operatively.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thrombin Generation - Endogenous Thrombin Potential (nM*min)	The change in thrombin generation will be measured in patients undergoing liver transplantation, as assessed through the Endogenous Thrombin Potential (nM*min)	The pattern of change in thrombin generation will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively
Thrombin Generation - Lag Time (Seconds)	The change in thrombin generation will be measured in patients undergoing liver transplantation as assessed by the Lag Time (Seconds)	The pattern of change in thrombin generation will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively
Thrombin Generation - Time to Peak (Seconds)	The change in thrombin generation will be measured in patients undergoing liver transplantation by the Time to Peak (Seconds)	The pattern of change in thrombin generation will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively
Thrombin Generation - Peak Height (nM)	The change in thrombin generation will be measured in patients undergoing liver transplantation by the Peak Height (nM)	The pattern of change in thrombin generation will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conventional Hemostatic Tests - Platelet Count	The platelet count from the complete blood count in x10^9/L	The pattern of change will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively
Conventional Hemostatic Tests - INR	The international normalized ratio (INR) in seconds	The pattern of change will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively
Conventional Hemostatic Tests - aPTT	The activated partial thromboplastin time (aPTT) in seconds	The pattern of change will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively
Conventional Hemostatic Tests - Fibrinogen Level	The Clauss Fibrinogen level in g/L	The pattern of change will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively
Viscoelastic Testing	Rotational thromboelastometry (ROTEM)	The pattern of change will be assessed intra-operatively at baseline through to study completion up to 12 hours post-operatively

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transfusion Outcomes - Red Blood Cells	The total number of red blood cells transfused	From intra-operatively to within 12 hours post-operatively
Transfusion Outcomes - Platelets	The total number of platelet units transfused	From intra-operatively to within 12 hours post-operatively
Transfusion Outcomes - Frozen Plasma	The total number of frozen plasma units transfused	From intra-operatively to within 12 hours post-operatively
Transfusion Outcomes - Prothrombin Complex Concentrate	The total number of units transfused	From intra-operatively to within 12 hours post-operatively
Transfusion Outcomes - Fibrinogen Concentrate	The total number of grams of fibrinogen transfused	From intra-operatively to within 12 hours post-operatively
Bleeding Outcomes - Delayed Abdominal Closure	Clinical bleeding outcome such as delayed abdominal	From intra-operatively to within 12 hours post-operatively
Bleeding Outcomes - Return to the Operating Room for Re-Exploration	Clinical bleeding outcome such as return to the operating room for re-exploration or evacuation of hematoma	From intra-operatively to within 12 hours post-operatively

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: Justyna Bartoszko, MD MSc FRCPC, Toronto General Hospital - University Health Network; Principal Investigator: Keyvan Karkouti, MD MSc FRCPC, Toronto General Hospital - University Health Network

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2021
• Primary Completion (Anticipated): January 1, 2022
• Study Completion (Anticipated): January 1, 2022

Study Registration Dates

• First Submitted: February 2, 2021
• First Submitted That Met QC Criteria: February 16, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): May 3, 2021
• Last Update Submitted That Met QC Criteria: April 29, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Liver Diseases; Hemostatic Disorders; Blood Coagulation Disorders; Disease
• Other Study ID Numbers: 20-5414.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No