Polycythemia Vera (High Red Blood Cell Count)

One percent to five percent of newborns can have a high red blood cell count (neonatal polycythemia).

• Polycythemia is an increased number of red blood cells in the blood. In polycythemia, the levels of hemoglobin (Hgb), hematocrit (Hct), or red blood cell (RBC) count may be elevated when measured in the complete blood count (CBC), as compared to normal.
• Hemoglobin levels greater than 16.5 g/dL (grams per deciliter) in women and greater than 18.5 g/dL in men suggest polycythemia. In terms of hematocrit, a value greater than 48 in women and 52 in men is indicative of polycythemia.
• Production of red blood cells (erythropoiesis) occurs in the bone marrow and is regulated in a series of specific steps.
• One of the important enzymes regulating this process is called erythropoietin (EPO). The majority of Epo is produced and released by the kidneys, and a smaller portion is released by the liver.
• Polycythemia can result from internal problems with the production of red blood cells. This is termed primary polycythemia. If polycythemia is caused due to another underlying medical problem, it is referred to as secondary polycythemia.
• Most cases of polycythemia are secondary and are caused by another medical condition. Primary polycythemias are relatively rare.
• 1%-5% of newborns can have polycythemia (neonatal polycythemia).

Symptoms of polycythemia vera can be vague and quite general such as headache, easy bleeding, and more.

Symptoms of polycythemia can vary widely. In some people with polycythemia, there may be no symptoms at all. In secondary polycythemia, most of the symptoms are related to the underlying condition responsible for polycythemia.

Symptoms of polycythemia vera can be vague and quite general. Some of the most significant symptoms include:

• Easy bruising
• Easy bleeding
• Blood clot formation (potentially leading to heart attacks, strokes, and blood clots in the lungs [pulmonary embolism])
• Bone and joint pain (hip pain or rib pain)
• Headache
• Itching
• Itching after taking a shower or bath (post-bath pruritus)
• Fatigue
• Dizziness
• Abdominal pain

In primary polycythemia, inherent or acquired problems with red blood cell production lead to polycythemia. Two main conditions that belong to this category are polycythemia vera (PV or polycythemia rubra vera [PRV]) and primary familial and congenital polycythemia (PFCP).

• Polycythemia vera (PV) is related to a genetic mutation in the JAK2 gene, which is thought to increase the sensitivity of bone marrow cells to Epo, resulting in increased red blood cell production. Levels of other types of blood cells (white blood cells and platelets) are also often increased in this condition.
• Primary familial and congenital polycythemia (PFCP) is a condition related to a mutation in the EPOR gene and causes increased production of red blood cells in response to EPO.

Contrary to primary polycythemia in which overproduction of red blood cells results from increased sensitivity or responsiveness to Epo (often with lower than normal levels of EPO), in secondary polycythemia, more red cells are produced because of high levels of circulating EPO.

The main reasons for higher than normal EPO are chronic hypoxia (poor blood oxygen levels over the long term), poor oxygen delivery due to abnormal red blood cell structure, and tumors releasing inappropriately high amounts of EPO.

Some of the common conditions that can result in elevated erythropoietin due to chronic hypoxia or poor oxygen supply include:

• Chronic obstructive pulmonary disease (COPD, emphysema, chronic bronchitis)
• Pulmonary hypertension
• Hypoventilation syndrome
• Congestive heart failure
• Obstructive sleep apnea
• Poor blood flow to the kidneys
• Living in high altitudes

2,3-BPG deficiency is a condition in which the hemoglobin molecule in the red blood cells has an abnormal structure. In this condition, hemoglobin has a higher affinity to hold on to oxygen and is less likely to release it to the tissues. This results in more red blood cells being produced in response to what the tissues in the body perceive as an inadequate oxygen level. The outcome is more circulating red blood cells.

Certain tumors have a tendency to secrete inappropriately high amounts of Epo, leading to polycythemia. The common Epo-releasing tumors are:

• Liver cancer (hepatocellular carcinoma)
• Kidney cancer (renal cell carcinoma)
• Adrenal adenoma or adenocarcinoma
• Uterine cancer

There also are more benign conditions that may cause increased EPO secretion, such as kidney cysts and kidney obstruction.

Chronic carbon monoxide exposure can also lead to polycythemia. Hemoglobin naturally has a higher affinity for carbon monoxide than for oxygen. Therefore, when carbon monoxide molecules attach to hemoglobin, polycythemia (increased red cell and hemoglobin production) may occur in order to compensate for the poor oxygen delivery by the existing hemoglobin molecules. A similar scenario can also occur with carbon dioxide in long-term cigarette smoking.

Polycythemia in newborns (neonatal polycythemia) is often caused by the transfer of maternal blood from the placenta or blood transfusions. Prolonged poor oxygen delivery to the fetus (intrauterine hypoxia) due to insufficiency of the placenta can also lead to neonatal polycythemia.

Relative polycythemia describes conditions in which red cell volume is high due to increased blood concentration of red cells as a result of dehydration. In these situations (vomiting, diarrhea, excessive sweating) the number of red blood cells is normal, but because of the fluid loss affecting the blood (plasma), red blood cell counts may seem elevated.

Stress erythrocytosis (also known as pseudopolycythemia or Gaisbock's syndrome) is seen in obese middle aged men who are being treated with a diuretic medication for hypertension. It is not unusual that such men are also cigarette smokers.

Some of the risk factors for polycythemia include:

• Chronic hypoxia
• Long-term cigarette smoking
• Familial and genetic predisposition
• Living in high altitudes
• Long-term exposure to carbon monoxide (tunnel workers, car garage attendants, residents of highly polluted cities)
• Ashkenazi Jewish ancestry (may have increased frequency of polycythemia vera due to genetic susceptibility)

People with primary polycythemia need to be aware of some of the potentially serious complications that may occur. The formation of blood clots (heart attacks, strokes, blood clots in the lungs [pulmonary embolism] or legs [deep vein thrombosis]) and uncontrolled hemorrhaging (nosebleeds, gastrointestinal bleeding) typically require prompt medical attention by the treating physician or emergency department.

Patients with primary polycythemia are usually cared for by their primary care physicians, internists, family physicians, and hematologists (doctors who specialize in blood disorders).

Conditions leading to secondary polycythemia can be managed by primary care physicians and internists in addition to specialists. For example, people with long-standing lung disease may routinely see their lung doctor (pulmonologist) and those with chronic heart disease may see their heart doctor (cardiologist).

In the majority of instances, polycythemia may be detected incidentally in routine blood work ordered by a physician for an unrelated medical reason. This may then prompt further investigation to find the cause of polycythemia.

• In evaluating a patient with polycythemia, a comprehensive medical history, physical examination, family history, and social and occupational history are very important. In the physical exam, special attention may be paid to the heart and lung exam. An enlarged spleen (splenomegaly) is one of the prominent features of polycythemia vera; therefore, a careful abdominal exam to evaluate for an enlarged spleen is important.
• Routine blood work including a complete blood count (CBC), clotting profile, and metabolic panels are basic components of laboratory tests in assessing the cause of polycythemia. Other typical tests to determine the potential causes of polycythemia include chest X-rays, electrocardiogram (ECG), echocardiogram, hemoglobin analysis, and carbon monoxide measurement.
• In polycythemia vera, usually other blood cells are also affected, represented by an abnormally high number of white blood cells (leukocytosis) and platelets (thrombocytosis). Bone marrow examinations (bone marrow aspiration or biopsy) are sometimes necessary to examine blood cell production in the bone marrow. Guidelines also recommend checking for the JAK2 gene mutation as a diagnostic criterion for polycythemia vera.
• Checking EPO levels are not required, but these can sometimes provide helpful information. In primary polycythemia, the EPO level is typically low, whereas, in EPO-secreting tumors, the level may be higher than normal. The results need to be interpreted carefully as the EPO level may be appropriately high in response to chronic hypoxia if that is the underlying cause of polycythemia.

The mainstay of therapy for polycythemia vera remains phlebotomy (bloodletting). The goal of phlebotomy is to keep the hematocrit around 45% in men and 42% in women. Initially, it may be necessary to do a phlebotomy every 2 to 3 days and remove 250 to 500 milliliters of blood each session. Once the goal is reached, maintenance phlebotomy can be performed less frequently.

A commonly recommended medication for the treatment of polycythemia is called hydroxyurea (Hydrea). This is especially advised in people at risk of clot formation. At an age greater than 70, having both an elevated platelet count (thrombocytosis) greater than 1.5 million and cardiovascular disease makes the use of hydroxyurea more favorable. Hydroxyurea is also recommended in patients who are unable to tolerate phlebotomy. Hydroxyurea can lower all elevated blood counts (WBC, red blood cells, and platelets), whereas phlebotomy only lowers the HCT.

Aspirin has also been used in treating polycythemia to lower the risk of clotting (thrombotic) events. Its use is generally avoided in those people with any bleeding history. Aspirin is usually used in conjunction with phlebotomy.

Treatment of secondary polycythemia depends on its cause:

• Supplemental oxygen can be provided for individuals with chronic hypoxia.
• Other therapies can be directed toward treating the cause of polycythemia (for example, appropriate treatment of heart failure or chronic lung disease).

Treatments for primary polycythemia play an important role in improving the outcome of the disease.

In individuals with primary polycythemia, some simple measures can be taken at home to control potential symptoms and avoid possible complications:

• It is important to stay well hydrated in order to avoid concentrating the blood even further by dehydration. In general, there are no restrictions on physical activity.
• If a person has an enlarged spleen, contact sports may be avoided to prevent splenic injury and rupture.
• It is best to avoid iron supplementation as this can promote more red blood cell production.

Frequent monitoring is recommended during early treatment with phlebotomy until an acceptable hematocrit is adequately maintained. Thereafter, blood letting can be done as needed to maintain appropriate hematocrit based on each individual's response to this therapy.

Some of the complications of primary polycythemia, as listed below, often require closer follow-up and monitoring. These complications include:

• Blood clot (thrombosis) causing heart attacks, stokes, clots in the legs or lungs, or clots in arteries. These events are considered the major causes of death by polycythemia.
• Severe blood loss or hemorrhage.
• Transformation to blood cancers (for example,leukemia, myelofibrosis).

• The outlook for primary polycythemia without treatment is generally poor, with a life expectancy of about 2 years. However, with phlebotomy alone, many patients lead normal lives and enjoy a normal life expectancy.
• The outlook for secondary polycythemia is largely dependent on the main cause.

• Many causes of secondary polycythemia are not preventable. However, some potential preventive measures are:
  • smoking cessation;
  • avoid prolonged carbon monoxide exposure; and
  • appropriate management of diseases such as chronic lung disease, heart disease or obstructive sleep apnea.
• Primary polycythemia due to mutation of genes is generally not preventable.