Thrombin Generation in Liver Transplant Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Diagnosis and Management of Impaired Thrombin Generation in Liver Transplant Surgery

Conditions
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Liver Transplantation, Thrombin, Hemostasis, Surgical, Blood Coagulation Disorder Due to Liver Disease, Blood Coagulation Disorders

Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients undergoing Liver Transplantation<br>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?
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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 |