Risk Factors and Predictors of Thrombosis in Myeloprolferative Neoplasms

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

Detailed Description
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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.

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

Conditions
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Thrombosis

Intervention / Treatment
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* Diagnostic Test: myeloproliferative neoplasms


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| myeloproliferative neoplasms<br>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<br>* BLOOD SAMPLING<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of thromboembolic events in Philadelphia negative myeloproliferative neoplasms | 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 | life expectancy and causes of death( e.g. thrombosis, bleeding, infections, leukemic transformation) | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thrombosis, myeloproliferative neoplasms