Polycythemia Rubra Vera

1. Definition
   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 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. 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)
      2. Primarily causes erythrocytosis
      3. 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. Causes
   1. Primary Polycythemia
      1. Chronic myeloproliferative neoplasm
   2. Secondary Polycythemia
      1. Tobacco Abuse (Smoker's Polycythemia)
      2. Renal Cell Carcinoma
      3. Chronic heart or lung disease
      4. Methemoglobinemia
      5. Living at high altitude
      6. Hydronephrosis
      7. Anabolic Steroid secreting tumor
      8. Erythropoietin secreting tumor
      9. Decreased plasma volume (e.g.. dehydration)
5. 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. Weakness
      5. 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
6. 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
7. Labs
   1. Red Blood Cell related increases
      1. Elevated Hemoglobin And Hematocrit
         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
8. Diagnosis
   1. Major Criteria (both required)
      1. JAK2 V617F mutation, JAK2 exon 12 mutation or similar AND
      2. Increased red cell mass
         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. Minor Criteria (at least one required)
      1. Endogenous erythroid colony formation in vitro (EPO-free medium)
      2. Bone Marrow Biopsy with hypercellularity for age
         1. Trilineage growth (erythroid, granulocytic, megakaryocytic)
      3. Serum erythropoetin level below normal reference range
         1. Test Sensitivity: 70%
         2. Test Specificity: 90%
   3. No obvious secondary polycythemia cause
      1. Normal arterial Oxygen Saturation (>92%)
9. 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)
10. Management: Myelosuppression
    1. Goal: Keep Hematocrit below threshold
       1. White men: Hematocrit <45%
       2. Black patients and all women: Hematocrit <42%
    2. Low risk (age <60 years old without prior thrombosis)
       1. Low dose Aspirin
       2. Repeated phlebotomy
    3. High risk (age >60 years old OR prior thrombosis, possibly Leukocytosis >10k/mm3)
       1. First-line
          1. Hydroxyurea
          2. Interferon alfa-2b
       2. Second-line
          1. JAK2 Inhibitor (e.g. Ruxolitinib)
       3. Other agents in elderly (>70-80 years old) or advanced disease (leukemogenicity risk)
          1. Busulfan
          2. Pibobraman
    4. Refractory (Hydroxyurea refractory, massive Splenomegaly, severe symptoms)
       1. JAK2 Inhibitor (e.g. Ruxolitinib)
11. Management: Pruritus
    1. Antihistamines
    2. Paroxetine
    3. Oatmeal Bath
    4. Interferon alfa-2b
    5. Diehn (2001) Br J Haematol 115:619-21 [PubMed]
12. Prognosis: Median survival in symptomatic patients
    1. Survival without treatment: 6-18 months
    2. Survival with treatment: >10 years
       1. Median survival: 14.1 years
       2. Median survival in age over 60 years with thrombosis history: 8.3 years
13. 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. Griesshammer (2015) Ann Hematol 94(6):901-10 +PMID:25832853 [PubMed]
    4. Stuart (2004) Am Fam Physician 69(9):2139-46 [PubMed]
    5. Tefferi (2001) Am J Med 109:146 [PubMed]
    6. Tefferi (2003) Mayo Clin Proc 78:174-94 [PubMed]