Polycythemia

Overview

• Definition: Increase in the absolute red blood cell (RBC) mass.
• Reflected By: Elevated hemoglobin levels or hematocrit.

Hemoglobin and Hematocrit Standards

• haematocrit:
  • Males: haematocrit >49%
  • Females:  >48%
• Hemoglobin:
  • Adult Male: haemoglobin >165 g/L
  • Menstruating Female: haemoglobin >160 g/L 

Polycythemia Etiology and Classification

Spurious Polycythemia – Relative (reduced plasma volume)

• Volume Contraction:
  • Causes: Severe dehydration (diarrhea, vomiting)
  • Gaisbock syndrome (obese, hypertensive males).

True Polycythemia – Absolute (increase in red cell mass)

Based on Serum Erythropoietin (EPO) Levels:

• Low Serum EPO Levels (Primary Polycythemia)
  • Polycythemia Vera
  • Primary Familial and Congenital Polycythemia
• High Serum EPO Levels (Secondary Polycythemia)
  • High Altitude
  • Respiratory Disorders: COPD, Pickwickian syndrome, uncontrolled asthma.
  • Cyanotic Heart Diseases: Right-to-left shunts.
  • Renal Disorders: Renal cysts, kidney cancer, renal artery stenosis.
  • Elevated Carboxyhemoglobin: Smokers, closed-space workers.
  • Hemoglobinopathies: High-affinity hemoglobins.
  • EPO-secreting Tumors: Hepatomas, uterine leiomyomas.
  • Iatrogenic Causes: EPO analogs, anabolic steroids, testosterone replacement therapy.

Neonatal Polycythemia

• Compensatory Mechanism: Response to intrauterine hypoxia, high fetal hemoglobin affinity for oxygen.

Polycythemia Vera (PV)

• Subtype: Myeloproliferative disorder.
• Characteristics: Overproduction of all three cell lines, predominantly red blood cells.
• Risks: Thrombotic events due to blood hyperviscosity, potential progression to leukemia.

Epidemiology

• Prevalence: ~22 cases per 100,000 population.
• Demographics: More common in Jewish patients of Eastern European descent.
• Gender Ratio: Male-to-female ratio of 2:1.
• Median Age: 60 years; seldom seen before age 40.
• Most PV patients do not have a family history of the disease.

Pathophysiology

• High EPO Levels: Triggered by hypoxia, leading to erythropoiesis.
• Low EPO Levels: Mutations in JAK2 (95% of PV cases), causing constitutive activation and hypersensitivity to EPO.

Histopathology

• Bone Marrow Findings: Hypercellular marrow, erythroid hyperplasia, subtle megakaryocytic atypia.

Clinical Presentation

History

• Common Symptoms: Fatigue, headache, dizziness, blurry vision, transient ischemic attacks.
• Common symptoms of hyperviscosity of any cause include:
  • cardiocerebral compromise
    • chest pain
    • transient ischaemic attack
    • headache
    • fatigue
    • blurred vision
• Specific Symptoms:
  • Pruritus after warm showers
  • epistaxis
  • GI bleeding
  • early satiety
  • left hypochondrial pain (splenic discomfort)
• Thrombotic Complications:
  • Budd-Chiari syndrome
  • digital infarcts.
• Etiology-Specific History:
  • Smoking, high altitude stay, congenital cardiac disease, family history.
• Erythromelalgia
  • is a rare condition that primarily affects the feet and, less commonly, the hands (extremities).
  • It is characterised by intense, burning pain of affected extremities, severe redness (erythema), and increased skin temperature that may be episodic or almost continuous in nature.

Physical Examination

• Facial Ruddiness: Abnormal facial redness.
• Cyanosis and Clubbing: Suggest congenital heart disease.
• Nicotine Staining: Indicates smoking.
• Obesity and Barrel Chest: Suggest Pickwickian syndrome or obstructive lung disease.
• Palpable Spleen: Splenomegaly.

Evaluation

Upfront investigations

• Full blood examination; electrolytes, urea and creatinine; liver function tests
• Iron studies
• Oxygen saturations
• EPO level

Selective investigations dependent on history/clinical examination findings

• JAK2 V617F mutation*
• CALR/MPL mutation*
• BCR-ABL1 fusion gene*
• Bone marrow biopsy
• Sleep study (secondary polycythaemia)
• Arterial blood gas (evaluating for hypoxia and carboxyhaemoglobin)
• US abdomen/CT abdomen, pelvis, brain (EPO-secreting tumours)
• Transthoracic echocardiography
• Chest X-ray for chronic lung pathologies
• Haemoglobin electrophoresis – high‑affinity haemoglobin
• EPO receptor mutations
• FSH/LH and total testosterone

*Currently, the Medicare Benefits Schedule (MBS) in Australia offers a rebate for JAK2, MPL and CALR gene testing in the diagnostic work-up by, or on behalf of, a specialist physician for patients with clinical and laboratory evidence of polycythaemia vera, essential thrombocytosis and primary myelofibrosis. The MBS also offers a rebate for BCR-ABL1 gene testing in the diagnosis and monitoring of chronic myeloid leukaemia that does not specify restrictions on qualifications of ordering physicians.²⁸
CT, computed tomography; EPO, erythropoietin; FSH, follicle stimulating hormone; LH, luteinising hormone; US, ultrasonography

Radioisotope Studies

• Chromium-labeled RBC Transfusions: Determines true RBC mass.

Serum EPO Levels

• Low EPO: Suggests primary polycythemia; test for JAK2 mutations.
• High EPO: Indicates secondary polycythemia; further evaluation needed.

Additional Tests

• Arterial Oxygen Saturation: Identifies pulmonary or cardiac causes.
• Co-oximeter, Carboxyhemoglobin, P50 Measurement: Rules out methemoglobinemia and high-affinity hemoglobinopathies.
• Renal and Hepatic Function Tests: Detect secondary causes.
• Ultrasound and Doppler Studies: Identify secondary causes.

Treatment/Management

For Secondary Polycythemia : Address Underlying Cause.

Management of Polycythemia Vera (PV)

Goal: Prevent thrombotic complications.

Phlebotomy

• Purpose: Maintain hematocrit <0.45.
• Benefit: Reduces risk of cardiovascular disease and major thrombosis.
• Evidence: CYTO-PV trial demonstrated significant risk reduction.

Low-Dose Aspirin

• Dose: 100 mg/day.
• Indications: All patients without contraindications.
• Benefit: Reduces nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or cardiovascular death by 60%.
• Evidence: ECLAP study.

Cytoreductive Therapy

• Indications:
  • High-risk patients (age ≥60 years or history of thrombosis).
  • Progressive splenomegaly, leukocytosis, thrombocytosis.
  • Poor tolerance of venesection.
• First-line Agent: Hydroxyurea.
  • Mechanism: Oral antimetabolite preventing DNA synthesis.
  • Side Effects: Myelosuppression, leg ulcers, gastrointestinal toxicity.
• Alternative Agent: Interferon.
  • Advantages: Non-leukemogenic, non-teratogenic.
  • Preferred For: Younger patients, pregnancy.
  • Limitations: Significant side effects, high discontinuation rates.
• Pegylated Interferon Alfa-2a:
  • Advantages: Lower toxicity, reduced frequency dosing.
  • Benefits: Demonstrated hematological and molecular responses.

Prognosis

• Median Survival: Up to 27 years.
• Complications:
  • 12-21% evolve into post-polycythemia vera myelofibrosis.
  • 7% transform into acute myeloid leukemia within 20 years.

Management of Chronic Myeloid Leukemia (CML)

Goal: Achieve major molecular response and prolong survival.

Tyrosine Kinase Inhibitors (TKIs)

• First-Line TKIs: Imatinib, Dasatinib, Nilotinib.
  • Target: BCR-ABL1 oncogene.
  • Success: >75% achieve major molecular response.
  • 10-Year Survival: >83.3% on Imatinib.
• Second-Generation TKIs: For imatinib resistance or intolerance.
  • Agents: Dasatinib, Nilotinib.
  • Effectiveness: Demonstrated hematological and cytogenetic responses.
• Newer Generation TKIs:
  • Development: Phase I studies show efficacy in patients with exposure to at least three TKIs.

Allogeneic Stem Cell Transplant

• Curative Therapy: Only curative option.
• Current Role: Reserved for refractory or accelerated/blast phase CML.
• Goal: Minimize associated morbidity and mortality.

Management of Essential Thrombocytosis (ET)

Goal: Prevent thrombotic complications and manage cytoreductive therapy based on risk stratification.

Risk Stratification

• Very Low Risk: Age ≤60 years, no history of thrombosis, JAK2V617F mutation absent.
  • Management: Aspirin 100 mg daily, observation alone if no cardiovascular risk factors.
• Low Risk: Age ≤60 years, no history of thrombosis, JAK2V617F mutation present.
  • Management: Aspirin 100 mg daily.
• Intermediate Risk: Age >60 years, no history of thrombosis, JAK2V617F mutation absent.
  • Management: Aspirin 100 mg daily.
• High Risk: Age >60 years, JAK2V617F mutation present or history of thrombosis.
  • Management: Aspirin 100 mg daily, cytoreductive therapy.
  • Cytoreductive Therapy Target: Platelet count <450 × 10^9/L.
  • First-line Agent: Hydroxyurea.
  • Alternative Agent: Pegylated interferon alfa-2a for younger patients or women of childbearing potential.
  • Anagrelide: Non-inferior to hydroxyurea but limited by cardiotoxicity.

Management of Primary Myelofibrosis (PMF)

Goal: Manage based on risk using Dynamic International Prognostic Scoring System Plus (DIPSS-Plus).

DIPSS-Plus Scoring

• Low Risk (Score 0):
  • Median Survival: 15.4 years.
  • Treatment: Observation or supportive/symptom-directed therapy.
• Intermediate-1 Risk (Score 1):
  • Median Survival: 6.5 years.
  • Treatment: Supportive/symptom-directed therapy, clinical trial, JAK1/2 inhibitor for severe symptoms.
• Intermediate-2 Risk (Score 2-3):
  • Median Survival: 2.9 years.
  • Treatment: JAK1/2 inhibitor, possible allogeneic stem cell transplant.
• High Risk (Score 4-6):
  • Median Survival: 1.3 years.
  • Treatment: JAK1/2 inhibitor, allogeneic stem cell transplant if applicable.

Supportive/Symptom-Directed Therapy

• Options: Transfusions, prednisone, hydroxyurea, danazol, pegylated interferon alfa-2a, splenic irradiation, splenectomy.
• For Predominant Anemia: Androgens, prednisone, thalidomide/lenalidomide, danazol.

Ruxolitinib

• Use: Intermediate-1 and Intermediate-2 risk patients refractory to current therapy.
• Benefits: Reduces spleen size, myelofibrosis-related symptoms, and improves overall survival.
• Evidence: COMFORT studies.

Patient Education and Follow-up

• Smoking Cessation
• Genetic Counseling: For hemoglobinopathies.
• Lifelong Follow-up: Necessary for monitoring complications and disease progression.

Differential Diagnosis

• Primary Myelofibrosis
• Chronic Myeloid Leukemia
• Essential Thrombocythemia
• EPO Receptor Mutations

Prognosis

• Median Survival: ~14.1 years for PV.
• Better Prognosis: Thrombocytosis, pruritus.
• Worse Outcomes: Higher leukocyte counts, venous thrombosis, leukoerythroblastic blood smear.

Complications

• Bleeding: Epistaxis, GI bleeding.
• Thrombosis: Arterial and venous thrombosis.
• Progression to Leukemia: 5% cases, often refractory to treatment.

Timing of Referral to Hematologist

• Indications for Referral:
  • Persistent cytosis on peripheral blood count without a clear alternative cause.
  • Unexplained arterial or unusual site venous thrombosis regardless of full blood examination (FBE) parameters.
  • Evidence of elevated blood counts or anemia with constitutional symptoms.
• Genetic Testing:
  • Performing genetic testing for driver mutations (e.g., BCR-ABL1, JAK2) while awaiting hematology review may expedite the diagnosis.