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

• ClinicalTrials.gov Identifier: NCT05123326
• Recruitment Status: Recruiting
• First Posted: November 17, 2021
• Last Update Posted: November 17, 2021
• Sponsor: Postgraduate Institute of Medical Education and Research
• Information provided by (Responsible Party): Madhumita Premkumar, Postgraduate Institute of Medical Education and Research

Study Description

Brief Summary:

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]

Condition or disease	Intervention/treatment
Hepatic Vein Thromboses; Hepatic Venous Outflow Obstruction; Portal Vein Thrombosis; Portal Hypertension, Noncirrhotic; Portal Vein Occlusion; Portal Vein Embolism; JAK2 Mutation; CALR Gene Mutation; Prothrombin G20210A; Anticoagulants and Bleeding Disorders	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 Design

• Study Type: Observational
• Estimated Enrollment: 300 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Prospective Evaluation of Coagulation Status and Thromboelastometry Guided Management of Genetic and Acquired Thrombophilia in Patients With Portal Vein Thrombosis and Budd-Chiari Syndrome
• Actual Study Start Date: October 15, 2021
• Estimated Primary Completion Date: April 15, 2024
• Estimated Study Completion Date: October 15, 2024

Groups and Cohorts

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 Name: 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 Name: 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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Assessment of genetic predisposition of hypercoagulable states in PVT and HVOTO [ Time Frame: At enrolment ]
   JAK2, CALR, Factor V Leiden mutation
2. Assessment of genetic predisposition of hypercoagulable states in PVT and HVOTO [ Time Frame: At enrolment ]
   CALR mutation test
3. Assessment of genetic predisposition of hypercoagulable states in PVT and HVOTO [ Time Frame: At enrolment ]
   Factor V Leiden mutation
4. Assessment of genetic predisposition of hypercoagulable states in PVT and HVOTO [ Time Frame: At enrolment ]
   JAK2 mutation test
5. Occurrence of new hemorrhagic complications [ Time Frame: At enrolment-3 years ]
   Sites of bleeding in patients who are not on anticoagulation
6. Occurrence of new hemorrhagic complications in anticoagulated patients [ Time Frame: At enrolment-3 years ]
   Sites of bleeding in patients who are on anticoagulation

Biospecimen Retention:   Samples Without DNA

Blood and serum samples for thrombophilia evaluation.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Sampling Method: Non-Probability Sample

Study Population

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

Criteria

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

Contacts and Locations

Contacts

Contact: Madhumita Prem Kumar, MD DM; 0172-2754777; drmadhumitap@gmail.com

Contact: Harmanpreet Kaur Kaur, MSc; 0172-2754777; harmandhaliwal635@yahoo.com

Locations

India

Postgraduate Institute of Medical Education and Research; Recruiting

Chandigarh, Choose Any State/Province, India, 160012

Contact: Madhumita Premkumar, MD DM drmadhumitap@gmail.com

Contact: Harmanpreet Kaur, MSc 0172-2754777

Sub-Investigator: Harmanpreet Kaur Kaur, MSc

Sponsors and Collaborators

Postgraduate Institute of Medical Education and Research

Investigators

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

More Information

• Responsible Party: Madhumita Premkumar, Associate Professor, Postgraduate Institute of Medical Education and Research
• ClinicalTrials.gov Identifier: NCT05123326
• Other Study ID Numbers: PGI/IEC/2021/001451
• First Posted: November 17, 2021
• Last Update Posted: November 17, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hypertension, Portal; Budd-Chiari Syndrome; Thrombosis; Embolism; Venous Thrombosis; Hemostatic Disorders; Blood Coagulation Disorders; Vascular Diseases; Cardiovascular Diseases; Embolism and Thrombosis; Liver Diseases; Digestive System Diseases; Hematologic Diseases; Hemorrhagic Disorders