What is Polycythemia Vera?

Polycythemia vera (PV) is an uncommon blood cancer characterized as a myeloproliferative neoplasm. What this means is that the bone marrow has uncontrolled and abnormal cellular proliferation or growth. This causes the overabundance of cells being created to push out of the bone marrow crowding the vascular system with excess cells. In the case of Polycythemia vera there is an increase in Red Blood Cells (erythrocytes) but also White Blood Cells (leukocytes), as well as platelets (thrombocytes). It is most notable that unlike most other blood cancers (such as leukemias) Red Blood Cells are markedly increase, which is a hallmark of the disease. This extreme increase in circulating Red Blood Cells accounts for most of the signs and symptoms seen with Polycythemia vera. Polycythemia in itself means "many cells in the blood". Erythrocytosis is another term for Polycythemia. 

In general PV is seen and diagnosed more often in men than women. It is rarely seen in those under 40 years of age and becomes more prevalent as aging continues. In a given year, 1 in 36000 men will be diagnosed with PV, while just 1 in 77,000 women will be diagnosed. Roughly 1 out of 4500 people at any given time will be affected by the disease.

 PV is generally not an inheritable disorder and would not be expected to be passed down through generations. Like most cancers it's inception lies in a somatic genetic mutation that causes the bone marrow to overproduce Red Blood Cells. Being a somatic mutation, this means that the mutation occurred post-conception and was not a genetic mutation present at conception or birth, but as a result of a gene mutating during normal cell replication.

The vast majority of patients with PV have a mutation in the Janus Kinase 2 gene, also known as JAK2. JAK2 is an important protein involved in cell signaling. It is involved with regulating cell growth and replication as well as regulating cell production with the confines of the bone marrow. A mutation in this gene is like essentially losing the ability to say STOP! Without the ability of JAK2 to regulate cell production, the cells grow and divide and create more and more cells without cease. Cells continue to be made even in absence of erythropoietin, the hormone responsible for signaling that more RBCs should be produced. 

Care must be taken not to diagnose the etiology of polycythemia (or erythrocytosis) incorrectly. Polycythemia refers to a general condition in which the overall Red Blood Cell mass is increased within the patients circulation. Polycythemia vera refers to the malignant overproduction of cells within the bone marrow, a cancerous process. Vera in Latin translates to "True". So Polycythemia vera is a true polycythemia caused by a malignant cancerous process and could also be referred to as PRIMARY Polycythemia. Secondary polycythemia may occur, causing increased Red Blood Cell and Hemoglobin counts, but is not related to a cancerous process. 

Non-cancerous polycythemia/erythrocytosis can be caused by other factors that cause erythropoietin to be made, which is a hormone that tells the bone marrow to stimulate bone marrow. Conditions such as sleep apnea or COPD in which oxygen enters the blood at a lower rate, could trigger the body to produce more Red Blood Cells. Smoking, Alcohol use, diuretics can sometimes cause an Apparent Polycythemia. Chronic dehydration can also cause an apparent polycythemia, as the liquid portion of blood (plasma) is reduced. 

Rusfertide (PTG-300)

Rusfertide is an exciting new therapy aimed at patients with phlebotomy-dependent Polycythemia Vera. It is made by Protagonist Therapeutics and also goes by its inside name PTG-300. Rusfertide functions as a hepcidin mimetic, which means it mimics the function of the hormone Hepcidin. Hepcidin helps to control the levels of usable iron in the blood by regulating iron metabolism, storage, and absorption. This is important because many patients with Polycythemia vera have a secondary iron-deficiency as a result of increased erythropoiesis. Iron is being constantly used up to create Red Blood Cells in PV patients, leaving them with a deficiency in iron as a result. 

Blood donation, or in the case of case of PV patients, therapeutic phlebotomy, can worsen iron deficiency. Rusfertide can potentially eliminate the need for regular therapeutic phlebotomy and has been shown to help keep PV patient's hematocrits at or below 45%. This is due to Rusfertide's Hepcidin function, inhibiting the abundance of available iron, thus preventing the overproduction of Red Blood Cells since iron is required for Red Blood Cells production. 

Eliminating the overproduction of Red Blood Cells and the need for regular therapeutic phlebotomies should also allow PV patients to recover (to some level) from the iron deficiency seen in the disease. 

Rusfertide is still in clinical trial phase, with Phase 3 (NCT05210790) expected to have its study completed by 2025.