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.

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.

Eligibility Criteria:
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