Polycythemia Rubra Vera

1. Definitions
   1. Polycythemia Rubra Vera
      1. Excessive Red Blood Cell production due to chronic myeloproliferative neoplasm
2. Epidemiology
   1. Men affected more than women
   2. Age
      1. Median age of onset: 60-64 years old
      2. Under age 40 years old represent 20-25% of cases
   3. Incidence: 2.3 per 100,000 persons per year
   4. Prevelance: 44-57 per 100,000 persons (U.S.)
3. Pathophysiology
   1. Chronic myeloproliferative neoplasm (primary Polycythemia Vera)
      1. Other common myeloproliferative disorders include Essential Thrombocythemia and Myelofibrosis
      2. Associated with Janus Kinase 2 gene (JAK2) resulting in unregulated hematopoiesis
         1. JAK2 V617F mutation (96% of polycythemia cases)
         2. JAK2 exon 12 mutations (3% of polycythemia patients)
      3. Primarily causes erythrocytosis
      4. Also causes Leukocytosis and Thrombocytosis
   2. Excessive Red Blood Cell production (erythrocytosis)
      1. Results in increased blood viscosity and Blood Volume
      2. Ultimately results in thrombosis
4. Risk Factors
   1. Non-modifiable
      1. Older age
      2. Male gender
      3. Caucasian
      4. European descent
   2. Modifiable
      1. Tobacco Abuse
      2. Obesity
      3. Hypertension
      4. Hyperlipidemia
      5. Diabetes Mellitus
5. Differential Diagnosis
   1. Primary Polycythemia or Erythrocytosis
      1. Polycythemia Rubra Vera
      2. 2,3 Bisphosphoglycerate Deficiency (2,3 BPG Deficiency)
      3. Lindau-Von Hippel Disease
      4. Primary Familial and Congenital Polycythemia (EPOR)
      5. Other myeloproliferative neoplasm
         1. Essential Thrombocytosis or Thrombocythemia
         2. Primary Myelofibrosis
         3. Chronic Myelogenous Leukemia
         4. Myelodysplastic Syndrome
   2. Secondary Polycythemia or Erythrocytosis
      1. Decreased plasma volume or hemoconcentration (e.g.. Dehydration)
      2. Living at high altitude
         1. See High Altitude Related-Conditions
      3. Chronic heart or lung disease
         1. Chronic Hypoxia
         2. Left to Right Shunt
         3. Obesity hypoventilation syndrome
         4. Pickwickian Syndrome
         5. Sleep Apnea
      4. Drug-Induced or Toxin-Induced Polycythemia
         1. Tobacco Abuse (Smoker's Polycythemia)
         2. Anabolic Steroids
         3. Testosterone Replacement
         4. Erythropoietin
         5. Blood Doping
         6. Methemoglobinemia
         7. Chronic Carbon Monoxide Poisoning
      5. Renal Disease
         1. Renal Artery Stenosis
         2. Hydronephrosis
         3. Renal Transplant
      6. Erythropoietin secreting tumor
         1. Hepatocellular Carcinoma
         2. Renal Cell Carcinoma
         3. Hemangioblastoma
         4. Pheochromocytoma
         5. Uterine Leiomyomata
6. Symptoms
   1. Thrombotic event on presentation: 20-39% of cases
      1. Cerebrovascular Accident (CVA) or Transient Ischemic Attack (TIA)
      2. Myocardial Infarction
      3. Peripheral arterial thrombosis
      4. Deep Vein Thrombosis
      5. Portal Vein Thrombosis or hepatic vein thrombosis (budd-chiari syndrome)
   2. Constitutional symptoms
      1. Fatigue (88%)
      2. Weight loss (31%)
      3. Night Sweats (52%)
      4. Insomnia
      5. Difficult Concentration
      6. Weakness
      7. Fever (18%)
   3. Generalized symptoms
      1. Pruritus (62%)
         1. Generalized burning, itching or Paresthesias
         2. Onset often within 10 minutes and lasting for up to 40 minutes after provocative exposure
         3. Provoked by bathing, especially in warm water (Aquagenic Pruritus)
         4. Also provoked by Temperature changes, Alcohol, Exercise
      2. Bone pain (50%)
      3. Gout history
   4. Microvascular Occlusion symptoms
      1. Headache
      2. Tinnitus
      3. Dizziness
      4. Visual disturbance
      5. Transient Ischemic Attack symptoms
      6. Distal Paresthesias
      7. Acrocyanosis
      8. Erythromelalgia (29% of cases)
         1. Vasomotor findings with extremity congestion, redness, burning pain
         2. Improves with Aspirin
   5. Splenomegaly related symptoms
      1. Abdominal Pain
      2. Early satiety
      3. Weight loss
      4. Nausea
7. Signs
   1. See complications below
   2. Splenomegaly (35-45% of patients, especially in advanced Polycythemia Vera)
   3. Plethoric facies
      1. Ruddy facial Cyanosis
   4. Eyes
      1. Retinal vein engorgement
      2. Conjunctival small vessel injection
8. Labs
   1. Red Blood Cell related increases
      1. Elevated Hemoglobin And Hematocrit (often found incidentally)
         1. White men: Hemoglobin >18.5 mg/dl (Hematocrit >52%)
         2. Black men: Hemoglobin >16 mg/dl (Hematocrit >47%)
         3. Women: >16.5 mg/dl (Hematocrit >48%)
      2. Elevated Red Blood Bell count
         1. RBC Count >36 ml/kg in men (>33 ml/kg in women)
   2. Proliferation of other cell lines (50% of patients)
      1. Platelet Count (median): 400k/mm3
      2. Leukocyte count (median) 10.4k/mm3
   3. Liver Function Tests
      1. LDH increased in 50% of patients
   4. Diagnostic Testing (indicated for diagnosis after erythrocytosis found)
      1. Janus Kinase 2 Mutation (JAK2 V617F mutation
      2. Erythropoetin Level
      3. Bone Marrow Biopsy
         1. Fluorescence in situ hybridization
         2. Karyotype
9. Diagnosis: 2016 Revised WHO Criteria
   1. Major Criteria (both required)
      1. Increased red cell mass (erythrocytosis)
         1. Precaution: May miss masked Polycythemia Vera who are JAK2+, but normal RBC mass
         2. Men
            1. Hemoglobin >18.5 g/dl (WHO) or
            2. Hematocrit >52% (BCSH PVSG) or
            3. RBC Count >25% mean normal per WHO (e.g. >36 ml/kg)
         3. Women
            1. Hemoglobin >16.5 g/dl (WHO) or
            2. Hematocrit >48% (BCSH PVSG) or
            3. RBC Count >25% mean normal per WHO (e.g. >33 ml/kg)
      2. Bone Marrow Biopsy with hypercellularity for age
         1. Trilineage growth (erythroid, granulocytic, megakaryocytic) AND
         2. Pleomorphic mature Megakaryocytes
   2. Minor Criteria (at least one required)
      1. Janus Kinase 2 Mutation (JAK2 V617F mutation, JAK2 exon 12 mutation or similar)
         1. Present in 98% of patients with Polycthemia Vera
      2. Serum erythropoetin level below normal reference range
         1. Present in 81% of patients with Polycthemia Vera
         2. Test Sensitivity: 70%
         3. Test Specificity: 90%
   3. No obvious secondary polycythemia cause
      1. Normal arterial Oxygen Saturation (>92%)
   4. Interpretation
      1. Polycythemia Vera is unlikely if JAK2 V617F negative AND Erythropoietin normal or high
      2. All other JAK2 V617F and Erythropoietin results (with erythrocytosis) prompt Bone Marrow Biopsy
10. Complications
    1. Accelerated atherosclerotic and thrombotic disease
       1. Cerebrovascular Accident
       2. Myocardial Infarction
       3. Peripheral Vascular Disease
       4. Other rarely affected vessels
          1. Mesenteric thrombosis
          2. Hepatic vein thrombosis or Portal Vein Thrombosis
    2. Hemorrhage and Bleeding Diathesis with extreme Thrombocytosis >1.5M (acquired Von Willebrand Syndrome)
       1. Epistaxis
       2. Acute GI Bleed
    3. Myeloproliferative Disease Progression (typically after 10 years of PCV)
       1. Myelofibrosis (20% of patients)
       2. Acute Myeloid Leukemia (5% of patients)
11. Management: General
    1. Myelosuppression and other red cell reduction management is not currative
       1. Goals are to improve survival and improve quality of life, reduce symptoms and complications
       2. No treatment to date has been shown to reduce progression to Leukemia or Myelofibrosis
    2. Monitoring
       1. Repeat exam and labs (Complete Blood Count) every 3 to 6 months
    3. Risk Factor Reduction
       1. Tobacco Cessation
    4. Goal: Keep Hematocrit below threshold
       1. White men: Hematocrit <45%
       2. Black patients and all women: Hematocrit <42% (some guidelines recommend <45% in all patients)
       3. Phlebotomy reduces risk of thrombosis and improves survival
          1. Marchioli (2013) N Engl J Med 368(1): 22-33 [PubMed]
          2. Podoltsev (2018) Blood Adv 2(20): 2681-90 [PubMed]
    5. Low risk (age <60 years old without prior thrombosis)
       1. Repeated phlebotomy
       2. Low dose Aspirin (40 to 100 mg)
          1. Decreased risk of thrombotic events (MI, CVA, VTE) as well as decreased symptoms (e.g. Headache, Pruritus)
          2. Avoid in severe Thrombocytosis (>1000 x10^9) due to risk of acquired Von Willebrand Deficiency
          3. Landolfi (2004) N Engl J Med 350(2): 114-24 [PubMed]
    6. High risk (age >60 years old OR prior thrombosis, possibly Leukocytosis >10k/mm3)
       1. First-line
          1. Hydroxyurea
             1. Adverse effects include Anemia, Neutropenia, Oral Ulcers and Skin Ulcers, Hyperpigmentation
             2. Leukemogenicity risk (Exercise caution in age under 40 years old)
                1. Leukemic transformation 0.4% persons per year
                2. Myelofibrosis 5% at five years, 33.7% at 10 years
                3. Ferrari (2019) Hematologica 104(12): 2391-9 [PubMed]
       2. Anticoagulation and antiplatelet agent indications
          1. Arterial Thrombosis history
             1. Increase Aspirin to twice daily
          2. Venous thrombosis history
             1. Add Anticoagulation
       3. Refractory Course or Intolerance to Hydroxyurea (24% of patients)
          1. Younger patients
             1. Pegylated Interferon alfa-2b
                1. Adverse effects include severe skin toxicity, Asthenia
                2. Kiladjian (2008) Blood 112(8): 3065-72 [PubMed]
          2. Older patients (>70-80 years old) or advanced disease
             1. Busulfan (leukemogenicity risk)
                1. Adverse effects include cytopenia
                2. Douglas (2017) Leuk Lymphoma 58(1): 89-95 [PubMed]
          3. Symptomatic massive Splenomegaly or severe symptoms
             1. JAK2 Inhibitor (e.g. Ruxolitinib)
                1. Higher risk of Herpes Zoster infection (6% of patients)
                2. Vannucchi (2015) N Engl J Med 372(5): 426-35 [PubMed]
12. Management: Pruritus
    1. Occurs in 68% of patients (severe in 15%)
    2. Symptomatic Therapy
       1. Aspirin
       2. Antihistamines
       3. Paroxetine
       4. Oatmeal Bath
    3. Refractory cases
       1. Interferon alfa-2b
       2. Ruxolitinib
       3. Narrow Band Ultraviolet BPhototherapy
    4. References
       1. Diehn (2001) Br J Haematol 115:619-21 [PubMed]
13. Management: Pregnancy
    1. Polycythemia Vera is rare in pregnancy (<0.03 per 100,000)
    2. Stop Teratogenic medications (e.g. Hydroxyurea) at least 3 months before conception
       1. If Myelosuppression is needed, Interferon-alpha is the preferred cytoreductive agent in pregnancy
    3. Continue low dose Aspirin
    4. Maintain Hematocrit at Gestational age appropriate levels
    5. Avoid Iron Supplementation unless low
    6. Enoxaparin (Lovenox) for first 6 weeks postpartum to prevent Venous Thromboembolism
14. Prognosis: General
    1. Median survival in symptomatic patients
       1. Survival without treatment: 6-18 months (up to 2 years)
          1. Death is typically due to thrombosis
       2. Survival with treatment: >8-10 years
          1. Median survival if diagnosed before age 60 years: 24 years
          2. Median survival with Aspirin and Hydroxyurea : 13.5 to 14.1 years
          3. Median survival in age over 60 years with thrombosis history: 8.3 years
    2. Malignant transformation or Myelofibrosis risk
       1. Acute Myeloid Leukemia or Myelodysplastic Syndrome risk in 15 years: 5 to 18%
       2. Myelofibrosis risk in 15 years: 6 to 14%
    3. Factors associated with poor prognosis
       1. Age over 60 years
       2. Thrombosis history
       3. Leukocytosis
       4. Abnormal karyotype
       5. High JAK2 levels
       6. Cardiovascular Risk Factors (e.g. Tobacco Abuse, Hypertension, Hyperlipidemia, Diabetes Mellitus)
15. References
    1. Tefferi in Schrier (2015) Clinical Manifestations and Diagnosis of Polycythemia Vera, UpToDate, accessed 12/15/2015
    2. Tefferi in Schrier (2015) Prognosis and Treatment of Polycythemia Vera, UpToDate, accessed 12/15/2015
    3. Fox (2021) Am Fam Physician 103(11): 680-7 [PubMed]
    4. Griesshammer (2015) Ann Hematol 94(6):901-10 +PMID:25832853 [PubMed]
    5. Stuart (2004) Am Fam Physician 69(9):2139-46 [PubMed]
    6. Tefferi (2001) Am J Med 109:146 [PubMed]
    7. Tefferi (2003) Mayo Clin Proc 78:174-94 [PubMed]