Secondary Polycythemia

What is Secondary Polycythemia?

Polycythemia is a medical condition where there’s an abnormal increase in red blood cells in the body. In simpler terms, it’s like having too many red blood cells. To give a bit of context, a healthy adult typically has 23 to 29 milliliters of red blood cells per kilogram of body weight if they’re female, and 26 to 32 if they’re male. Patients who have more than 51% (for men) or 48% (for women) of their blood made up of red blood cells or have a certain amount of a protein called hemoglobin in their blood (185g/L for men, 165g/L for women) usually have extra red blood cells.

It’s important to clarify here that polycythemia is not the same as erythrocytosis. Absolute erythrocytosis is when the red blood cell amount is over 125% of what’s predicted normal for the person’s sex and body weight.

Absolute or true erythrocytosis is different from relative polycythemia. Relative polycythemia is when you have a higher-than-normal ratio of red blood cells to the rest of your blood, but the actual number of red cells you have is normal. This can happen if the liquid part of your blood (plasma) lowers in volume.

An increase in a hormone called erythropoietin (EPO), usually in response to long-term low oxygen levels in the body (chronic hypoxemia), leads to secondary polycythemia. Chronic hypoxemia can be caused by various conditions, like lung diseases such as chronic obstructive pulmonary disease (COPD), airway problems like sleep apnea, and muscle abnormalities like obesity hypoventilation syndrome which is a breathing disorder that affects some individuals with obesity.

What Causes Secondary Polycythemia?

Secondary polycythemia is when your body produces too many red blood cells because of high levels of a hormone called EPO. It’s different from primary polycythemia, because in secondary polycythemia, there’s no problem with the actual cells that become red blood cells. The increase in EPO can happen for several reasons, some you are born with (genetic) and some you acquire over time.

Polycythemia can come in two types: primary and secondary. Primary polycythemia happens when the cells that become red blood cells multiply too much due to a defect in them. These patients have low levels of EPO. There are two main types:
– Polycythemia vera: This disorder comes from having too many cells that become red blood cells, because of a mutation called JAK mutation. It makes these cells more sensitive to EPO.
– Pure erythrocytosis: These people have too many red blood cells, and no other issues causing this.

Secondary polycythemia is a collection of disorders where you have too many red blood cells because the body is responding to low oxygen in the tissues or because it’s producing too much EPO without needing to. This can be something you are born with (congenital) or something you develop (acquired). For example, research has found around 100 mutations resulting in more than 50 versions of certain genes, which create a higher affinity or desire for oxygen. These mutations are typically inherited.

Conversely, a mutation in the HIF gene leads to abnormal oxygen detection and increased production of red blood cells. Erythrocytosis (increased number of red blood cells) that runs in families comes from this mutation. Another cause is the use of anabolic steroids in athletes, which is associated with increased erythrocytosis.

Secondary polycythemia that is appropriate physiologically (meaning it is a healthy response to tissue with low oxygen) can be acquired. For example, it could be due to chronic lung disease, carbon monoxide poisoning, living at high altitudes, kidney disease, and more. It could also be congenital, where you might be born with a type of hemoglobin that really likes oxygen, a deficiency in a certain enzyme, hereditary raise in ATP, and oxygen sensing pathway gene mutations.

There’s also a type of secondary polycythemia that is inappropriate physiologically, where it’s not a healthy response. This can come from tumors that produce too much EPO, certain drugs including EPO, and kidney and adrenal diseases.

Relative polycythemia is when you have a high percentage of red blood cells compared to your blood volume, but you actually have a normal to high number of red blood cells and a normal to low volume of plasma (the liquid part of your blood). Even though there aren’t too many red blood cells, people with relative polycythemia risk forming clots in their blood vessels.

Chuvash Polycythemia (CP) is a type of polycythemia that is passed down in families, seen in the Chuvash people in central Russia. People with CP have very high levels of EPO, and their red blood cell precursor cells are very sensitive to EPO. They often die early because of blood clots and bleeding. CP can cause both primary and secondary polycythemia because of how it works.

Risk Factors and Frequency for Secondary Polycythemia

A study conducted by Galeus and colleagues in 2015 found that COPD (Chronic Obstructive Pulmonary Disease), congenital heart disease, and severe pulmonary hypertension were the most common causes of a condition known as secondary polycythemia. However, there is currently a lack of data on how widespread this condition is.

Signs and Symptoms of Secondary Polycythemia

Secondary polycythemia, a condition where your body produces too many red blood cells, often hints its presence through various signs and specific information in a patient’s history. Understanding the different causes of this condition can help doctors in their diagnosis.

People with secondary polycythemia typically report symptoms like fatigue, headaches, and dizziness. Sometimes, the increased thickness of their blood may cause brief visual disturbances. It’s important for doctors to ask about potential causes such as if a person smokes, if there’s any recent loss in weight, or if they’ve been experiencing coughing, palpitations, shortness of breath, or snoring. Details about a patient’s family history may also help in identifying any inherited causes. Additionally, questions about the use of anabolic steroids for muscle building or any prescribed drugs are usually helpful for the diagnosis.

During a physical examination, doctors might notice visible scratch marks due to itching, blue or purple tinted skin, and unusual nail and tooth conditions especially in smokers. The ratio of the patient’s weight and height, along with their level of alertness, can provide clues to the possible presence of obstructive sleep apnea, a sleep-disordered breathing condition. The doctors may also find that the patient’s spleen is enlarged, which may cause the patient to feel full early into a meal. In some cases, the liver may also be enlarged. If a narrowing of the arteries leading to the kidneys is suspected, a swooshing sound can be heard while checking the patient’s body sounds.

Testing for Secondary Polycythemia

When investigating secondary polycythemia, a condition where your blood has too many red blood cells, your doctor will perform several tests. These include a complete blood count to measure your hemoglobin and hematocrit levels, tests checking the health of your kidneys and liver, ferritin levels, an ultrasound of the abdomen, and a chest x-ray.

Polycythemia can be confirmed by evaluating your red cell mass using a chromium 51 test along with the volume of plasma in your blood. However, this test is not used often because it’s not widely available. Another challenge is that the supply of radioactive isotopes used in the testing isn’t available everywhere.

At the beginning of your investigation, your doctor will order an erythropoietin assay. This is a test that measures the level of a hormone (EPO) in your blood that tells your body to make more red blood cells. A high EPO level suggests secondary polycythemia, but normal levels don’t necessarily rule it out because EPO levels can change over time. There’s also another test where your blood cells are grown in a lab to help confirm secondary polycythemia.

Your doctor may also test for a gene mutation called JAK2 that is linked to a type of polycythemia called polycythemia vera. To rule this out, iron levels and cytogenetic analysis (a test looking at the structure and number of your chromosomes) are required. Your doctor may also consider a bone marrow exam.

A pulse oximetry, a test that measures the amount of oxygen in your blood, is also essential. If your oxygen saturation is less than 92%, it could suggest that you have low levels of oxygen in your blood, which is a common cause of secondary polycythemia. Lung function tests and a sleep study might also be done to check for conditions causing low blood oxygen levels, such as sleep apnea.

If you have a condition that causes your blood to hold onto oxygen more tightly than it should, your oxygen separation curve will be evaluated. This test measures how well oxygen can get off your blood cells and into your body. The gold standard for this condition is a PaO2-50 score, a measure of oxygen pressure when half of your blood is saturated with oxygen. Doctors also use gene sequencing to check for abnormalities in the proteins that carry oxygen in your blood.

Kidney diseases are often linked to secondary polycythemia. Thus, tests like intravenous pyelography, a renal ultrasound, and a CT scan will be used to evaluate your kidneys. Doctors might also need to do a CT scan of your liver and brain to check for other possible causes. Gene mutation testing could be needed to diagnose a congenital condition, meaning one you were born with.

One challenging aspect of these tests is that having a lot of fatty tissue can make the results harder to interpret. This is because red blood cell mass as it relates to body weight is usually lower in people with more body fat. If after testing your red cell mass is found to be normal, but your plasma volume is low, the high hematocrit value may be due to relative polycythemia.

Treatment Options for Secondary Polycythemia

The treatment for secondary polycythemia, a condition where your body makes too many red blood cells, depends on what’s causing it. The goal is to address the factors causing this blood irregularity.

If you smoke, it’s advisable to quit and seek support to do so. Some medications, like diuretics and androgens, can contribute to this condition. If you’re on these, your doctor may review, change or adjust your medication. Since your body needs extra iron to produce normal, healthy red blood cells during this condition, your doctor might suggest taking iron supplements.

Low flow oxygen therapy can help correct the oxygen deficiency that leads to secondary polycythemia, and this can be particularly beneficial for those with chronic obstructive pulmonary disease (COPD). It’s crucial to use it wisely and under supervision to avoid any complications. For patients who struggle with obesity related breathing issues, weight loss can help correct the problem.

In some cases, doctors may suggest surgery to remove tumors that cause an overproduction of erythropoietin, a hormone that stimulates red blood cell production. Some benign kidney lesions causing secondary polycythemia can also be treated effectively. Occasionally, doctors may recommend temporary relief through phlebotomy, a procedure where blood is drawn from your body to reduce the number of red blood cells.

A low-dose aspirin may be suggested to prevent blood clots for people with secondary polycythemia. Another method that has shown a decrease in cardiovascular deaths is venesection, a similar procedure to phlebotomy, however, this will be based on your doctor’s opinion.

Patients with abnormally high red blood cell count that isn’t beneficial might be treated with phlebotomy to lower the red blood cell count. However, it should only be performed before surgery or if the high-red-blood-cell-count is not good for you. A balance must be struck between enough red blood cells for proper oxygenation and avoiding too many that make your blood too thick.

The depend on individual patient’s responses and underlying causes to set the goal for the hematocrit, a test that measures the proportion of red blood cells to the total blood volume. Generally, the goal is to keep it below 60%. In patients with COPD, phlebotomy can lower resistance in pulmonary arteries and improve right heart function, especially if the hematocrit is between 50 to 55%. Some may be offered medications that help relax and widen blood vessels according to their needs.

The specific target for hematocrit must be customized to the patient’s unique situation. Isovolumic phlebotomy, which maintains your blood volume while reducing your red blood cell count, may be particularly beneficial for some patients, such as those with cyanotic heart disease. However, it’ s important to avoid making too many red blood cell removals, as it can cause iron deficiency.

If you’ve unknown cause of erythrocytosis but a hematocrit over 54%, it could be suggested to reduce it to 50%. A target of 45% could be indicated for patients with conditions that increase the risk of blood clots. These patients shouldn’t receive treatment aimed to reduce blood cells. The use of ACE inhibitors is also recommended.

Generally, the guidelines for managing secondary polycythemia are to determine and address the root cause, remove all aggravating factors, avoid severe iron deficiency, apply proper measures, consider whether hemoglobin maintenance through phlebotomy would be beneficial, and avoid any therapy that suppresses bone marrow.

Several factors are considered before choosing phlebotomy, including whether it’s physiologically necessary, if the increased red cell mass causes adverse effects, presence of symptoms like dizziness and shortness of breath, and a history of blood clots. These factors will guide your doctor in providing you the best possible care according to your condition.

What else can Secondary Polycythemia be?

When trying to diagnose secondary polycythemia, doctors have to consider a list of conditions that could potentially have the same symptoms. Some possible conditions are:

• Dehydration (which can cause what is known as relative polycythemia)
• Lung disease like Chronic Obstructive Pulmonary Disease
• Polycythemia vera, a rare disorder causing increased red blood cells production
• Chronic smoking
• Heart defects like atrial septal defect or ventricular septal defect (in children)
• Cor pulmonale, a condition that causes the right side of the heart to fail
• Obstructive sleep apnea
• Drug abuse
• Conditions post-renal transplant
• Renal vascular pathology, including abnormal connections between arteries and veins in the body (arteriovenous malformation) and narrowing of the main blood vessel to the kidney (renal artery stenosis)
• Adrenal tumors, including those discovered accidentally (incidentaloma)
• Different types of cancers such as craniopharyngiomas (tumor at the base of the brain), renal cancer, liver cancer, and adrenal carcinoma

It is vital that doctors test for these conditions to make an accurate diagnosis.

What to expect with Secondary Polycythemia

In a research study by Galeas and colleagues, it was found that the average time from when a diagnosis was made to when a patient passed away was about 21.1 months. This was roughly half the time compared to patients with a disease known as polycythemia vera. The same study also found that about 5% of patients with a condition called secondary erythrocytosis experienced thrombotic episodes, which are blood clot incidents. However, the future health outcome or prognosis for patients was closely tied to the original cause of their illness and the occurrence of any complications.

Possible Complications When Diagnosed with Secondary Polycythemia

Potential Health Risks:

• Strokes, commonly caused by increased red blood cell count (also associated with anabolic steroid use in athletes)[13]
• Venous thromboembolism, or blood clots in the veins (preventative low-dose aspirin often used)[7]
• Pulmonary hypertension leading to coughing up blood and an enlarged heart[6][12]
• Iron deficiency
• Increased thickness of the entire blood
• Compromised blood circulation and oxygen supply
• Decreased mental alertness
• Bouts of fatigue
• Generalized weakness
• Poor capacity for exercise
• Increased blood thickness

Preventing Secondary Polycythemia

Patients should be advised to drink enough liquids to avoid getting dehydrated, and to not take any medication without first talking to their primary doctor. It’s important to stop smoking and stop drinking alcohol. Also, patients should be informed about the signs of a blood clot, also known as thrombosis and to keep an eye out for them. Some research suggests that taking a small amount of aspirin could lower the risk of getting a blood clot.

Regular check-ins with both the primary doctor and any specialists are strongly encouraged. Patients should be taught about anabolic steroids, which are drugs that mimic the effects of testosterone in the body, and why they should avoid them. If a patient lives in a high altitude area, they may want to consider moving. If a patient has lung disease, using oxygen long-term has been found to be beneficial.