I. Definition

  1. Excessive Red Blood Cell production due to chronic myeloproliferative neoplasm

II. 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.)

III. 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

IV. 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)

V. 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

VI. 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

VII. 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

VIII. 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%)

IX. 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)

X. 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)

XII. 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

XIII. 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]

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Ontology: Polycythemia Vera (C0032463)

Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (CHV) a condition that produces excessive red blood cells
Definition (MSHCZE) Krevní onemocnění charakterizované zvýšenou tvorbou červených krvinek, ale též některých bílých krvinek, granulocytů a krevních destiček v kostní dřeni a jejich zmnožením v krvi. Druh myeloproliferativního onemocnění, hladina erytropoetinu je na rozdíl od sekundární polycytemie nízká. Probíhá chronicky, kromě celkových příznaků bývají zejm. oběhové poruchy způsobené zvýšenou viskozitou krve a jejím větším množstvím a krvácivé či trombotické komplikace; může být hyperurikemie. Nápadný je vzhled nemocných s výraznou pletorou. Po řadě let někdy vyústí v jiné, závažnější krevní onemocnění charakteru leukemie nebo do fibrózy kostní dřeně. Léčí se opakovanými krevními odběry, erytrocytaferézou, některými cytostatiky či podáním radioaktivního fosforu. (cit. Velký lékařský slovník online, 2012 http://lekarske.slovniky.cz/ )
Definition (NCI_NCI-GLOSS) A disease in which there are too many red blood cells in the bone marrow and blood, causing the blood to thicken. The number of white blood cells and platelets may also increase. The extra blood cells may collect in the spleen and cause it to become enlarged. They may also cause bleeding problems and make clots form in blood vessels.
Definition (NCI) A chronic myeloproliferative neoplasm characterized by an increased red blood cell production. Excessive proliferation of the myeloid lineage is observed as well. The major symptoms are related to hypertension or to vascular abnormalities caused by the increased red cell mass. The cause is unknown. With currently available treatment, the median survival exceeds 10 years. (WHO, 2001)
Definition (MSH) A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs.
Definition (CSP) myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume; associated frequently with splenomegaly, leukocytosis, and thrombocythemia.
Concepts Neoplastic Process (T191)
MSH D011087
ICD9 238.4
ICD10 D45 , M9950/1
SnomedCT 31569001, 278190000, 134182002, 269652000, 154644004, 109992005, 128841001
English Osler Vaquez Disease, Osler-Vaquez Disease, Disease, Osler-Vaquez, Erythremia, Erythremias, PPP-Primary prolif polycythaem, Prim proliferat polycythaemia, Prim proliferat polycythemia, Erythraemia, POLYCYTHEMIA RUBRA VERA, POLYCYTHEMIA VERA, PRV, OSLER VAQUEZ DIS, [M]Polycythaemia rubra vera, [M]Polycythaemia vera, [M]Polycythemia rubra vera, [M]Polycythemia vera, polycythemia vera, polycythemia vera (diagnosis), Polycythaemia vera -RETIRED-, Primary polycythemia, Polycythemia Vera [Disease/Finding], Vera, Polycythemia Rubra, Polycythemia Rubra Veras, Polycythemia Rubra Vera, Veras, Polycythemia Rubra, erythraemia, polycythaemia vera, proliferative polycythemia, vaquez's disease, p vera, primary polycythemia, splenomegalic polycythemia, erythrocythemia, osler's disease, Polycythemia Ruba Vera, Primary Polycythemia, Erythremia (morphologic abnormality), [M]Polycythemia vera (morphologic abnormality), PV, Polycythemia rubra vera, Polycythemia vera, Osler's disease, Vaquez's disease, PPP - Primary proliferative polycythaemia, PPP - Primary proliferative polycythemia, PRV - Polycythaemia rubra vera, PRV - Polycythemia rubra vera, Polycythaemia rubra vera, Polycythaemia vera, Primary proliferative polycythaemia, Primary proliferative polycythemia, Chronic erythraemia [obs], Chronic erythremia [obs], Osler-Vaquez syndrome, Polycythaemia vera (clinical), Polycythemia vera (clinical), Polycythemia vera (disorder), Polycythemia vera (morphologic abnormality), Proliferative polycythaemia, Proliferative polycythemia, p.vera, polycythemia ruba vera, Osler-Vaquez, Vaquez-Osler, erythremia, polycythemia; rubra vera, polycythemia; vera, rubra; polycythemia rubra vera, vera; polycythemia, Polycythemia vera -RETIRED-, Polycythemia Vera, Primary polycythaemia, polycythaemia rubra vera, polycythemia rubra vera
Dutch primaire polycytemie, polycythaemia rubra vera, polycytemie vera, polycytemie rubra vera, ziekte van Vaquez, polycytemie; rubra vera, polycytemie; vera, rubra; polycythaemia rubra vera, vera; polycythaemia vera, polycythaemia vera, Erythremie, Polycythaemia vera, Vasquez-Osler-ziekte, Ziekte van Vasquez-Osler
French Polyglobulie essentielle, Maladie de Vasquez, Polyglobulie primaire, Polyglobulie primitive, Polycythémie vraie, Polyglobulie primitive essentielle, Maladie de Vaquez, Polyglobulie vraie
German Polycythaemia rubra vera, primaere Polyzythaemie, Vaquez Syndrom, Polycathaemia vera, Polycythaemia vera, Vasquez-Osler-Syndrom, Erythrämie
Italian Policitemia primitiva, Malattia di Vasquez, Malattia di Osler-Vaquez, Eritremia, Policitemia vera
Portuguese Policitemia rubra vera, Policitemia primária, Doença de Vaquez, Policitemia Rubra Vera, Policitemia vera, Doença de Osler-Vasquez, Eritremia, Policitemia Vera
Spanish Policitemia rubra vera, Policitemia primaria, Enfermedad de Vázquez, Policitemia rubra verdadera, Policitemia verdadera, Policitemia Rubra Vera, [M] policitemia vera, policitemia vera (concepto no activo), eritremia, policitemia rubra vera (anomalía morfológica), eritremia (anomalía morfológica), policitemia rubra vera, eritremia crónica, eritrocitemia, policitemia proliferativa, policitemia vera (clínica), policitemia vera (trastorno), policitemia vera, policitemia verdadera (anomalía morfológica), policitemia verdadera (clínica), policitemia verdadera (trastorno), policitemia verdadera, síndrome de Osler - Vasquez, Policitemia vera, Enfermedad de Osler-Vaquez, Eritremia, Policitemia Vera
Japanese 原発性多血症, 原発性赤血球増加症, ゲンパツセイタケツショウ, ゲンパツセイセッケッキュウゾウカショウ, バケービョウ, シンセイタケツショウ, シンセイセッケッキュウゾウカショウ, オスラー・ワーケ病, オスラー・バケー病, Osler-Vaquez病, 多血症-真性, 真性多血症, 真性赤血球増加症, 真正多血症, 真正赤血球増加症, 赤血球増加症-真性, 赤血病-慢性, 赤血病, オスラー-ワーケ病, バケー-オスラー病, バケー病, 多血症-真正
Swedish Polycytemia vera
Czech polycythemia vera, Vasquezova choroba, Polycytemia vera, Primární polycytemie, Polycytemia rubra vera, polycythaemia vera, Oslerova-Vaquezova nemoc, polycythaemia rubra vera, pravá polycytemie
Finnish Itsenäinen polysytemia
Russian ERITREMIIA, OSLERA-VAKEZA BOLEZN', POLITSITEMIIA ISTINNAIA, ОСЛЕРА-ВАКЕЗА БОЛЕЗНЬ, ПОЛИЦИТЕМИЯ ИСТИННАЯ, ЭРИТРЕМИЯ
Korean 진성 적혈구 증가증
Croatian POLICITEMIJA RUBRA VERA
Polish Choroba Oslera-Vaqueza, Czerwienica prawdziwa
Hungarian Polycythaemia rubra vera, Primaer polycythaemia, Vaquez-betegség, Polycytemia rubra vera, Elsődleges polycythaemia, Polycythaemia vera
Norwegian Polycythaemia rubra vera, Polycythaemia vera