Global Coagulation Assessment in Portal Vein Thrombosis and Budd-Chiari Syndrome (Liv-Thrombus)

Prospective Evaluation of Coagulation Status and Thromboelastometry Guided Management of Genetic and Acquired Thrombophilia in Patients With Portal Vein Thrombosis and Budd-Chiari Syndrome

Portal vein thrombosis is defined as partial or complete occlusion of the portal vein lumen by the blood clot or its replacement by multiple collateral vessels with the hepato-petal flow, known as 'portal cavernoma'. [1,2] Based on the published literature, 15-25% of patients with cirrhosis have portal vein thrombosis (PVT) [3], and 35-50% of patients with hepatocellular carcinoma (HCC) have malignant PVT [4] compared to 1-3.8 per 100,000 patients in the general population. [5] The reported cumulative incidence of PVT in patients of Child-Pugh A and B is 4.6% and 10.7% at 1 and 5 years respectively with higher incidence among those with decompensated disease or with an underlying hypercoagulable disorder. [6]. Similarly, the prevalence of PVT in compensated cirrhosis is around 1% which increases to 8 - 25% in liver transplant (LT) candidates and 40% in patients with hepatocellular carcinoma (HCC) [7,8]. Based on the published literature 7-9 % of all chronic liver disease patients have hepatic vein outflow tract obstruction (HVOTO) in the Indian population. [9] HVOTO is defined as obstruction to hepatic venous outflow at any site from the right atrium inlet to the small hepatic venules. The Budd-Chiari syndrome (BCS) results from occlusion of one or more hepatic veins (HV) and/or the inferior vena cava (IVC). In the West, the most common cause is HV occlusion by thrombosis. More recent Indian studies have however shown that isolated HV and combined IVC+HV obstruction are now more common. [10]

In the post COVID-19 era, there has been great interest in the prothrombotic states associated with the SARS-Cov-2 virus infection, and the adverse effects of some vaccines. [11] With the availability of better molecular tests for hypercoagulable states, use of global coagulation tests (GCT) like rotational thromboelastometry (ROTEM), thromboelastography (TEG) and Sonoclot, use of therapeutic procedures like Transjugular intrahepatic portosystemic shunt (TIPS), availability of novel oral anticoagulants (NOAC), the natural course of disease can be changed with good outcomes. [12] Standard Coagulation tests (SCTs) like PT, aPTT, and platelet count are not predictive of bleeding or coagulation risk as they exclude the cellular elements of hemostasis and are unable to assess the effect of thrombomodulin and cannot assess the stage of the coagulation pathway which is affected. Global coagulation tests provide dynamic information on the coagulation pathway that is not available from conventional tests. [13]

Study Overview

• Status: Recruiting
• Conditions: Portal Vein Thrombosis; Anticoagulants and Bleeding Disorders; Hepatic Vein Thromboses; Hepatic Venous Outflow Obstruction; Portal Hypertension, Noncirrhotic; Portal Vein Occlusion; Portal Vein Embolism; JAK2 Mutation; CALR Gene Mutation; Prothrombin G20210A
• Intervention / Treatment: Diagnostic test: Rotational thromboelastometry; Diagnostic test: Genetic tests for Thrombophilia; Diagnostic test: ELISA tests/ Functional assays

Detailed Description

Our proposed study is important for the following 4 reasons.

1. SCTs cannot be used to demonstrate the thrombomodulin mediated normal thrombin generation in patients with liver disease, so the monitoring of such patient using global coagulation tests can be validated. The use of point-of-care global coagulation tests like ROTEM and Sonoclot enables us to identify the true prothrombotic and hypocoagulable states which can be used to assess for increased clot strength, clot formation time, and indicate hyperfibrinolysis. The use of conventional tests like prothrombin time, partial thromboplastin time and INR cannot bolster the therapeutic strategy.
2. This study will also help to determine role of global coagulation tests rather than PT/INR /aPTT in monitoring the dose and response of anticoagulants like vitamin K antagonists and novel oral anticoagulants (NOAC) in patients who are on therapeutic anticoagulation for HVOTO/PVT.
3. This study will also help to determine the prevalence and role of CALR, JAK2V617F, factor V Leiden mutations in patients with PVT and HVOTO in our population.
4. We will also be prospectively assessing the rate of thrombophilia complications in the Post COVID-19 era, and the study will generate information regarding new incidence of PVT/HVOTO in those exposed to COVID-19.

Therefore, the current study is the need of the hour, as we intend to assess the relevance of PVT and outcomes, test the genetic predisposition of Indian patients to hyper coagulable states, develop anticoagulation algorithms using NOAC, and determine the true burden on disease in India.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Madhumita Prem Kumar, MD DM; Phone Number: 0172-2754777; Email: drmadhumitap@gmail.com
• Study Contact Backup: Name: Harmanpreet Kaur Kaur, MSc; Phone Number: 0172-2754777; Email: harmandhaliwal635@yahoo.com

Study Locations

• India
  • Choose Any State/Province
    • Chandigarh, Choose Any State/Province, India, 160012
      • Recruiting
      • Postgraduate Institute of Medical Education and Research
      • Contact: Madhumita Premkumar, MD DM; Email: drmadhumitap@gmail.com
      • Contact: Harmanpreet Kaur, MSc; Phone Number: 0172-2754777
      • Sub-Investigator: Harmanpreet Kaur Kaur, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

All patients with PVT and HVOTO fitting the inclusion criteria will be prospectively enrolled in the study

Description

Inclusion Criteria:

• Gender: Either gender
• Age:18 - 65 years of age
• Patient with portal vein thrombosis documented on imaging (USG with color doppler, CECT abdomen and CEMRI abdomen

Exclusion Criteria:

• Patients who do not consent to the study.
• Patient with pregnancy and lactation
• Patients with a history of blood transfusions in the last two weeks
• Patients who are too sick to undergo screening tests.
• Patients on hemodialysis
• Chronic heart failure and chronic pulmonary or end-stage renal disease
• Patients who are on plasma therapy

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
PVT; Portal Vein Thrombosis (PVT) refers to partial or complete occlusion of the portal vein lumen by a blood clot or its replacement by multiple collateral vessels with the hepato-petal flow, commonly known as 'portal cavernoma.' 240 patients to be recruited	Diagnostic test: Rotational thromboelastometry; ROTEM/ Sonoclot tests will be done in all patients at enrolment and after initiating anticoagulation in those who are eligible for the same.; Other Names: Global coagulation test; Diagnostic test: Genetic tests for Thrombophilia; Tests for JAK2 mutation, CAL R mutation and Factor V Leiden mutation will be done.; Diagnostic test: ELISA tests/ Functional assays; Antithrombin III, Protein C, Protein S, Factor VIII, VWF using commercial assays
HVOTO; Occlusion of two or more hepatic veins. 100 patients	Diagnostic test: Rotational thromboelastometry; ROTEM/ Sonoclot tests will be done in all patients at enrolment and after initiating anticoagulation in those who are eligible for the same.; Other Names: Global coagulation test; Diagnostic test: Genetic tests for Thrombophilia; Tests for JAK2 mutation, CAL R mutation and Factor V Leiden mutation will be done.; Diagnostic test: ELISA tests/ Functional assays; Antithrombin III, Protein C, Protein S, Factor VIII, VWF using commercial assays

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical presentation	Number of participants with clinical and imaging evidence of PVT and HVOTO in our patient population	At enrolment
Clinical presentation- Extent of disease	Grading of PVT and HVOTO in our patient population	At enrolment
Occurrence of new thrombotic complications	Description of new sites of thrombosis spectrum of PVT and HVOTO in our patient population	At enrolment-3 years
Occurrence of all thrombotic complications after anticoagulation	Description of new sites of thrombosis spectrum of PVT and HVOTO after anticoagulation	At enrolment-3 years
Comparison of performance of standard coagulation tests vs. global coagulation tests to determine the hypercoagulable defect	PT aPTT INR	At enrolment
Comparison of performance of global coagulation tests to determine the hypercoagulable defect	ROTEM/Sonoclot	At enrolment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of genetic predisposition of hypercoagulable states in PVT and HVOTO	JAK2, CALR, Factor V Leiden mutation	At enrolment
Assessment of genetic predisposition of hypercoagulable states in PVT and HVOTO	CALR mutation test	At enrolment
Assessment of genetic predisposition of hypercoagulable states in PVT and HVOTO	Factor V Leiden mutation	At enrolment
Assessment of genetic predisposition of hypercoagulable states in PVT and HVOTO	JAK2 mutation test	At enrolment
Occurrence of new hemorrhagic complications	Sites of bleeding in patients who are not on anticoagulation	At enrolment-3 years
Occurrence of new hemorrhagic complications in anticoagulated patients	Sites of bleeding in patients who are on anticoagulation	At enrolment-3 years

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Madhumita Premkumar, MD DM, Postgraduate Institute of Medical Education and Research

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2021
• Primary Completion (Estimated): October 15, 2024
• Study Completion (Estimated): October 15, 2024

Study Registration Dates

• First Submitted: November 3, 2021
• First Submitted That Met QC Criteria: November 5, 2021
• First Posted (Actual): November 17, 2021

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Liver Diseases; Hemorrhagic Disorders; Embolism and Thrombosis; Hemostatic Disorders; Blood Coagulation Disorders; Embolism; Thrombosis; Venous Thrombosis; Hypertension, Portal; Budd-Chiari Syndrome
• Other Study ID Numbers: PGI/IEC/2021/001451

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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