Polycythemia Vera

 

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. 

Signs and Symptoms

Many patients with Polycythemia vera may not know they have it. It is generally a slow and eventual process.  It may not be until they have routine blood work done, such as a CBC (Complete Blood Count), that their doctor is tipped off to something being wrong. The CBC of a patient with PV may show increased absolute Red Blood Cell count, increased Hemoglobin, as well as an increase in hematocrit percentage. Hemoglobin is major protein within a Red Blood cell that not only gives Red Blood cells their red hue, but it is also responsible for carrying oxygen throughout the body and to the tissues. It's no wonder that if the amount of Red Blood Cells increase, hemoglobin will generally follow and increase as well. The Hematocrit is a percentage of Red Blood Cells related to the total amount of blood volume. The remaining portion of blood volume that isn't Red Blood Cells, is mostly plasma. For some with PV, they can see a slight but generally not malignant increase in White Blood Cells as well as platelets. 

Normal RBC counts are roughly 4.5 to 6.0×10^12/L for men, and 4.0 to 5×10^12/L for women. Normal hemoglobin ranges 14 to 17 grams per deciliter(dL) for men and 12 to 15 grams per deciliter for women. Hematocrits range from 40-50% in men and 35-45% in women. Counts above this range, coupled with other symptoms could lead a doctor to suspect Polycythemia vera. Ranges will differ slightly based on location due to slight differences in instrumentation and patient population. 

Normal Blood Counts per MayoClinic laboratories

Polycythemia vera is dangerous however, because with an increase of Red Blood Cells beyond what is normal, the blood starts to become thicker and less viscous. This makes circulating the blood throughout the body much more difficult and can lead to dangerous situations such as blood clots and strokes. The situation in which the thickening, or an increase of viscosity of the blood, is called hyperviscosity syndrome. It is not specific to PV, and patient's with other hematologic malignancies such as Waldenstroms macroglobulinemia, leukemias, Multiple Myeloma, etc. Patient's with PV that start to experience hyperviscosity syndrome can expect to see most non-specific symptoms such as 

• Headache
• Nausea
• Vision Changes and retinopathy
• Dizziness/Vertigo
• Seizures and potentially even coma. 
• Dyspnea (Shortness of breath)
• Fatigue/Weakness
• Stroke
• Night Sweats
• Bruising / Extended Bleeding
• Weight Loss

Nearly one fifth of all patients with PV are found to have clots within their circulatory system. A large majority of clots can cause and/or be related to stroke or TIAs (Transient Ischemic Attacks aka Mini-stroke).

Increased blood viscosity in PV is related to decreased blood flow (ischemia), especially to the brain which leads to an increased risk of thrombotic (clotting) events. Similarly, clots and hyperviscous blood can cause organ damage throughout the body, as well as heart attacks. 

Other symptoms include

Erythromelalgia with blotchy, discolored, red skin. This is due to the increase of red blood cells in the body and the slower circulation of the cells. The skin may be warm to the touch as well. A burning pain sensation can also occur as parts of the vasculature in the extremities can get periodically blocked due to the viscous blood. 

Itchy skin, especially after a warm bath/shower -- nearly half of all patients with PV will have itchy skin. It can be the first symptom to show before the disease progresses. It is thought that this is caused by an abnormal function of histamine release as well as cytokine release. (cytokines are cell signaling molecule)

Gout -- gout is a painful type of arthritis caused by an excess buildup of uric acid in the body. Uric acid crystals become deposited in areas of a patient's joints, usually causing immense pain. The big toe is the most common joint to experience this. In general gouty arthritis this is usually caused by the bodies failure to remove uric acid from circulation such as seen with a low functioning kidney. It can also be due to excessive intake through foods, etc. In the case of PV, it is related to the high turnover of Red Blood Cells causing excess UA to be produced,  and potentially the decreased excretion of Uric Acid due to organ damage related to PV. Increased Uric Acid and gout is also related to the myelofibrosis that can sometimes be seen in PV patients.

Splenomegaly -- an enlarged spleen. One of the spleen's important functions is filtering out and removing old or damaged Red Blood Cells. In PV, since there are so many Red Blood Cells, there is an marked increase in the amount of old/damaged Red Blood Cells that the spleen has to process. This causes the spleen to enlarge as it becomes overworked and the cells build up. If it becomes too large, patient's can feel discomfort in that area.  

Myelofibrosis --- a severe scarring of the bone marrow that can occur as part of the PV disease progression. Myelofibrosis is not unique to PV and can happen under many other conditions. Over time, after consistently overproducing cells for extended periods of time, the bone marrow can become so overrun by scar tissue from the damaging effects of over proliferation, that it is no longer able to effectively make cells. This results in a broad DECREASE in cells across the board. One could expect to see decreased Red Blood Cell counts at this point (resulting in anemia), as well as a decrease in White Blood Cell counts and Platelets. Not all patients will progress to Myelofibrosis but nearly 10% may. Myelofibrosis also increases the risk of having gout symptoms as seen above. 

Diagnosis

Many patients with Polycythemia vera may not know they have the disease for some time. Initial symptoms may come and go, or be vague enough to not pinpoint to any one problem until the disease progresses. 

Some many initially present with a headache, fever, itchy/warm/red skin, dizziness, etc. Some patients may have an obvious abdominal bulge due to splenomegaly. 

As part of any workup, the doctor will almost always order a CBC (Complete Blood Count). Since Polycythemia vera's hallmark is the presence of an increased Red Blood Cell mass, a CBC would be an excellent tool in aiding in the diagnosis of PV. For men, a Hemoglobin concentration of greater than 16.5 g/dL, a hematocrit above 50%, and an increased total Red Blood Cell count would be highly indicative for disease. For women, normal hemoglobin and hematocrit levels are slightly lower than men so roughly 16g/dL and 48% hematocrit could potentially raise alarm.

 If the doctor can rule out secondary reasons for these being increased, such as dehydration, these numbers would be a cause for your doctor to potentially follow closer to a Polycythemia vera diagnosis. Results far above the previously mentioned numbers would likely aid in diagnosis. Numbers that high but borderline normal, may need more probing. Presenting with any of the symptoms listed here would likely aid in diagnosis. Many instances of increased Hemoglobin/Red Cells/Hematocrit are not due to Polycythemia vera, but to secondary processes. 

Your doctor may want to test for mutations within the Janus Kinase 2 (JAK2) gene. As previously mentioned, this gene is responsible for creating a protein that is involved in cell signaling. It tells the bone marrow to "start" or "stop" the creation of new blood cells. A very common mutation "JAK2(V617F)" is found in the overwhelming majority of patients with Polycythemia vera. A laboratory can test your blood and search for this mutation within the gene. It is also possible for the laboratories to search for other metalations within the gene if testing comes up negative for the JAK2(V617F) mutation allele. 

Erythropoietin -- a hormone that signals for the body to create more red blood cells. Patients with PV will generally have very low levels of EPO, given that EPO works off a feedback loop, if red cells and tissue oxygenation are abundant there's no need for more EPO to be created. Patients with high RBC/Hemoglobin(Hgb)/Hematocrit(Hct) counts suffering from dehydration, COPD, sleep apnea, etc., will not have these severely low levels. Your doctor may use JAK2 mutation in conjunction with EPO testing to be sure. 

Bone Marrow Biopsy -- your doctor may recommend a bone marrow biopsy and/or bone marrow aspirate. A needle is inserted in the bone, generally through the area of the Iliac Crest on the hip. This is the most common and safest site for biopsy due to its location away from major organs and blood vessels. The aspirate portion of the procedure involves removing some of the fluid portion of the marrow itself for examination. Slides will generally be made from this to be viewed microscopically. During the same procedure, a piece of solid bone marrow may be removed for analysis. The end results would generally show a bone marrow with far too many Red Blood Cells being created at a given time.

Treatment 

Treatment of Polycythemia vera will depend on certain things like overall health and age, severity of disease and likelihood of progression, and other risk factors. 

Those of younger age, typically under 60 with no history of clotting disorders or events are generally considered lower risk than those of more advanced age and/or those with previous clotting events. 

Unfortunately there is no definitive cure for PV. There are a number of treatments available to lessen symptoms and improve outcomes. PV carries a fairly optimistic prognosis unlike some cancers and hematological malignancies. On average, most people can live twenty years past their diagnosis date if they remain committed to their health and treatment plan. The most common cause of death in PV patients is clotting, so it is essential to be on top of things post-diagnosis. Other complications include progressing disease which may transform into myelofibrosis, AML (Acute Myelogenous Leukemia), or MDS (Myelodysplastic Syndrome). The treatments available generally do not lessen the risk of progression towards AML or MDS. Roughly 10 percent of patient's with PV may experience transformation info AML or MDS. Patients who progress to AML or MDS will see shorted expectations and worse prognosis. 

Therapeutic Phlebotomy -- It is exactly as it sounds. When you go to the doctor and have labs drawn, a nurse or phlebotomist will perform a phlebotomy or "venipuncture" to acquire blood from the patient for testing. This is essentially the same idea. Therapeutic phlebotomy involves a venipuncture in which blood is removed from the patient in order to relieve many of the symptoms and potential future problems of having hyperviscous blood. 

 

Up to 500mL is removed during a single sitting (the same amount removed during blood donation). Lesser amounts may be taken depending on the patient's cardiovascular heath and age. Initially, phlebotomies will take place as often as possible (once a day, every other day) until the patient's hematocrit reaches a normal 45%. From there a plan will be devised and often patients will only need phlebotomies once every month or every other month. It is possible however that due to frequent phlebotomies, iron within the blood may decrease. This treatment alone can buy the patient a large amount of their life back. Many of the symptoms listed here will be alleviated by having normal blood levels. This does not prevent transformation into other cancers such as AML/MDS however. For low risk patients, this is one of the only treatments that may be necessary. No drugs or chemotherapies needed.

Aspirin therapy -- for low risk patients without a history of bleeding issues, low dose aspirin may be prescribed. Aspirin inhibits platelet function which allows for better management of clotting in PV patients who have a much higher risk of clotting. Platelets are fundamental in the clotting process, thus why this is beneficial. 

Antihistamines -- This can be beneficial in treating patients seeing an increase in itchiness, especially after warm water contact

Hydroxyurea -- Hydroxyurea (HU) or hydroxycarbamide is a drug taken by mouth that is generally prescribed to patients with higher risk factors. It is a myelosuppressive drug which means that it suppresses the bone marrow from producing cells. It does this by inhibiting the production of DNA within the cells, which in turns means the cells can no longer replicate and grow. This will eventually produce lower RBC counts as well as other cells as well. One would expect platelet counts to drop as well (since elevated platelet counts are often seen in PV). One caveat to HU is that there may be a link to hydroxyurea use and progression to leukemia. Most studies show this risk is very small or non-existent. Often times, symptomatic Sickle Cell Anemia patients will be on this drug as well. 

Ruxolitinib -- also known as Jakafi or Jakavi is a janus kinase inhibitor. It will selectively inhibit JAK1 and JAK2 enzymes from functioning which will assist in inhibiting those with JAK2 enzymes that have formed from mutated JAK2 genes. If you remember from earlier reading on the main page, this JAK2 mutation causes it to be stuck "on" and signals to the bone marrow to perpetually create cells. Ruxolitinib would help shut down this activity and potentially help the bone marrow cease the overproduction of cells. Generally this drug is given for patients who do not respond to Hydroxyurea or cannot receive Hydroxyurea due to allergy or other negative response. 

Ropeginterferon Alfa-2b-njft (BESREMi) -- A form of Interferon alfa. It interacts with receptors within the bone marrow to modulate cell signaling the promotes "anti-proliferative" effects as well as immune modulating and pro-apoptotic (cell death) events. This was recently approved by the FDA in 2021 as an official treatment.