Incidence of Iron Deficiency in Polycythemia Vera (PV) and Association With Disease Features

Iron deficiency is a known feature of PV, occurs because of accelerated erythropoiesis, gastrointestinal blood loss and phlebotomy. Incidence and effect of iron deficiency in these patients is not well characterized. The study will assess the incidence of iron deficiency at diagnosis and during the course of PV, assess effect of iron deficiency on patient symptoms and its correlation with disease features.

This is a multicenter, non-interventional, non-randomized, prospective, observational study in an adult population (patients >18 years old) of patients who have been diagnosed with PV and are being followed in either community or academic medical centers in Israel.

Study Overview

• Status: Unknown
• Conditions: Polycythemia Vera
• Intervention / Treatment: Other: questionnaires

Detailed Description

Background:

Within intestinal epithelial cells, some of the imported iron is incorporated into ferritin and other storage forms. A fraction of the iron taken up from the intestinal lumen passes through the cell, and is exported across the basolateral membrane to enter the body. Ferroportin, a metal ion transporter, serves as the basolateral iron exporter. Hepcidin regulates basolateral iron export by binding to ferroportin to trigger its internalization and lysosomal degradation. Each day, normal adults need 25 mg of iron to support hemoglobin production in maturing erythrocytes. This amount is much greater than the iron absorbed daily through the intestine. Obviously, iron needed for erythropoiesis must be acquired from supplies already existing in the body. The primary source of plasma iron is the reticuloendothelial macrophage system, which recovers iron from senescent and damaged erythrocytes. Other significant site of iron exchange is the liver.

Dietary iron absorption is enhanced in response to insufficient iron stores, increased erythropoietic demand or hypoxia. It is diminished in response to iron surfeit and inflammation. Based on these observations, four different "regulators" have been defined functionally: 1) The stores regulator modulates absorption several fold, increasing it in iron deficiency and decreasing it in iron overload. 2) The erythroid regulator is more potent-it can increase iron absorption 6- to 10-fold when erythropoiesis becomes iron -restricted, result either from iron deficiency or from accelerated production of erythroid precursors. 3) The hypoxia regulator mediates an increase in iron absorption in response to hypoxia, to allow for production of hemoproteins that bind and carry oxygen. 4) An inflammatory regulator also exists, which acts to decrease iron absorption in response to inflammation. All of these regulators act through a common, humoral effector that coordinates intestinal iron absorption and macrophage iron recycling. Hepcidin plays a major role in iron metabolism. It is produced in the liver, cleaved from a larger precursor molecule and secreted into the plasma. Circulating hepcidin attaches to ferroportin expressed on enterocytes and macrophages, causing ferroportin to be internalized into the cell and degraded in lysosomes. Hepcidin is induced in response to iron overload and inflammation. It is turned off in response to iron deficiency , ineffective erythropoiesis and hypoxia.

Polycythemia vera (PV) is one of the myeloproliferative neoplasms (MPNs) and is characterized by marrow hyperplasia with an increased number of erythrocytes, leukocytes and platelets in peripheral blood. Several studies have shown that iron deficiency is common in PV patients and can significantly influence the quality of their life. These complications are a result of expansive erythropoiesis, in addition to phlebotomy and/or gastrointestinal bleedings. The role of JAK2V617F in pathogenesis of iron deficiency in PV is also very intriguing. Kinase JAK2 is involved in signal transduction via the erythropoietin receptor. EPO is one of the hepcidin synthesis regulators. Some of the data has confirmed that JAK2 mutation may be involved in the regulation of the iron status in myeloproliferative disorders.

There are several reports in the literature on thrombotic complications in iron-deficient adults. Secondary thrombocytosis has been implicated in many cases.

In addition to the increased thrombotic risk associated with high platelet count, the decrease in antioxidant defense in iron deficiency may cause increased oxidant stress, which in turn may result in a tendency toward platelet aggregation. The abnormal platelet count and function observed in iron deficiency anemia could act synergistically to promote thrombus formation. Iron deficiency may contribute to a hypercoagulable state by affecting blood flow patterns within the vessels because of reduced deformability and increased viscosity of microcytic red blood cell.

Purpose:

Incidence and effect of iron deficiency in patients with PV is not well characterized. The study will assess the incidence of iron deficiency at diagnosis and during the course of PV, assess effect of iron deficiency on patient symptoms and its correlation with disease features.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

• Study Contact: Name: Noa Lavi, Dr; Phone Number: 972-50-2061332; Email: lavi.noa@gmail.com
• Study Contact Backup: Name: Martin Ellis, Prof.; Phone Number: 972-53-7482482; Email: martinel@clalit.org.il

Study Locations

• Israel
  • Afula, Israel
    • Emek Medical Center
    • Contact: Evgeni Chubar, Dr
  • Beer Sheva, Israel
    • Soroka Medical Center
    • Contact: Anna Gurevich
  • Hadera, Israel
    • Hillel Yaffe Medical Center
    • Contact: Lea Arbov
  • Haifa, Israel
    • Rambam Medical Center
    • Contact: Noa Lavi
  • Haifa, Israel
    • Bnei Zion Medical Center
    • Contact: Yelena Mischenko, Dr
  • Kfar Saba, Israel
    • Meir Medical Center
    • Contact: Martin Ellis, Prof
    • Principal Investigator: Martin Ellis
  • Ramat Gan, Israel
    • Sheba Medical Center
    • Contact: Adrian Duek
  • Rehovot, Israel
    • Kaplan Medical Center
    • Contact: Anfisa Santevsky, Dr
  • Tel Aviv, Israel
    • Maccabi
    • Contact: Sigal Tavor, Dr
    • Sub-Investigator: Shirly Shapira, Dr
  • Tel Aviv, Israel
    • Tel Aviv Sourasky
    • Contact: Irit Avivi, Prof
  • Zefat, Israel
    • Ziv Medical Center
    • Contact: Nagib Dali
  • Zerifin, Israel
    • Assaf Harofeh Medical Center
    • Contact: Odit Gotvin, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

An adult population (patients >18 years old) of men and women who have been diagnosed with clinically overt PV will be enrolled. Sites will include both community and academic centers across Isreal.

Description

Inclusion Criteria:

• Age ≥18 years
• Diagnosis of Polycythemia Vera (PV)
• Willing and able to provide written informed consent
• Willing and able to complete patient assessment questionnaires either alone or with minimal assistance from a caregiver and/or trained site personnel
• Under the supervision of a physician for the current care of PV including but not limited to watchful waiting, acetylsalicylic acid (ASA) 81mg or greater, antithrombotic therapy, Phlebotomy (PHL), Hydroxyurea (HU), interferon (recombinant or pegylated), busulfan, anagrelide

Exclusion Criteria:

• Diagnosis of myelofibrosis (MF) [including primary MF, post-PV MF, or post-essential thrombocythemia MF (post-ET MF)]
• Diagnosis of secondary Acute Myeloid Leukemia (AML)
• Diagnosis of Myelodysplastic Syndrome (MDS)
• Splenectomy

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
Patients with PV, not newly diagnosed; Patients with clinically overt PV treated with watchful waiting (with or without aspirin), Phlebotomy (PHL), Hydrea or any other treatment. Influence of iron parameters on Patient-reported symptoms will be evaluated by questionnaires Blood serum samples will be taken for iron parameters analysis	Other: questionnaires; • Influence of iron parameters on Patient-reported symptoms as assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) for assessment of the severity of symptoms, Quality of life evaluation by The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and fatigue assessment by PROMIS Fatigue Scale: Short Form
Newly diagnosed patients with PV; Patients with clinically overt PV, newly diagnosed, before any treatment and before phlebotomy initiation. Influence of iron parameters on Patient-reported symptoms will be evaluated by questionnaires Blood serum samples will be taken for iron parameters analysis	Other: questionnaires; • Influence of iron parameters on Patient-reported symptoms as assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) for assessment of the severity of symptoms, Quality of life evaluation by The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and fatigue assessment by PROMIS Fatigue Scale: Short Form

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of iron deficiency in patients with PV	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Association between iron deficiency and other clinical features	2 years
Influence of therapy (phlebotomies, hydroxyurea, other therapies) on iron parameters	2 years
Influence of iron parameters on Patient-reported symptoms	2 years
Influence of iron deficiency on arterial and venous thrombosis rate	2 years

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus
• Collaborators: Meir Medical Center
• Investigators: Principal Investigator: Noa Lavi, Dr, Rambam Health Care Campus

Publications and helpful links

General Publications

• Pearson TC, Grimes AJ, Slater NG, Wetherley-Mein G. Viscosity and iron deficiency in treated polycythaemia. Br J Haematol. 1981 Sep;49(1):123-7. doi: 10.1111/j.1365-2141.1981.tb07205.x.
• Hutton RD. The effect of iron deficiency on whole blood viscosity in polycythaemic patients. Br J Haematol. 1979 Oct;43(2):191-9. doi: 10.1111/j.1365-2141.1979.tb03741.x.
• Kwapisz J, Zekanowska E, Jasiniewska J. Decreased serum prohepcidin concentration in patients with polycythemia vera. J Zhejiang Univ Sci B. 2009 Nov;10(11):791-5. doi: 10.1631/jzus.B0920217.
• Rector WG Jr, Fortuin NJ, Conley CL. Non-hematologic effects of chronic iron deficiency. A study of patients with polycythemia vera treated solely with venesections. Medicine (Baltimore). 1982 Nov;61(6):382-9. doi: 10.1097/00005792-198211000-00004. No abstract available.
• Franchini M, Targher G, Montagnana M, Lippi G. Iron and thrombosis. Ann Hematol. 2008 Mar;87(3):167-73. doi: 10.1007/s00277-007-0416-1. Epub 2007 Dec 8.
• Birgegard G, Carlsson M, Sandhagen B, Mannting F. Does iron deficiency in treated polycythemia vera affect whole blood viscosity? Acta Med Scand. 1984;216(2):165-9. doi: 10.1111/j.0954-6820.1984.tb03788.x.

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Anticipated): July 1, 2018
• Study Completion (Anticipated): August 1, 2018

Study Registration Dates

• First Submitted: June 18, 2016
• First Submitted That Met QC Criteria: June 21, 2016
• First Posted (Estimate): June 22, 2016

Study Record Updates

• Last Update Posted (Estimate): June 22, 2016
• Last Update Submitted That Met QC Criteria: June 21, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: polycythemia vera; iron deficiency
• Additional Relevant MeSH Terms: Metabolic Diseases; Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Anemia, Iron-Deficiency; Polycythemia Vera; Polycythemia
• Other Study ID Numbers: 0186-16 CTIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No