II. Definitions
- Polycythemia Rubra Vera
- Excessive Red Blood Cell production due to chronic myeloproliferative neoplasm
III. Epidemiology
- Men affected more than women
- Age
- Median age of onset: 60-64 years old
- Under age 40 years old represent 20-25% of cases
- Incidence: 2.3 per 100,000 persons per year
- Prevelance: 44-57 per 100,000 persons (U.S.)
IV. Pathophysiology
- Chronic myeloproliferative neoplasm (primary Polycythemia Vera)
- Other common myeloproliferative disorders include Essential Thrombocythemia and Myelofibrosis
- Associated with Janus Kinase 2 gene (JAK2) resulting in unregulated hematopoiesis
- JAK2 V617F mutation (96% of polycythemia cases)
- JAK2 exon 12 mutations (3% of polycythemia patients)
- Primarily causes erythrocytosis
- Also causes Leukocytosis and Thrombocytosis
- Excessive Red Blood Cell production (erythrocytosis)
- Results in increased blood viscosity and Blood Volume
- Ultimately results in thrombosis
V. Risk Factors
- Non-modifiable
- Older age
- Male gender
- Caucasian
- European descent
- Modifiable
VI. Differential Diagnosis
- Primary Polycythemia or Erythrocytosis
- Polycythemia Rubra Vera
- 2,3 Bisphosphoglycerate Deficiency (2,3 BPG Deficiency)
- Lindau-Von Hippel Disease
- Primary Familial and Congenital Polycythemia (EPOR)
- Other myeloproliferative neoplasm
- Secondary Polycythemia or Erythrocytosis
- Decreased plasma volume or hemoconcentration (e.g.. Dehydration)
- Living at high altitude
- Chronic heart or lung disease
- Chronic Hypoxia
- Left to Right Shunt
- Obesity Hypoventilation Syndrome
- Pickwickian syndrome
- Sleep Apnea
- Drug-Induced or Toxin-Induced Polycythemia
- Tobacco Abuse (Smoker's Polycythemia)
- Anabolic Steroids
- Testosterone Replacement
- Erythropoietin
- Blood Doping
- Methemoglobinemia
- Chronic Carbon Monoxide Poisoning
- Renal Disease
- ErythropoietinSecreting tumor
VII. Symptoms
- Thrombotic event on presentation: 20-39% of cases
- Cerebrovascular Accident (CVA) or Transient Ischemic Attack (TIA)
- Myocardial Infarction
- Peripheral arterial thrombosis
- Deep Vein Thrombosis
- Portal Vein Thrombosis or hepatic vein thrombosis (budd-chiari syndrome)
- Constitutional symptoms
- Fatigue (88%)
- Weight loss (31%)
- Night Sweats (52%)
- Insomnia
- Difficult Concentration
- Weakness
- Fever (18%)
-
Generalized symptoms
- Pruritus (62%)
- Generalized burning, itching or Paresthesias
- Onset often within 10 minutes and lasting for up to 40 minutes after provocative exposure
- Provoked by bathing, especially in warm water (Aquagenic Pruritus)
- Also provoked by Temperature changes, Alcohol, Exercise
- Bone pain (50%)
- Gout history
- Pruritus (62%)
- Microvascular Occlusion symptoms
- Headache
- Tinnitus
- Dizziness
- Visual disturbance
- Transient Ischemic Attack symptoms
- Distal Paresthesias
- Acrocyanosis
- Erythromelalgia (29% of cases)
- Vasomotor findings with extremity congestion, redness, burning pain
- Improves with Aspirin
-
Splenomegaly related symptoms
- Abdominal Pain
- Early satiety
- Weight loss
- Nausea
VIII. Signs
- See complications below
- Splenomegaly (35-45% of patients, especially in advanced Polycythemia Vera)
- Plethoric facies
- Ruddy facial Cyanosis
- Eyes
- Retinal vein engorgement
- Conjunctival small vessel injection
IX. Labs
-
Red Blood Cell related increases
- Elevated Hemoglobin And Hematocrit (often found incidentally)
- White men: Hemoglobin >18.5 mg/dl (Hematocrit >52%)
- Black men: Hemoglobin >16 mg/dl (Hematocrit >47%)
- Women: >16.5 mg/dl (Hematocrit >48%)
- Elevated Red Blood Bell count
- RBC Count >36 ml/kg in men (>33 ml/kg in women)
- Elevated Hemoglobin And Hematocrit (often found incidentally)
- Proliferation of other cell lines (50% of patients)
- Platelet Count (median): 400k/mm3
- Leukocyte count (median) 10.4k/mm3
-
Liver Function Tests
- LDH increased in 50% of patients
- Diagnostic Testing (indicated for diagnosis after erythrocytosis found)
- Janus Kinase 2 Mutation (JAK2 V617F mutation
- Erythropoetin Level
- Bone Marrow Biopsy
- Fluorescence in situ hybridization
- Karyotype
X. Diagnosis: 2016 Revised WHO Criteria
- Major Criteria (both required)
- Increased red cell mass (erythrocytosis)
- Precaution: May miss masked Polycythemia Vera who are JAK2+, but normal RBC mass
- Men
- Hemoglobin >18.5 g/dl (WHO) or
- Hematocrit >52% (BCSH PVSG) or
- RBC Count >25% mean normal per WHO (e.g. >36 ml/kg)
- Women
- Hemoglobin >16.5 g/dl (WHO) or
- Hematocrit >48% (BCSH PVSG) or
- RBC Count >25% mean normal per WHO (e.g. >33 ml/kg)
- Bone Marrow Biopsy with hypercellularity for age
- Trilineage growth (erythroid, granulocytic, megakaryocytic) AND
- Pleomorphic mature Megakaryocytes
- Increased red cell mass (erythrocytosis)
- Minor Criteria (at least one required)
- Janus Kinase 2 Mutation (JAK2 V617F mutation, JAK2 exon 12 mutation or similar)
- Present in 98% of patients with Polycthemia Vera
- Serum erythropoetin level below normal reference range
- Present in 81% of patients with Polycthemia Vera
- Test Sensitivity: 70%
- Test Specificity: 90%
- Janus Kinase 2 Mutation (JAK2 V617F mutation, JAK2 exon 12 mutation or similar)
- No obvious secondary polycythemia cause
- Normal arterial Oxygen Saturation (>92%)
- Interpretation
- Polycythemia Vera is unlikely if JAK2 V617F negative AND Erythropoietin normal or high
- All other JAK2 V617F and Erythropoietin results (with erythrocytosis) prompt Bone Marrow Biopsy
XI. Complications
- Accelerated atherosclerotic and thrombotic disease
- Cerebrovascular Accident
- Myocardial Infarction
- Peripheral Vascular Disease
- Other rarely affected vessels
- Mesenteric thrombosis
- Hepatic vein thrombosis or Portal Vein Thrombosis
- Hemorrhage and Bleeding Diathesis with extreme Thrombocytosis >1.5M (acquired Von Willebrand Syndrome)
- Myeloproliferative Disease Progression (typically after 10 years of PCV)
- Myelofibrosis (20% of patients)
- Acute Myeloid Leukemia (5% of patients)
XII. Management: General
- Myelosuppression and other red cell reduction management is not currative
- Goals are to improve survival and improve quality of life, reduce symptoms and complications
- No treatment to date has been shown to reduce progression to Leukemia or Myelofibrosis
- Monitoring
- Repeat exam and labs (Complete Blood Count) every 3 to 6 months
- Risk Factor Reduction
- Goal: Keep Hematocrit below threshold
- White men: Hematocrit <45%
- Black patients and all women: Hematocrit <42% (some guidelines recommend <45% in all patients)
- Phlebotomy reduces risk of thrombosis and improves survival
- Low risk (age <60 years old without prior thrombosis)
- Repeated phlebotomy
- Low dose Aspirin (40 to 100 mg)
- Decreased risk of thrombotic events (MI, CVA, VTE) as well as decreased symptoms (e.g. Headache, Pruritus)
- Avoid in severe Thrombocytosis (>1000 x10^9) due to risk of acquired Von Willebrand Deficiency
- Landolfi (2004) N Engl J Med 350(2): 114-24 [PubMed]
- High risk (age >60 years old OR prior thrombosis, possibly Leukocytosis >10k/mm3)
- First-line
- Hydroxyurea
- Adverse effects include Anemia, Neutropenia, Oral Ulcers and Skin Ulcers, Hyperpigmentation
- Leukemogenicity risk (Exercise caution in age under 40 years old)
- Leukemic transformation 0.4% persons per year
- Myelofibrosis 5% at five years, 33.7% at 10 years
- Ferrari (2019) Hematologica 104(12): 2391-9 [PubMed]
- Hydroxyurea
- Anticoagulation and antiplatelet agent indications
- Arterial Thrombosis history
- Increase Aspirin to twice daily
- Venous thrombosis history
- Add Anticoagulation
- Arterial Thrombosis history
- Refractory Course or Intolerance to Hydroxyurea (24% of patients)
- Younger patients
- Pegylated Interferon Alfa-2B
- Adverse effects include severe skin toxicity, Asthenia
- Kiladjian (2008) Blood 112(8): 3065-72 [PubMed]
- Pegylated Interferon Alfa-2B
- Older patients (>70-80 years old) or advanced disease
- Busulfan (leukemogenicity risk)
- Adverse effects include cytopenia
- Douglas (2017) Leuk Lymphoma 58(1): 89-95 [PubMed]
- Busulfan (leukemogenicity risk)
- Symptomatic massive Splenomegaly or severe symptoms
- JAK2 Inhibitor (e.g. Ruxolitinib)
- Higher risk of Herpes Zoster infection (6% of patients)
- Vannucchi (2015) N Engl J Med 372(5): 426-35 [PubMed]
- JAK2 Inhibitor (e.g. Ruxolitinib)
- Younger patients
- First-line
XIII. Management: Pruritus
- Occurs in 68% of patients (severe in 15%)
- Symptomatic Therapy
- Refractory cases
- References
XIV. Management: Pregnancy
- Polycythemia Vera is rare in pregnancy (<0.03 per 100,000)
- Stop Teratogenic medications (e.g. Hydroxyurea) at least 3 months before conception
- If Myelosuppression is needed, Interferon-alpha is the preferred cytoreductive agent in pregnancy
- Continue low dose Aspirin
- Maintain Hematocrit at Gestational age appropriate levels
- Avoid Iron Supplementation unless low
- Enoxaparin (Lovenox) for first 6 weeks postpartum to prevent Venous Thromboembolism
XV. Prognosis: General
- Median survival in symptomatic patients
- Survival without treatment: 6-18 months (up to 2 years)
- Death is typically due to thrombosis
- Survival with treatment: >8-10 years
- Median survival if diagnosed before age 60 years: 24 years
- Median survival with Aspirin and Hydroxyurea : 13.5 to 14.1 years
- Median survival in age over 60 years with thrombosis history: 8.3 years
- Survival without treatment: 6-18 months (up to 2 years)
- Malignant transformation or Myelofibrosis risk
- Acute Myeloid Leukemia or Myelodysplastic Syndrome risk in 15 years: 5 to 18%
- Myelofibrosis risk in 15 years: 6 to 14%
- Factors associated with poor prognosis
- Age over 60 years
- Thrombosis history
- Leukocytosis
- Abnormal karyotype
- High JAK2 levels
- Cardiovascular Risk Factors (e.g. Tobacco Abuse, Hypertension, Hyperlipidemia, Diabetes Mellitus)
XVI. References
- Tefferi in Schrier (2015) Clinical Manifestations and Diagnosis of Polycythemia Vera, UpToDate, accessed 12/15/2015
- Tefferi in Schrier (2015) Prognosis and Treatment of Polycythemia Vera, UpToDate, accessed 12/15/2015
- Fox (2021) Am Fam Physician 103(11): 680-7 [PubMed]
- Griesshammer (2015) Ann Hematol 94(6):901-10 +PMID:25832853 [PubMed]
- Stuart (2004) Am Fam Physician 69(9):2139-46 [PubMed]
- Tefferi (2001) Am J Med 109:146 [PubMed]
- Tefferi (2003) Mayo Clin Proc 78:174-94 [PubMed]