Polycythemia: Too Many Red Blood Cells - Causes, Symptoms & Treatment

What Is Polycythemia and Why Does It Happen?

Polycythemia is a condition where your bone marrow produces too many red blood cells, making your blood thicker than normal. This increases the risk of blood clots that can cause stroke, heart attack, or pulmonary embolism. The condition can be primary (polycythemia vera, a type of blood cancer) or secondary (a response to low oxygen levels).

The term "polycythemia" comes from Greek words meaning "many cells in the blood." When you have polycythemia, your blood becomes more viscous because it contains an abnormally high concentration of red blood cells. To understand why this matters, consider that blood needs to flow smoothly through your blood vessels to deliver oxygen to your organs. When blood becomes too thick, it flows more slowly and is more likely to form clots.

Your body normally regulates red blood cell production very precisely. Red blood cells are manufactured in your bone marrow under the control of a hormone called erythropoietin (EPO), which is produced by your kidneys. When oxygen levels in your blood drop, your kidneys release more EPO, signaling your bone marrow to produce more red blood cells. When oxygen levels normalize, EPO production decreases and red blood cell production slows down.

In polycythemia, this careful balance is disrupted. Either the bone marrow produces red blood cells independently of EPO signals (as in polycythemia vera), or something causes chronically elevated EPO levels (as in secondary polycythemia). The result is the same: too many red blood cells circulating in your blood.

The key measurement used to diagnose and monitor polycythemia is the hematocrit, which represents the percentage of your blood volume that consists of red blood cells. Normal hematocrit ranges are approximately 38-50% for men and 36-44% for women. In polycythemia, hematocrit levels may exceed 50-55% or even higher, significantly increasing the risk of thrombotic complications.

Understanding Blood Thickness and Clot Risk

When hematocrit rises above 45%, blood viscosity increases exponentially rather than linearly. This means that even small increases in hematocrit above this threshold dramatically increase the resistance to blood flow. The heart must work harder to pump this thicker blood, and the slow-moving blood is much more likely to form clots, particularly in smaller blood vessels and areas of turbulent flow.

Blood clots are the most serious complication of polycythemia and can occur in unusual locations. While clots commonly form in leg veins (deep vein thrombosis) or travel to the lungs (pulmonary embolism), polycythemia is also associated with clots in the arteries of the brain (causing stroke), heart (causing heart attack), and even in unusual locations like the splanchnic veins (veins draining the intestines), portal vein (main vein to the liver), or cerebral venous sinuses.

Types of Polycythemia

Understanding the type of polycythemia is essential for appropriate treatment. The main categories include:

What Is Polycythemia Vera and How Serious Is It?

Polycythemia vera (PV) is a chronic blood cancer caused by acquired mutations in the JAK2 gene that cause bone marrow stem cells to overproduce red blood cells. While serious, it is generally manageable with treatment, and most patients live 14 or more years after diagnosis. The main risks are blood clots and, rarely, transformation to more aggressive blood cancers.

Polycythemia vera belongs to a group of blood disorders called myeloproliferative neoplasms (MPNs). In these conditions, the bone marrow produces too many of one or more types of blood cells. In PV, the primary problem is overproduction of red blood cells, although white blood cells and platelets may also be elevated.

The discovery of the JAK2 V617F mutation in 2005 revolutionized our understanding of polycythemia vera. This mutation is present in over 95% of PV patients and causes the JAK2 protein to be constantly active, stimulating blood cell production even without the normal EPO signal. The remaining 5% of patients typically have mutations in JAK2 exon 12 or other related genes.

Unlike many cancers, polycythemia vera is not typically aggressive and does not spread to other organs. However, it is a clonal disorder, meaning it arises from a single abnormal stem cell in the bone marrow that has a growth advantage over normal cells. Over time, these mutated cells come to dominate blood cell production.

Risk Stratification in Polycythemia Vera

Doctors classify PV patients into risk categories to guide treatment decisions. The main factors determining risk are:

• Age over 60 years: Older patients have higher thrombosis risk
• History of blood clots: Previous thrombosis strongly predicts future events
• Cardiovascular risk factors: Hypertension, diabetes, high cholesterol, smoking
• Very high white blood cell counts: Leukocytosis indicates more aggressive disease

Low-risk patients (younger than 60 with no prior thrombosis) are typically managed with phlebotomy and low-dose aspirin alone. High-risk patients usually require additional cytoreductive therapy (medications that reduce blood cell production) to minimize thrombotic complications.

Long-Term Outlook and Complications

The prognosis for polycythemia vera has improved substantially with modern management. Studies show median survival of 14-15 years from diagnosis, with many patients living considerably longer. However, there are important long-term considerations:

Thrombosis remains the leading cause of death and disability in PV. Even with optimal treatment, the annual rate of major thrombotic events is approximately 2-4%. Arterial events (stroke, heart attack) are more common than venous events (deep vein thrombosis, pulmonary embolism).

Myelofibrosis transformation occurs in approximately 10-20% of patients over 15-20 years. In myelofibrosis, the bone marrow becomes scarred and can no longer produce blood cells effectively. This can cause severe anemia, enlarged spleen, and constitutional symptoms.

Acute leukemia transformation is rare, occurring in approximately 3-5% of patients. Some of this risk may be related to prior treatment with certain medications, although the disease itself also carries some inherent risk of transformation.

What Causes Secondary Polycythemia?

Secondary polycythemia occurs when the body produces more red blood cells in response to low oxygen levels or, rarely, from tumors that produce erythropoietin. Common causes include chronic lung disease (COPD), sleep apnea, smoking, living at high altitude, and congenital heart defects. Unlike polycythemia vera, secondary polycythemia is not a cancer and often improves when the underlying cause is treated.

In secondary polycythemia, the bone marrow is responding appropriately to signals from the body – it's just that those signals are abnormally elevated. The most common reason is chronic hypoxia (low oxygen), which triggers the kidneys to produce more erythropoietin, which in turn stimulates red blood cell production.

Understanding the cause of secondary polycythemia is crucial because treatment focuses on addressing the underlying condition rather than just reducing the red blood cell count. In many cases, correcting the hypoxia or other cause will normalize the blood counts without additional intervention.

Common Causes of Secondary Polycythemia

Chronic obstructive pulmonary disease (COPD) is one of the most common causes. When the lungs cannot adequately oxygenate the blood, the body compensates by making more oxygen-carrying red blood cells. Similarly, other lung conditions such as pulmonary fibrosis, emphysema, and severe asthma can trigger this response.

Obstructive sleep apnea causes intermittent oxygen deprivation during sleep, which can be sufficient to stimulate chronic red blood cell overproduction. Many people with sleep apnea are unaware they have it, so polycythemia may be the first clue to this diagnosis.

Smoking causes polycythemia through multiple mechanisms. Carbon monoxide in cigarette smoke binds to hemoglobin much more strongly than oxygen, effectively reducing the blood's oxygen-carrying capacity. The body responds by producing more red blood cells to compensate. Chronic lung damage from smoking compounds this effect.

High altitude residence is a normal physiological adaptation rather than a disease. At elevations above 2,500 meters (8,200 feet), the lower oxygen pressure stimulates increased red blood cell production. This is beneficial for delivering oxygen to tissues but can become problematic if hematocrit rises excessively.

Congenital heart defects that cause right-to-left shunting (allowing deoxygenated blood to bypass the lungs) lead to chronic hypoxia and secondary polycythemia. This is particularly common in adults with uncorrected or partially corrected congenital heart disease.

EPO-producing tumors are a rare but important cause. Certain tumors, particularly kidney cancers, hepatocellular carcinoma, and cerebellar hemangioblastomas, can produce erythropoietin autonomously. This results in polycythemia that resolves when the tumor is removed.

What Are the Symptoms of Polycythemia?

Polycythemia symptoms include headaches, dizziness, blurred vision, fatigue, itching (especially after bathing), reddish skin color, night sweats, and a feeling of fullness in the upper abdomen from enlarged spleen. Many people have no symptoms and are diagnosed during routine blood tests. Symptoms result from thickened blood and reduced oxygen delivery to tissues.

The symptoms of polycythemia can be subtle and often develop gradually over months or years. Because the body has time to adapt to the slowly increasing blood thickness, many people are surprised to learn they have polycythemia when it's discovered on routine laboratory testing. However, once aware of the condition, patients often recognize symptoms they had previously attributed to aging or other causes.

The symptoms of polycythemia generally fall into three categories: those related to increased blood viscosity, those related to histamine release, and those related to spleen enlargement. Understanding these categories helps explain why the symptoms occur and how treatment can help.

Symptoms from Increased Blood Viscosity

Headaches are among the most common symptoms, affecting 50-60% of patients. They result from reduced blood flow to the brain due to increased blood thickness. The headaches are often described as dull and persistent, frequently worse in the morning.

Dizziness and lightheadedness occur for similar reasons – the brain is not receiving optimal blood flow. Some patients describe a "foggy" feeling or difficulty concentrating. These symptoms often improve dramatically after phlebotomy treatment reduces blood thickness.

Visual disturbances such as blurred vision, seeing spots, or transient vision loss can occur when blood flow to the eyes is compromised. The small blood vessels in the retina are particularly susceptible to the effects of thick blood.

Fatigue affects many polycythemia patients, which seems paradoxical since they have more oxygen-carrying red blood cells. However, when blood is too thick, it flows poorly through small blood vessels, and tissues may actually receive less oxygen despite the higher hemoglobin concentration.

Reddish or ruddy skin color (plethora) is visible in many patients, particularly noticeable on the face, hands, and mucous membranes. The conjunctivae (whites of the eyes) may appear bloodshot. Some patients notice their skin color normalizes after phlebotomy.

Erythromelalgia is a distinctive symptom involving burning pain, warmth, and redness of the hands and feet. It is caused by microvascular dysfunction and platelet activation. Low-dose aspirin often provides rapid relief of this painful symptom.

Aquagenic Pruritus – The Classic Itching Symptom

Itching after bathing (aquagenic pruritus) is one of the most distinctive symptoms of polycythemia vera, affecting approximately 40% of patients. The itching typically begins within minutes of contact with water and can be intense enough to significantly impair quality of life. It may last for 30-60 minutes after bathing.

The mechanism involves release of histamine from increased numbers of mast cells and basophils in the skin. The exact trigger from water contact is not fully understood but may relate to temperature changes or water's osmotic effects on the skin. Standard antihistamines often provide only partial relief, but treatment that reduces blood cell production (particularly ruxolitinib) can be very effective for this troublesome symptom.

Spleen Enlargement and Related Symptoms

The spleen normally filters old and damaged blood cells from circulation. In polycythemia vera, the spleen often enlarges (splenomegaly) as it works overtime processing the excess blood cells. Additionally, the spleen can become a site of blood cell production (extramedullary hematopoiesis), contributing to its enlargement.

Spleen enlargement can cause a feeling of fullness or discomfort in the upper left abdomen, early satiety (feeling full after eating small amounts), and occasionally left-sided or referred left shoulder pain. In severe cases, the enlarged spleen can be felt as a firm mass below the left rib cage.

Constitutional Symptoms

Some patients experience constitutional symptoms including night sweats, unexplained weight loss, and low-grade fevers. These symptoms are more common in advanced disease or when transformation to myelofibrosis is occurring. They result from inflammatory cytokines produced by the abnormal blood cells.

How Is Polycythemia Diagnosed?

Polycythemia is diagnosed through blood tests showing elevated hemoglobin (>16.5 g/dL in men, >16 g/dL in women) or hematocrit (>49% in men, >48% in women). For polycythemia vera, the JAK2 mutation test is positive in over 95% of cases. Additional tests include erythropoietin levels (low in PV, high in secondary), bone marrow biopsy, and tests to identify secondary causes.

The diagnosis of polycythemia begins with recognition of elevated red blood cell indices on a complete blood count (CBC). However, determining the type of polycythemia and its cause requires additional testing. The diagnostic approach has been standardized by the World Health Organization (WHO) and involves a combination of blood tests, genetic testing, and sometimes bone marrow examination.

Initial Blood Tests

The complete blood count (CBC) is the foundation of diagnosis. The key values are:

• Hemoglobin: The protein in red blood cells that carries oxygen. Elevated above 16.5 g/dL in men or 16.0 g/dL in women suggests polycythemia.
• Hematocrit: The percentage of blood volume occupied by red blood cells. Values above 49% in men or 48% in women are elevated.
• Red blood cell count: The number of red cells per microliter of blood.
• White blood cell count and platelet count: Often elevated in polycythemia vera but normal in secondary causes.

JAK2 Mutation Testing

Testing for the JAK2 V617F mutation is essential when polycythemia vera is suspected. This blood test detects the specific DNA mutation present in over 95% of PV patients. A positive test strongly supports the diagnosis of PV. If the V617F mutation is negative but PV is still suspected, testing for JAK2 exon 12 mutations should be performed, as these account for most remaining cases.

Erythropoietin Level

Measuring the serum erythropoietin (EPO) level helps distinguish between primary and secondary causes:

• Low or low-normal EPO: Suggests polycythemia vera, where the bone marrow produces red cells independently of EPO
• Elevated EPO: Suggests secondary polycythemia, where the body is responding to hypoxia or an EPO-producing tumor

WHO Diagnostic Criteria for Polycythemia Vera

The 2022 WHO criteria require meeting all three major criteria OR the first two major criteria plus the minor criterion:

Major Criteria:

1. Hemoglobin >16.5 g/dL (men) or >16.0 g/dL (women), OR hematocrit >49% (men) or >48% (women), OR increased red cell mass
2. Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) and pleomorphic mature megakaryocytes
3. Presence of JAK2 V617F or JAK2 exon 12 mutation

Minor Criterion:

• Subnormal serum erythropoietin level

Bone Marrow Biopsy

A bone marrow biopsy is often performed to confirm the diagnosis and rule out other conditions. In polycythemia vera, the marrow typically shows increased cellularity with expansion of all three cell lines (red cells, white cells, and platelets). The appearance of megakaryocytes (platelet-producing cells) is particularly characteristic.

Bone marrow examination also helps assess for any evidence of fibrosis, which could indicate early transformation to myelofibrosis, and provides a baseline for future comparison.

Evaluation for Secondary Causes

If polycythemia vera is not confirmed, evaluation for secondary causes should include:

• Oxygen saturation and arterial blood gas to assess for hypoxia
• Pulmonary function tests to evaluate lung function
• Sleep study if sleep apnea is suspected
• Carboxyhemoglobin level in smokers
• Imaging studies (ultrasound, CT scan) of kidneys and liver to look for EPO-producing tumors
• Echocardiogram if heart disease is suspected

How Is Polycythemia Treated?

Treatment of polycythemia focuses on reducing blood clot risk by keeping hematocrit below 45%. First-line treatment is phlebotomy (removing blood, similar to blood donation) combined with low-dose aspirin. High-risk patients may need cytoreductive drugs like hydroxyurea or ruxolitinib. Secondary polycythemia is treated by addressing the underlying cause such as stopping smoking or treating sleep apnea.

The treatment approach for polycythemia depends on the type (primary vs. secondary) and the individual's risk of complications. For polycythemia vera, the goals are to prevent blood clots, control symptoms, minimize risk of disease progression, and maintain quality of life. For secondary polycythemia, the primary goal is treating the underlying cause.

Phlebotomy: The Foundation of Treatment

Phlebotomy (also called venesection or therapeutic blood removal) is the cornerstone of polycythemia treatment. The procedure is similar to blood donation: approximately 450-500 mL of blood is removed through a needle in the arm. This directly reduces the number of circulating red blood cells and decreases blood viscosity.

The goal is to maintain hematocrit below 45%. This target was established by the landmark CYTO-PV trial, which demonstrated that patients maintained below 45% had significantly fewer cardiovascular events than those maintained at 45-50%.

Initially, phlebotomy may be needed weekly or every other week until the target hematocrit is achieved. Once controlled, the frequency decreases based on how quickly hematocrit rises – some patients need treatment monthly, others only a few times per year. The procedure is generally well-tolerated, though some people experience temporary lightheadedness or fatigue afterward.

A side effect of frequent phlebotomy is iron deficiency, as iron is lost with each blood removal. While this may cause some symptoms of iron deficiency (fatigue, mild anemia), iron supplementation is generally avoided as it would stimulate red blood cell production and negate the benefit of phlebotomy.

Low-Dose Aspirin

Low-dose aspirin (typically 75-100 mg daily) is recommended for most polycythemia vera patients unless contraindicated. The ECLAP trial showed that aspirin reduces the risk of cardiovascular events (heart attack, stroke, venous thrombosis) without significantly increasing bleeding risk.

Aspirin also provides rapid relief of erythromelalgia (burning pain in hands and feet) and may help with some other microvascular symptoms. It works by preventing platelet activation and aggregation, reducing the tendency for blood clots to form.

Cytoreductive Therapy

Patients at high risk for thrombosis (age >60 or prior thrombosis) typically require medications that reduce blood cell production in addition to phlebotomy:

Hydroxyurea is the most commonly used cytoreductive agent. It works by inhibiting DNA synthesis, reducing production of all blood cell types. Hydroxyurea is effective, well-tolerated, and has decades of clinical experience. Side effects may include leg ulcers, nail changes, and mouth sores. There has been theoretical concern about long-term leukemia risk, but this remains controversial and has not been clearly demonstrated in studies.

Ruxolitinib is a JAK inhibitor that directly targets the abnormal JAK2 signaling driving the disease. It is particularly effective for spleen enlargement and constitutional symptoms like night sweats, itching, and fatigue. Ruxolitinib may be used as first-line therapy for high-risk patients or for those who cannot tolerate or do not respond to hydroxyurea.

Pegylated interferon alfa is increasingly used, particularly in younger patients and during pregnancy (when hydroxyurea is contraindicated). Interferon can achieve molecular responses (reduction in the JAK2-mutated cell population) in some patients. Side effects include flu-like symptoms, fatigue, and depression, but the pegylated formulations are generally better tolerated than older versions.

Treatment of Secondary Polycythemia

For secondary polycythemia, treatment focuses on the underlying cause:

• COPD and lung disease: Optimize pulmonary function with bronchodilators, steroids, supplemental oxygen as needed
• Sleep apnea: Continuous positive airway pressure (CPAP) therapy is often curative for the polycythemia
• Smoking: Smoking cessation; hematocrit often normalizes within months of quitting
• High altitude: Consider relocation or periodic phlebotomy if hematocrit is very high
• EPO-producing tumors: Surgical removal when possible

Phlebotomy may still be used in secondary polycythemia if hematocrit is extremely high (generally >55-60%) or if symptoms are severe, but the benefits are less clear than in polycythemia vera.

Managing Symptoms and Quality of Life

Beyond reducing thrombosis risk, treatment should address symptoms:

• Itching: Antihistamines, selective serotonin reuptake inhibitors (SSRIs), phototherapy with narrow-band UVB, or ruxolitinib for severe cases
• Erythromelalgia: Low-dose aspirin is usually very effective
• Spleen enlargement: Ruxolitinib significantly reduces spleen size; splenectomy is rarely needed
• Constitutional symptoms: Often improve with cytoreductive therapy, especially ruxolitinib

How Do You Live Well with Polycythemia?

Living well with polycythemia involves staying well hydrated, taking medications as prescribed, attending regular monitoring appointments, recognizing warning signs of blood clots, and managing cardiovascular risk factors. Most people with properly treated polycythemia lead normal, active lives. Lifestyle modifications including moderate exercise, avoiding smoking, and managing stress are important parts of care.

A diagnosis of polycythemia, particularly polycythemia vera, means living with a chronic condition that requires ongoing management. However, with modern treatment, the vast majority of patients maintain excellent quality of life and can participate in normal activities.

Hydration Is Essential

Staying well hydrated is one of the most important things you can do. Dehydration concentrates the blood further, increasing viscosity and clot risk. Aim for at least 8-10 glasses of water daily, more in hot weather or during exercise. Avoid excessive alcohol, which can cause dehydration, and be cautious with caffeine for the same reason.

Cardiovascular Risk Management

Because blood clots are the main complication of polycythemia, managing cardiovascular risk factors is crucial:

• Blood pressure control: Hypertension increases clot risk; work with your doctor to maintain normal blood pressure
• Cholesterol management: High cholesterol contributes to arterial disease and thrombosis
• Diabetes control: Poorly controlled diabetes increases cardiovascular risk
• Weight management: Obesity is a risk factor for both cardiovascular disease and blood clots
• Smoking cessation: Absolutely essential; smoking dramatically increases clot risk

Exercise and Activity

Regular moderate exercise is beneficial and encouraged. Physical activity improves cardiovascular health, helps maintain healthy weight, and may reduce stress. However, be sensible:

• Avoid extreme heat, which can trigger itching and dehydration
• Stay hydrated during exercise
• Consider compression stockings during long periods of sitting or standing
• During air travel, walk periodically, stay hydrated, and consider compression stockings

Monitoring and Follow-up

Regular follow-up with your hematologist is essential. Typical monitoring includes:

• Blood counts: Usually every 1-3 months to monitor hematocrit and adjust treatment
• Physical examination: Assessment of spleen size and symptoms
• Annual review: Comprehensive assessment including evaluation for disease progression

Pregnancy and Polycythemia Vera

Women with polycythemia vera can have successful pregnancies, but they require specialized care from a hematologist and high-risk obstetrician. Pregnancy increases clot risk, which is already elevated in PV. Hydroxyurea must be stopped before conception due to potential fetal harm, and management typically involves phlebotomy, low-dose aspirin, and sometimes interferon or low-molecular-weight heparin.

Emotional and Psychological Support

Living with a chronic blood disorder can be emotionally challenging. It's normal to feel anxious about your health, especially when first diagnosed. Consider:

• Connecting with patient support organizations like MPN Advocacy & Education International
• Speaking with a counselor if anxiety about your health is affecting your quality of life
• Joining online support communities to connect with others living with polycythemia
• Educating family members about your condition so they can provide support

When Should You Seek Medical Care?

Seek immediate emergency care for signs of stroke (sudden weakness, speech problems, severe headache), heart attack (chest pain, shortness of breath), or pulmonary embolism (sudden breathing difficulty). Contact your doctor promptly for new or worsening symptoms, severe itching affecting quality of life, signs of infection if on cytoreductive therapy, or concerns about your blood counts.

Knowing when to seek medical attention is important for anyone living with polycythemia. While most day-to-day symptoms can be managed at routine appointments, certain situations require urgent evaluation.

Contact Your Doctor Within 24 Hours For:

• Deep vein thrombosis symptoms: painful, swollen, warm, red leg (without breathing symptoms)
• Severe headache that is different from your usual pattern
• Vision changes
• New abdominal pain, especially in the upper left (enlarged spleen) or upper right (possible portal vein thrombosis)
• Signs of infection if you're on cytoreductive therapy (fever, chills, severe sore throat)
• Significant bleeding (blood in urine, stool, or heavy bruising)

Discuss at Your Next Appointment:

• Increasing fatigue not explained by other factors
• Night sweats or unexplained weight loss
• Itching that is not responding to current treatment
• Questions about medications or treatment plan
• Planning for travel, surgery, or pregnancy