Risk Factors and Predictors of Thrombosis in Myeloprolferative Neoplasms

February 18, 2021 updated by: Maha Mohammed Abdel-Aziz, Assiut University

Risk Factors and Predictors of Thrombosis in Patients With Philadelphia Negative Myeloprolferative Neoplasms

To assess the clinical risk factors and predictable biomarkers of thrombotic complications in cases of philadelphia negative myeloproliferative disorders.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Classic BCR-ABL negative chronic myeloproliferative neoplasms (MPN) are stem cell disorders characterized by abnormal myeloid proliferation and increased blood cell counts and comprise polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).

Myeloproliferative neoplasms (MPN) are common malignancies in elderly individuals as the combined annual incidence rates of classical MPNs were reported to be 0.84, 1.03, and 0.47 per 100,000 respectively for PV, ET, and PMF but with a wide variation in prevalence rates reported in different studies. The 5-year relative survival rates are 84.8, 89.9, and 39% for PV, ET and PMF patients, respectively.

Thromboembolic complications represent a major cause of morbidity and mortality in MPN, particularly in PV and ET. The mechanisms underlying increased thrombotic risk in chronic myeloproliferative neoplasms (MPN) are incompletely understood.

Several pathophysiological mechanisms help explain the increased likelihood of thrombosis in these patients. Factors, such as leukocyte and platelet activation leading to the formation of leukocyte-platelet aggregates, activation of the coagulation cascade by microparticles, high levels of inflammatory cytokines, and endothelial dysfunction have a crucial role in thrombosis in MPN patients.

Accurate prediction of the thrombotic risk still represents a challenge and adequate predictive biomarkers are not available. The mechanisms underlying thrombosis involve a complex interplay among blood cells, the endothelium and the coagulation system. Both increased blood counts and cellular activation, which is due to hyperactivation of intracellular signaling pathways and enhanced interaction between blood cells, are implicated in the thrombotic predisposition.

The JAK2V617F mutation is a diagnostic marker for MPN and it also plays an important role in patient treatment since inhibition of JAK2-associated proliferative pathways has the potential to inhibit cell proliferation in MPNs. This mutation is present in ~95% of PV patients and 50% of ET or PMF patients. Thrombosis and hemostasis are major complications that affect the life expectancy of patients with MPN.

Current guidelines recommend testing for JAK2 mutations in any patient suspected to have an MPN. JAK2 mutation leads to distinct changes in hematopoietic cells that increase the likelihood of thrombus formation.

The risk of thrombosis, in both PV and ET, exceeds 20% and a substantial proportion of patients experience vasomotor disturbances (e.g. headaches, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, ocular disturbances, tinnitus) and in case of PV, pruritus.

Mean platelet volume (MPV) is largely considered as a useful indirect marker of platelet activation. Larger platelets are metabolically and enzymatically more active, and have a greater prothrombotic potential. Elevated MPV is associated with other markers of platelet activity, including increased platelet aggregation, increased thromboxane synthesis and beta-thromboglobulin release, and increased expression of adhesion molecules.

High sensitivity CRP is an inflammatory marker might be useful to reflect a condition of chronic inflammation which is associated with the disease severity .

In addition, Elevated CRP and elevated LDH are risk factors for survival in MPN patients.

Elevated γ-Glutamyl (γ-GT) transferase is an independent risk factor for Splanchnic venous thrombosis (SVT) presence in MPN.

About 30% of vascular events in Ph-negative MPN patients are VTE, which generally present as lower limb deep vein thrombosis or pulmonary artery embolism. However, in Ph-negative MPN, VTE characteristically occurs in uncommon locations such as splanchnic veins, including hepatic veins (presenting Budd-Chiari syndrome), portal and mesenteric veins, or, less frequently, cerebral veins or sinuses. In patients with MPN, the prevalence of CVT is 3-7% of cases.

Myeloproliferative neoplasms are known to be pro-thrombotic diseases (arterial and venous). For both of ET and PV, thromboses occur more frequently in arterial sites (between 64 and 75% for PV, and between 72 and 91% for ET).

JAK2 mutation can affect cardiac arteries and veins in ET and PV, which results in thrombosis, ischemia and other cardiovascular events. JAK/STAT signaling pathway plays an important role in heart diseases. High incidence of atrial arrhythmias among patients with ET or PV. The patients were older, cumulating more cardiovascular risk factors inducing more thrombotic events mainly in arteries, and have a higher incidence of death.

The importance of treatment compliance has now been clearly established in many pathological conditions as poor adherence has a negative impact on clinical evolution and non-adherence to cytoreductive therapy was associated with a significant reduction in the complete haematological remission rate but no significant association between thrombosis or death and non-adherence was found. This may be related to the fact that thrombosis is a more acute event, depending on the immediate hemostatic status at the time of thrombus constitution, whereas the phenotypic evolution of chronic haematological malignancies may be more the result of long term evolution of the clone, reflecting its exposure to therapeutic pressure.

Patients with MPN should also avoid factors that are known to increase risk of VTE, including systemic hormone therapy such as oral contraceptive pills and smoking, and optimize cardiovascular risk factors, including control of blood pressure, diabetes, and cholesterol, in order to minimize thrombotic complications.

Study Type

Observational

Enrollment (Anticipated)

165

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Egypt
      • Assiut, Egypt, 22413749
        • Recruiting
        • Clinical Hematology Unit

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

prospective cohort study

Description

Inclusion Criteria:

age > 18 years

All patients diagnosed as BCR-ABL negative myeloproliferative neoplasm e.g:

Polycythemia vera Essential thrombocythemia Primary myelofibrosis

Exclusion Criteria:

  • BCR- ABL positive MPN e.g CML
  • Secondary erythrocytosis.
  • Secondary thrombocytosis.
  • Secondary bone marrow fibrosis.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
myeloproliferative neoplasms
  • history taking
  • physical examination
  • laboratory investigations: Complete blood counts Bone marrow examination JAK2 V617F mutation. High-sensitivity C-reactive protein ESR Uric acid level LDH GGT BCR- ABL fusion gene IL-8 , TNF-Alpha Serum ferritin Serum albumin, transferrin, alpha feto protein Complement system: C3, C4.
Diagnostic test: myeloproliferative neoplasms
BLOOD SAMPLING

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of thromboembolic events in Philadelphia negative myeloproliferative neoplasms
Time Frame: 3 years
Incidence of thromboembolic events e.g. portal vein thrombosis, deep venous thrombosis or pulmonary embolism at patients newly diagnosed as philadelphia negative myeloproliferative neoplasms during the period of the study
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
survival of patients with Philadelphia negative myeloproliferative neoplasms
Time Frame: 3 years
life expectancy and causes of death( e.g. thrombosis, bleeding, infections, leukemic transformation)
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assiut University

Investigators

  • Study Director: howida nafady, extracted from this organization's records

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 20, 2019

Primary Completion (Anticipated)

December 31, 2022

Study Completion (Anticipated)

December 31, 2022

Study Registration Dates

First Submitted

June 28, 2018

First Submitted That Met QC Criteria

July 23, 2018

First Posted (Actual)

July 26, 2018

Study Record Updates

Last Update Posted (Actual)

February 21, 2021

Last Update Submitted That Met QC Criteria

February 18, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MPN
  • HABIBA (Other Identifier: clinical hematology unit)

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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