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polycythemia rubra vera (PRV, PV, erythremia)

Etiology: - associated with mutations in JAK2 Pathology: 1) primary disease of the pluripotent hematopoietic stem cell 2) excessive production of multiple lineages of hematopoietic cell lineages 3) extramedullary hematopoiesis 4) erythropoietin-independent proliferation of erythrocytes 5) stages of polycythemia vera a) proliferative stage 1] bone marrow produces large numbers of erythrocytes with or without increases in leukocytes & platelets 2] physical exam reveals a palpable spleen b) spent stage 1] ineffective erythropoiesis 2] anemia, thrombocytopenia, leukopenia 3] extramedullary hematopoiesis in: -> spleen, lymph nodes & kidney c) myeloid metaplasia -> development of acute leukemia Genetics: associated with mutations in JAK2 Clinical manifestations: 1) see polycythemia 2) thrombosis or bleeding 3) erythromelalgia (red hot painful extremities) 4) aquagenic pruritus (pruritus exacerbated by bathing) 5) hepatosplenomegaly (75%) 6) facial plethora 7) pruritus exacerbated by bathing in hot water 8) hypertension Laboratory: 1) bone marrow a) hypercellular, especially megakaryocytes b) absent iron stores c) marrow fibrosis may develop (late-stage) 2) complete blood count (CBC) a) increased red blood cell mass - hemoglobin > 16.5 (women), 18.5 (men) g/dL (untreated) - hematocrit > 50% (women), 55% (men) (untreated) - hemoglobin > 16.5 g/dL & features of PRV [3] b) microcytosis c) white blood cell (WBC) count generally > 12,000/mm3 (leukocytosis) d) platelet count generally > 400,000/mm3 (thrombocytosis) e) basophil count (basophilia) 3) serum ferritin, serum iron & transferrin saturation may be low [13] 4) peripheral blood smear in follow-up exams - leukoerythroblastic blood smear with tear drop cells, nucleated erythrocytes & immature myeloid precursors suggest evolution to myelofibrosis [3] 5) arterial blood gas (ABG) a) normal hemoglobin oxygen saturation b) carboxyhemoglobin is normal 6) serum erythropoietin inappropriately low 7) leukocyte alkaline phosphatase (LAP) > 100 mg of phosphorus liberate per 10E10 cells 8) serum vitamin B12 > 900 pg/mL 9) serum uric acid (hyperuricemia) [3] 10) direct measurement erythrocyte mass with Cr-51 labeling a) may be needed when hematocrit is < 60% b) not recommended [3] 11) burst-forming unit-erythroid growth in vitro - spontaneous colony growth 12) JAK2 V617F mutation (65-97%) Special laboratory: - bone marrow biopsyz; - hypercellular marrow with erythroid, granulocytic, & megakaryocytic hyperplasia Diagnostic criteria: - hematocrit > 56% (women), 60% (men) (untreated) in the absence of causes of secondary erythrocytosis & presence of splenomegaly, or - any 2 of the following - JAK2 mutation - normal hemoglobin oxygen saturation - increased red blood cell mass - splenomegaly - plus 2 of the following - white blood cell (WBC) count > 12,000/mm3 - platelet count > 400,000 - serum leukocyte alkaline phosphatase (LAP) > 100 - serum vitamin B12 > 900 pg/mL Radiology: - abdominal CT or ultrasound to evaluate splenomegaly, hepatosplenomegaly & rule out other conditions Complications: 1) most complications result from hyperviscosity of the blood a) cardiopulmonary system & CNS at greatest risk b) complications include [6] 1] arterial thromboembolism a] myocardial infarction b] stroke, TIA c] sudden cardiac death 2] venous thromboembolism a] deep vein thrombosis b] pulmonary embolism c] hepatic vein thrombosis (Budd-Chiari syndrome) 2) thrombotic & hemorrhagic complications are common especially during or after invasive procedures 3) 20% evolve into myelofibrosis - extramedullary hematopoiesis results in heptatosplenomegaly 4) 10% evolve into AML [3] Differential diagnosis: - secondary polycythemia a) hypoxemia (most common) - COPD - sleep apnea - congenital heart disease - intrapulmonary shunt - chronic mountain sickness b) volume contraction (diuretic use) c) ectopic or excessive erythropoietin - renal cell carcinoma, renal artery stenosis, other kidney disease - hepatocellular carcininoma - uterine fibroids - use of androgens - thrombosis d) high-affinity hemoglobin - age < 30 years - JAK2 negative - pruritus uncommon - essential thrombocythemia (diagnosis of exclusion) - thrombocythemia, blood hemoglobin & hematocrit normal [13] Management: 1) therapy indicated at diagnosis [3] 2) aspirin 81 mg [3]; ref [8] suggests 325 mg QD a) useful for erythromelalgia & cardiovascular risk reduction b) main problems in PRV are related to thrombocytosis & thrombosis c) high incidence of bleeding in aspirin-treated PRV patients d) high-dose aspirin is associated with bleeding [3] e) 100 mg QD may be safe & effective in patients without history of thrombosis 3) therapeutic phlebotomy a) initial: 200-500 mL of blood daily to a hematocrit of 40% or less [7] b) maintenance 200-500 mL of blood 3 times/week to maintainvhematocrit 40-45% [7]; < 45% [11] c) do not replenish iron stores, mild iron-deficiency inhibits erythropoiesis 4) platelet apheresis as indicated for thrombocytosis 5) chemotherapeutic agents (cytoreductive therapy) - decreases risk of thrombosis in high-risk patients (patients > 60 years or history of thromboembolism, stroke or myocardial infarction) [3] - hydroxyurea - busulfan - chlorambucil - radioactive phosphorus - increased incidence of leukemia with alkylating agents & P-32 6) interferon-alfa - ropeginterferon alfa-2b njft (Besremi) FDA-approved 7) anticoagulation for thrombotic complications - may increase the risk of bleeding 8) surgical procedures a) control both erythrocyte & platelet count b) urgent procedures: phlebotomy & plateletpheresis c) elective procedures: hydroxyurea (treatment until stable for 2 months) 9) prognosis - median survival 10 years - 70% of patients remain stable - 20% evolve into myelofibrosis - 10% evolve into AML [3]

Related

CD177 (polycythemia rubra vera protein 1, PRV-1, NB1 glycoprotein, NB1 GP, human neutrophil alloantigen 2a, HNA-2a, NB1, PRV1, UNQ595/PRO1181) criteria for diagnosis of polycythemia vera

General

chronic myeloproliferative disorder erythrocytosis polycythemia

Database Correlations

OMIM 263300

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 600-602
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 435-37
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 206
  5. Messinzy M and Pearson TC, ABC of clinical haematology. Polycythaemia, primary (essential) thrombocythaemia and myelofibrosis. BMJ 314:587, 1997 ID: 9055722 - Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
  6. Journal Watch 24(4):32, 2004 Landolfi R et al, Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 350:114, 2004 PMID: 14711910 - Spivak J, Daily aspirin--only half the answer. N Engl J Med 350:99, 2004 PMID: 14711906
  7. UpToDate 13.3 http://www.utdol.com
  8. Geriatrics at your Fingertips, 13th edition, 2011 Reuben DB et al (eds) American Geriatric Society
  9. Barbui T, Carobbio A, Rambaldi A, Finazzi G. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood. 2009 Jul 23;114(4):759-63. PMID: 19372254
  10. Siegel FP et al. Aquagenic pruritus in polycythemia vera: Characteristics and influence on quality of life in 441 patients. Am J Hematol 2013 Aug; 88:665 PMID: 23657863
  11. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  12. Tefferi A Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013 Jun;88(6):507-16 PMID: 23695894
  13. NEJM Knowledge+ Hematology