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Polycythemia Rubra Vera
Aka: Polycythemia Rubra Vera, Polycythemia Vera
- Definition
- Excessive Red Blood Cell production due to chronic myeloproliferative neoplasm
- Epidemiology
- Men affected more than women
- Age
- Median age of onset: 60 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.)
- Pathophysiology
- Chronic myeloproliferative neoplasm (primary Polycythemia Vera)
- 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
- Causes
- Primary Polycythemia
- Chronic myeloproliferative neoplasm
- Secondary Polycythemia
- Tobacco Abuse (Smoker's Polycythemia)
- Renal Cell Carcinoma
- Chronic heart or lung disease
- Methemoglobinemia
- Living at high altitude
- Hydronephrosis
- Anabolic Steroid secreting tumor
- Erythropoietin secreting tumor
- Decreased plasma volume (e.g.. dehydration)
- 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%)
- 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
- 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
- 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
- Labs
- Red Blood Cell related increases
- Elevated Hemoglobin And Hematocrit
- 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)
- 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
- Diagnosis
- Major Criteria (both required)
- JAK2 V617F mutation, JAK2 exon 12 mutation or similar AND
- Increased red cell mass
- 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)
- Minor Criteria (at least one required)
- Endogenous erythroid colony formation in vitro (EPO-free medium)
- Bone Marrow Biopsy with hypercellularity for age
- Trilineage growth (erythroid, granulocytic, megakaryocytic)
- Serum erythropoetin level below normal reference range
- Test Sensitivity: 70%
- Test Specificity: 90%
- No obvious secondary polycythemia cause
- Normal arterial Oxygen Saturation (>92%)
- 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)
- Epistaxis
- Acute GI Bleed
- Myeloproliferative Disease Progression (typically after 10 years of PCV)
- Myelofibrosis (20% of patients)
- Acute Myeloid Leukemia (5% of patients)
- Management: Myelosuppression
- Goal: Keep Hematocrit below threshold
- White men: Hematocrit <45%
- Black patients and all women: Hematocrit <42%
- Low risk (age <60 years old without prior thrombosis)
- Low dose Aspirin
- Repeated phlebotomy
- High risk (age >60 years old OR prior thrombosis, possibly Leukocytosis >10k/mm3)
- First-line
- Hydroxyurea
- Interferon alfa-2b
- Second-line
- JAK2 Inhibitor (e.g. Ruxolitinib)
- Other agents in elderly (>70-80 years old) or advanced disease (leukemogenicity risk)
- Busulfan
- Pibobraman
- Refractory (Hydroxyurea refractory, massive Splenomegaly, severe symptoms)
- JAK2 Inhibitor (e.g. Ruxolitinib)
- Management: Pruritus
- Antihistamines
- Paroxetine
- Oatmeal Bath
- Interferon alfa-2b
- Diehn (2001) Br J Haematol 115:619-21 [PubMed]
- Prognosis: Median survival in symptomatic patients
- Survival without treatment: 6-18 months
- Survival with treatment: >10 years
- Median survival: 14.1 years
- Median survival in age over 60 years with thrombosis history: 8.3 years
- 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
- 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]