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  1. 1. PolycythemiaPolycythemia Victor Politi, M.D., FACPVictor Politi, M.D., FACP Medical Director, SVCMC, School ofMedical Director, SVCMC, School of Allied Health Professions, PhysicianAllied Health Professions, Physician Assistant ProgramAssistant Program
  2. 2. IntroductionIntroduction  Polycythemia vera is a chronicPolycythemia vera is a chronic myeloproliferative disorder characterizedmyeloproliferative disorder characterized by increased red blood cell mass (RCM),by increased red blood cell mass (RCM), or erythrocytosisor erythrocytosis  The resultant hyperviscosity of the bloodThe resultant hyperviscosity of the blood predisposes such patients to thrombosispredisposes such patients to thrombosis
  3. 3. IntroductionIntroduction  Increased RCM is accompanied byIncreased RCM is accompanied by increased white blood cell (myeloid) andincreased white blood cell (myeloid) and platelet (megakaryocytic) production,platelet (megakaryocytic) production, which is due to an abnormal clone of thewhich is due to an abnormal clone of the hematopoietic stem cells with increasedhematopoietic stem cells with increased sensitivity to the different growth factorssensitivity to the different growth factors for maturation.for maturation.
  4. 4.  Its etiology is not fully established, butIts etiology is not fully established, but hypersensitivity to interleukin-3 may play ahypersensitivity to interleukin-3 may play a role in the sustained erythrocytosisrole in the sustained erythrocytosis observed in this disease.observed in this disease. IntroductionIntroduction
  5. 5. IntroductionIntroduction  Polycythemia vera should be suspected inPolycythemia vera should be suspected in patients with elevated hemoglobin orpatients with elevated hemoglobin or hematocrit levels, splenomegaly, or portalhematocrit levels, splenomegaly, or portal venous thrombosis.venous thrombosis.
  6. 6. IntroductionIntroduction  Secondary causes of increased red bloodSecondary causes of increased red blood cell mass (e.g., heavy smoking, chroniccell mass (e.g., heavy smoking, chronic pulmonary disease, renal disease) arepulmonary disease, renal disease) are more common than polycythemia veramore common than polycythemia vera and must be excludedand must be excluded
  7. 7. IntroductionIntroduction  Patients may present with complaints of pruritusPatients may present with complaints of pruritus after bathing, burning pains in the distalafter bathing, burning pains in the distal extremities (erythromelalgia), gastrointestinalextremities (erythromelalgia), gastrointestinal disturbances, or nonspecific complaints such asdisturbances, or nonspecific complaints such as weakness, headaches, or dizziness.weakness, headaches, or dizziness.  Other patients are diagnosed after an incidentalOther patients are diagnosed after an incidental finding of an elevated hemoglobin and/orfinding of an elevated hemoglobin and/or hematocrit level on a complete blood count.hematocrit level on a complete blood count.
  8. 8. IntroductionIntroduction  Diagnosis is made using criteriaDiagnosis is made using criteria developed by the Polycythemia Veradeveloped by the Polycythemia Vera Study Group; major criteria includeStudy Group; major criteria include elevated red blood cell mass, normalelevated red blood cell mass, normal oxygen saturation, and palpableoxygen saturation, and palpable splenomegaly.splenomegaly.
  9. 9. IntroductionIntroduction  Untreated patients may survive for six toUntreated patients may survive for six to 18 months, whereas adequate treatment18 months, whereas adequate treatment may extend life expectancy to more thanmay extend life expectancy to more than 10 years.10 years.
  10. 10. IntroductionIntroduction  Treatment includes phlebotomy with theTreatment includes phlebotomy with the possible addition of myelosuppressivepossible addition of myelosuppressive agents based on a risk-stratified approach.agents based on a risk-stratified approach.  Agents under investigation includeAgents under investigation include interferon alfa-2b, anagrelide, and aspirin.interferon alfa-2b, anagrelide, and aspirin. Consultation with a hematologist isConsultation with a hematologist is recommended.recommended.
  11. 11. IntroductionIntroduction  Alternative Names:Alternative Names:  Primary polycythemiaPrimary polycythemia  Polycythemia rubra veraPolycythemia rubra vera  Myeloproliferative disorderMyeloproliferative disorder  ErythremiaErythremia  Splenomegalic polycythemiaSplenomegalic polycythemia  Vaquez's diseaseVaquez's disease  Osler's diseaseOsler's disease  Polycythemia with chronic cyanosisPolycythemia with chronic cyanosis  Myelopathic polycythemiaMyelopathic polycythemia  Erythrocytosis megalosplenicaErythrocytosis megalosplenica  Cryptogenic polycythemiaCryptogenic polycythemia
  12. 12. PathophysiologyPathophysiology  Normal stem cells are present in the boneNormal stem cells are present in the bone marrow of patients with PV.marrow of patients with PV.  Also present are abnormal clonal stemAlso present are abnormal clonal stem cells that interfere with or suppress normalcells that interfere with or suppress normal stem cell growth and maturation.stem cell growth and maturation.
  13. 13.  Evidence indicates that the etiology ofEvidence indicates that the etiology of panmyelosis is unregulated neoplasticpanmyelosis is unregulated neoplastic proliferation.proliferation.  The origin of the stem cell transformationThe origin of the stem cell transformation remains unknownremains unknown PathophysiologyPathophysiology
  14. 14. Polycythemia veraPolycythemia vera  Bone marrow film at 100X magnificationBone marrow film at 100X magnification demonstrating hypercellularity anddemonstrating hypercellularity and increased number of megakaryocytesincreased number of megakaryocytes
  15. 15. PathophysiologyPathophysiology  Thromboses and bleeding are frequent inThromboses and bleeding are frequent in persons with PV and myeloproliferativepersons with PV and myeloproliferative disease (MPD), and they result from thedisease (MPD), and they result from the disruption of hemostatic mechanismsdisruption of hemostatic mechanisms because ofbecause of an increased level of red blood cellsan increased level of red blood cells an elevation of the platelet countan elevation of the platelet count
  16. 16.  Tissue factor is also synthesized by bloodTissue factor is also synthesized by blood leukocytes, the level of which is increasedleukocytes, the level of which is increased in persons with MPD, which can contributein persons with MPD, which can contribute to thrombosis.to thrombosis. PathophysiologyPathophysiology
  17. 17.  Hyperhomocystinemia is a risk factor forHyperhomocystinemia is a risk factor for thrombosis and is also widely prevalent inthrombosis and is also widely prevalent in patients with MPD (35% in controls, 56%patients with MPD (35% in controls, 56% in persons with PV).in persons with PV). PathophysiologyPathophysiology
  18. 18.  Polycythemia vera is a rare diseasePolycythemia vera is a rare disease  The peak incidence of PV is age 50-70The peak incidence of PV is age 50-70 yearsyears However, it occurs in persons of all ageHowever, it occurs in persons of all age groups, including those in early adulthood andgroups, including those in early adulthood and childhood, albeit rarely.childhood, albeit rarely.  The disease is slightly more common inThe disease is slightly more common in males than in females.males than in females. StatisticsStatistics
  19. 19.  The disease usually develops slowlyThe disease usually develops slowly  Symptoms are often insidious in onsetSymptoms are often insidious in onset They are often related to blood hyperviscosityThey are often related to blood hyperviscosity secondary to a marked increase in the cellularsecondary to a marked increase in the cellular elements of blood, which impairselements of blood, which impairs microcirculation.microcirculation. HistoryHistory
  20. 20.  Symptoms are related to hyperviscosity,Symptoms are related to hyperviscosity, sludging of blood flow, and thromboses,sludging of blood flow, and thromboses, which lead to poor oxygen delivery andwhich lead to poor oxygen delivery and symptoms that include:symptoms that include: headache, dizziness, vertigo, tinnitus, visualheadache, dizziness, vertigo, tinnitus, visual disturbances, angina pectoris, or intermittentdisturbances, angina pectoris, or intermittent claudicationsclaudications HistoryHistory
  21. 21.  Bleeding complications ,, includeBleeding complications ,, include epistaxis, gum bleeding, ecchymoses, andepistaxis, gum bleeding, ecchymoses, and GI bleeding.GI bleeding.  Thrombotic complications ,, includeThrombotic complications ,, include venous thrombosis or thromboembolismvenous thrombosis or thromboembolism and an increased prevalence of strokeand an increased prevalence of stroke and other arterial thromboses.and other arterial thromboses. HistoryHistory
  22. 22.  Abdominal pain due to peptic ulcerAbdominal pain due to peptic ulcer disease is present because PV isdisease is present because PV is associated with increased histamine levelsassociated with increased histamine levels and gastric acidity or possible Budd-Chiariand gastric acidity or possible Budd-Chiari syndrome (hepatic portal vein thrombosis)syndrome (hepatic portal vein thrombosis) or mesenteric vein thrombosis.or mesenteric vein thrombosis. HistoryHistory
  23. 23.  Splenomegaly, when present, can causeSplenomegaly, when present, can cause early satiety because ofearly satiety because of gastric filling being impaired by the enlargedgastric filling being impaired by the enlarged spleen or, rarely, symptoms of splenicspleen or, rarely, symptoms of splenic infarction.infarction.  Weight loss may result from early satietyWeight loss may result from early satiety or from the increased myeloproliferativeor from the increased myeloproliferative activity of the abnormal clone.activity of the abnormal clone. HistoryHistory
  24. 24.  Pruritus results from increased histaminePruritus results from increased histamine levels released from increased basophilslevels released from increased basophils and mast cells and can be exacerbated byand mast cells and can be exacerbated by a warm bath or shower.a warm bath or shower.  This occurs in up to 40% of patients.This occurs in up to 40% of patients. HistoryHistory
  25. 25.  The following symptoms are due to theThe following symptoms are due to the manifestations of myeloproliferativemanifestations of myeloproliferative disorders with extramedullarydisorders with extramedullary hematopoiesis:hematopoiesis: Splenomegaly - Present in 75% of patients atSplenomegaly - Present in 75% of patients at the time of diagnosisthe time of diagnosis Hepatomegaly - Present in approximatelyHepatomegaly - Present in approximately 30% of patients with PV30% of patients with PV PhysicalPhysical
  26. 26.  Hypertension is common in patients withHypertension is common in patients with PV. The red blood cell mass shouldPV. The red blood cell mass should differentiate PV from Gaisbock syndrome,differentiate PV from Gaisbock syndrome, which is hypertension andwhich is hypertension and pseudopolycythemia (ie, high hemoglobinpseudopolycythemia (ie, high hemoglobin levels due to low plasma volume).levels due to low plasma volume). PhysicalPhysical
  27. 27.  Polycythemia is characterized byPolycythemia is characterized by increased cell counts in all cell lines in theincreased cell counts in all cell lines in the myeloid series (ie, red blood cells, whitemyeloid series (ie, red blood cells, white blood cells [preferentially granulocytes],blood cells [preferentially granulocytes], and platelets).and platelets). PhysicalPhysical
  28. 28.  However, if red blood cell levels are increased,However, if red blood cell levels are increased, several conditions must be excluded, including:several conditions must be excluded, including:  conditions that increase red blood cells secondary toconditions that increase red blood cells secondary to systemic hypoxic conditions or an artificial conditionsystemic hypoxic conditions or an artificial condition stimulating Epo secretion in the kidneysstimulating Epo secretion in the kidneys  granulocytosis from infections or mobilization bygranulocytosis from infections or mobilization by secondary causes, as in leukemoid reactionssecondary causes, as in leukemoid reactions  thrombocytosis from bleeding and iron deficiency.thrombocytosis from bleeding and iron deficiency. PhysicalPhysical
  29. 29. Secondary Causes of IncreasedSecondary Causes of Increased Red Cell Mass (Erythrocytosis)Red Cell Mass (Erythrocytosis)  Chronic pulmonary or cardiac diseaseChronic pulmonary or cardiac disease  Decreased 2,3-diphosphoglycerateDecreased 2,3-diphosphoglycerate  High oxygen affinity hemoglobinopathyHigh oxygen affinity hemoglobinopathy  Increased carboxyhemoglobin (in smokers) andIncreased carboxyhemoglobin (in smokers) and methemoglobinmethemoglobin  Residence at high altitudeResidence at high altitude  Adrenal cortical hypersecretionAdrenal cortical hypersecretion  HydronephrosisHydronephrosis  Tumors producing erythropoietin or anabolic steroidsTumors producing erythropoietin or anabolic steroids  Relative (stress)Relative (stress)  Disorders associated with decreased plasma volumeDisorders associated with decreased plasma volume (e.g., diarrhea, emesis, renal diseases)(e.g., diarrhea, emesis, renal diseases)
  30. 30. DiagnosisDiagnosis  PV should be suspected when hemoglobinPV should be suspected when hemoglobin and/or hematocrit levels are elevatedand/or hematocrit levels are elevated (> than 18 g per dL [180 g per L] in white men(> than 18 g per dL [180 g per L] in white men and > than 16 g per dL [160 g per L] in blacksand > than 16 g per dL [160 g per L] in blacks and women)and women)  hematocrit level greater than 52 percenthematocrit level greater than 52 percent (0.52) in white men and 47 percent (0.47)(0.52) in white men and 47 percent (0.47) in blacks and womenin blacks and women
  31. 31. DiagnosisDiagnosis  PV also should be suspected in patientsPV also should be suspected in patients with portal venous thrombosis andwith portal venous thrombosis and splenomegaly with or withoutsplenomegaly with or without thrombocytosis and leukocytosis.thrombocytosis and leukocytosis.
  32. 32. Diagnosis:Diagnosis: Other Signs and Symptoms ofOther Signs and Symptoms of Polycythemia VeraPolycythemia Vera  More CommonMore Common  Hematocrit level >52 percentHematocrit level >52 percent (0.52) in white men, >47(0.52) in white men, >47 percent (0.47) in blacks andpercent (0.47) in blacks and womenwomen  Hemoglobin level >18 g per dLHemoglobin level >18 g per dL (180 g per L) in white men,(180 g per L) in white men, >16 g per dL (160 g per L) in>16 g per dL (160 g per L) in blacks and women)blacks and women)  PlethoraPlethora  Pruritus after bathingPruritus after bathing  SplenomegalySplenomegaly  Weight lossWeight loss  WeaknessWeakness  SweatingSweating  Less CommonLess Common  Bruising/epistaxisBruising/epistaxis  Budd-Chiari syndromeBudd-Chiari syndrome  ErythromelalgiaErythromelalgia  GoutGout  Hemorrhagic eventsHemorrhagic events  HepatomegalyHepatomegaly  Ischemic digitsIschemic digits  Thrombotic eventsThrombotic events  Transient neurologicTransient neurologic complaints (headache, tinnitus,complaints (headache, tinnitus, dizziness, blurred vision,dizziness, blurred vision, paresthesias)paresthesias)  Atypical chest painAtypical chest pain
  33. 33.  In making the diagnosis of PV, once aIn making the diagnosis of PV, once a secondary cause is ruled out, thesecondary cause is ruled out, the diagnosis of PV is made using adiagnosis of PV is made using a combination of major and minor criteriacombination of major and minor criteria defined by the Polycythemia Vera Studydefined by the Polycythemia Vera Study Group (PVSG).Group (PVSG).  Although new diagnostic modalities haveAlthough new diagnostic modalities have been developed, these criteria remain thebeen developed, these criteria remain the standard method to diagnose PVstandard method to diagnose PV DiagnosisDiagnosis
  34. 34.  A diagnosis of polycythemia vera is made when a patent fulfillsA diagnosis of polycythemia vera is made when a patent fulfills  all three of the major criteriaall three of the major criteria  OrOr  any two major and any two minor criteriaany two major and any two minor criteria  Major CriteriaMajor Criteria  total RBC voltotal RBC vol  Men > or = to 36 mL/kgMen > or = to 36 mL/kg  Women > or = to 32 mL/kgWomen > or = to 32 mL/kg  arterial 02 saturation > or = to 92%arterial 02 saturation > or = to 92%  SplenomegalySplenomegaly  Minor CriteriaMinor Criteria  Thrombocytosis with platelet count > 400,000/mLThrombocytosis with platelet count > 400,000/mL  Leukocytosis with WBC > 12,000/mLLeukocytosis with WBC > 12,000/mL  Increased leukocyte alkaline phosphatase LAP > 100U/L (no infection)Increased leukocyte alkaline phosphatase LAP > 100U/L (no infection)  Serum B12 > 900 pg/mL or binding capacity UB12 BC > 2200 pg/mLSerum B12 > 900 pg/mL or binding capacity UB12 BC > 2200 pg/mL
  35. 35. Serum Epo assaySerum Epo assay  Epo levels in patients with PV are oftenEpo levels in patients with PV are often below the lower limit of normal comparedbelow the lower limit of normal compared with patients with secondarywith patients with secondary erythrocytosis and pseudoerythrocytosiserythrocytosis and pseudoerythrocytosis but the levels for PV and secondarybut the levels for PV and secondary erythrocytosis or pseudoerythrocytosiserythrocytosis or pseudoerythrocytosis overlap and are nonspecific for differentiatingoverlap and are nonspecific for differentiating these conditions.these conditions.
  36. 36. Bone marrow morphology andBone marrow morphology and histologyhistology  Overall hypercellularity with expansion of all cellOverall hypercellularity with expansion of all cell lines with megakaryocytic proliferation and thelines with megakaryocytic proliferation and the presence of myelofibrosis can help diagnose PVpresence of myelofibrosis can help diagnose PV and MPDand MPD  PV patients may have normal bone marrowPV patients may have normal bone marrow findingsfindings  These results are nonspecific and may beThese results are nonspecific and may be observed in the other Philadelphiaobserved in the other Philadelphia chromosome–negative MPDs.chromosome–negative MPDs.
  37. 37. Bone marrow findings forBone marrow findings for Polycythemia vera includePolycythemia vera include  Moderate to marked hypercellularityModerate to marked hypercellularity  trilineage hyperplasiatrilineage hyperplasia  megakaryocytes increased;megakaryocytes increased; hyperlobulatedhyperlobulated  dilated sinusoids with intravasculardilated sinusoids with intravascular hematopoiesishematopoiesis  decreased or absent iron storesdecreased or absent iron stores  increased reticulin (only in a minority ofincreased reticulin (only in a minority of patients)patients)
  38. 38. LabsLabs  Peripheral blood findingsPeripheral blood findings Increased hemoglobin & hematocritIncreased hemoglobin & hematocrit Normal red blood cell morphology, unless ironNormal red blood cell morphology, unless iron deficient or spent phasedeficient or spent phase Normoblasts may be presentNormoblasts may be present Mild to moderate leukocytosisMild to moderate leukocytosis Mild neutrophilia and/or basophiliaMild neutrophilia and/or basophilia ThrombocytosisThrombocytosis
  39. 39.  This disease may also alter the results of theThis disease may also alter the results of the following tests:following tests:  Lactate dehydrogenaseLactate dehydrogenase  u/au/a  Serum uric acidSerum uric acid  T- wbcT- wbc  RBC countRBC count  Platelet aggregation testPlatelet aggregation test  Leukocyte alkaline phosphataseLeukocyte alkaline phosphatase  HemoglobinHemoglobin  ESRESR  ErythropoietinErythropoietin LabsLabs
  40. 40.  Automated red blood cell counts and hematocrit valuesAutomated red blood cell counts and hematocrit values (including hemoglobin levels) may be deceptive with(including hemoglobin levels) may be deceptive with regard to the total red blood cell mass.regard to the total red blood cell mass.  Direct measurement of the red blood cell mass shouldDirect measurement of the red blood cell mass should show an increase with a normal or slightly decreasedshow an increase with a normal or slightly decreased plasma volume.plasma volume.  This is a nuclear medicine test that uses radiochromium-labeledThis is a nuclear medicine test that uses radiochromium-labeled red blood cells to measure actual red blood cell and plasmared blood cells to measure actual red blood cell and plasma volume.volume.  However, patients with hemoglobin concentrations of atHowever, patients with hemoglobin concentrations of at least 20 g/dL or hematocrit values of at least 60% inleast 20 g/dL or hematocrit values of at least 60% in males and 56% in females always have an elevated redmales and 56% in females always have an elevated red blood cell mass.blood cell mass. LabsLabs
  41. 41.  The red blood cells in patients with PV areThe red blood cells in patients with PV are usually normochromic normocytic unlessusually normochromic normocytic unless the patient has been bleeding fromthe patient has been bleeding from underlying peptic ulcer disease orunderlying peptic ulcer disease or phlebotomy treatment (wherein the cellsphlebotomy treatment (wherein the cells may be hypochromic and microcytic,may be hypochromic and microcytic, reflecting low iron stores).reflecting low iron stores). LabsLabs
  42. 42.  An elevated white blood cell count (>12,000/µL)An elevated white blood cell count (>12,000/µL) occurs in approximately 60% of patients. It isoccurs in approximately 60% of patients. It is mainly composed of neutrophils with a left shiftmainly composed of neutrophils with a left shift and a few immature cells.and a few immature cells.  Mild basophilia occurs in 60% of patients.Mild basophilia occurs in 60% of patients.  The leukocyte alkaline phosphatase score is elevatedThe leukocyte alkaline phosphatase score is elevated (>100 U/L) in 70% of patients.(>100 U/L) in 70% of patients.  This technique is only semiquantitative and isThis technique is only semiquantitative and is susceptible to laboratory errors unless it can besusceptible to laboratory errors unless it can be performed by flow cytometry, which is not routinelyperformed by flow cytometry, which is not routinely availableavailable LabsLabs
  43. 43.  The platelet count is elevated to 400,000-The platelet count is elevated to 400,000- 800,000/mL in approximately 50% of800,000/mL in approximately 50% of patients.patients. LabsLabs
  44. 44.  The release of potassium into the serumThe release of potassium into the serum caused by the increased number ofcaused by the increased number of platelets during in vitro coagulation mayplatelets during in vitro coagulation may cause a pseudohyperkalemia in thecause a pseudohyperkalemia in the serum, while the true plasma potassiumserum, while the true plasma potassium level in vivo is actually within the referencelevel in vivo is actually within the reference range, as shown by measuring plasmarange, as shown by measuring plasma levels and the lack of ECG changes.levels and the lack of ECG changes. LabsLabs
  45. 45.  Abnormal platelet function (as measuredAbnormal platelet function (as measured by platelet aggregation tests withby platelet aggregation tests with epinephrine, adenosine diphosphate, orepinephrine, adenosine diphosphate, or collagen) may be demonstrated, butcollagen) may be demonstrated, but bleeding time may be normal.bleeding time may be normal.  Some patients' platelet-rich plasmaSome patients' platelet-rich plasma aggregates spontaneously without theaggregates spontaneously without the addition of any of the above substances.addition of any of the above substances.  This indicates a propensity for thrombosesThis indicates a propensity for thromboses LabsLabs
  46. 46.  Bone marrow studies are not necessary toBone marrow studies are not necessary to establish the diagnosis but the findings of:establish the diagnosis but the findings of: hypercellularityhypercellularity hyperplasia of the erythroid, granulocytic andhyperplasia of the erythroid, granulocytic and megakaryocytic cell linesmegakaryocytic cell lines myelofibrosismyelofibrosis  support the diagnosis of asupport the diagnosis of a myeloproliferative process.myeloproliferative process. LabsLabs
  47. 47.  Iron stores are decreased or absentIron stores are decreased or absent because of the increased red blood cellbecause of the increased red blood cell mass, and macrophages may be maskedmass, and macrophages may be masked in the myeloid hyperplasia that is present.in the myeloid hyperplasia that is present. LabsLabs
  48. 48.  Fibrosis is increased and detected earlyFibrosis is increased and detected early by silver stains for reticulinby silver stains for reticulin LabsLabs
  49. 49.  Cytogenetics of the bone marrow cellsCytogenetics of the bone marrow cells show a clonal abnormality inshow a clonal abnormality in 30% of patients who are not treated and in30% of patients who are not treated and in 50% of patients who are treated with50% of patients who are treated with alkylating or myelosuppressive agents.alkylating or myelosuppressive agents. These chromosomal abnormalities includeThese chromosomal abnormalities include deletions of the long arm of chromosome 5 or 20deletions of the long arm of chromosome 5 or 20 (5q-, 20q-) and trisomy 8 (+8) or 9 (+9).(5q-, 20q-) and trisomy 8 (+8) or 9 (+9). Leukemic transformation is usually associated withLeukemic transformation is usually associated with multiple or complex abnormalities.multiple or complex abnormalities. LabsLabs
  50. 50.  Hyperuricemia occurs in 40% of patientsHyperuricemia occurs in 40% of patients and reflects the high turnover rate of boneand reflects the high turnover rate of bone marrow cells releasing DNA metabolites.marrow cells releasing DNA metabolites. LabsLabs
  51. 51. Imaging StudiesImaging Studies  An enlarged spleen is often palpable andAn enlarged spleen is often palpable and does not require any imaging studies.does not require any imaging studies.  In some patients with posteriorly enlargedIn some patients with posteriorly enlarged spleens or in those who are obese,spleens or in those who are obese, ultrasonography or CT scanning may beultrasonography or CT scanning may be able to detect an enlargement missedable to detect an enlargement missed during the physical examination.during the physical examination.
  52. 52. Other TestsOther Tests  The serum Epo level should be decreasedThe serum Epo level should be decreased in nearly all patients with PV and no recentin nearly all patients with PV and no recent hemorrhage.hemorrhage.  This distinguishes polycythemia fromThis distinguishes polycythemia from secondary causes of polycythemia insecondary causes of polycythemia in which the serum Epo level is generallywhich the serum Epo level is generally within the reference range or is elevated.within the reference range or is elevated. Each lab has its own reference range forEach lab has its own reference range for serum Epo levelserum Epo level
  53. 53. TreatmentTreatment  The objective of treatment is to reduce theThe objective of treatment is to reduce the high blood viscosity (thickness of thehigh blood viscosity (thickness of the blood) due to the increased red blood cellblood) due to the increased red blood cell mass and to prevent hemorrhage andmass and to prevent hemorrhage and thrombosis.thrombosis.  No single treatment is available for PV.No single treatment is available for PV.  Thrombosis accounts for the majority ofThrombosis accounts for the majority of morbidity and mortality. The major goal ofmorbidity and mortality. The major goal of treatment is to prevent thrombotic events.treatment is to prevent thrombotic events.
  54. 54.  Examples of thrombotic events includeExamples of thrombotic events include arterial and venous thrombosis,arterial and venous thrombosis, cerebrovascular accident, deep venouscerebrovascular accident, deep venous thrombosis, myocardial infarction,thrombosis, myocardial infarction, peripheral arterial occlusion, andperipheral arterial occlusion, and pulmonary infarctpulmonary infarct TreatmentTreatment
  55. 55. TreatmentTreatment  The mainstay of treatment for PV isThe mainstay of treatment for PV is phlebotomy, which is aimed at reducingphlebotomy, which is aimed at reducing hyperviscosity by decreasing the venoushyperviscosity by decreasing the venous hematocrit level to less than 45 percenthematocrit level to less than 45 percent (0.45) in white men and 42 percent (0.42)(0.45) in white men and 42 percent (0.42) in blacks and women.in blacks and women.  The PVSG reported the best medianThe PVSG reported the best median survival, 12.6 years, for this type ofsurvival, 12.6 years, for this type of treatment.treatment.
  56. 56.  Phlebotomy is a simple procedure withoutPhlebotomy is a simple procedure without many risks, except for the eventualmany risks, except for the eventual development of iron deficiencydevelopment of iron deficiency
  57. 57. TreatmentTreatment  Patients with hematocrit values of lessPatients with hematocrit values of less than 70% may be bled twice a week tothan 70% may be bled twice a week to reduce the hematocrit to the range ofreduce the hematocrit to the range of 40%.40%.  Patients with severe plethora who havePatients with severe plethora who have altered mentation or associated vascularaltered mentation or associated vascular compromise can be bled more vigorously,compromise can be bled more vigorously, with daily removal of 500 mL of wholewith daily removal of 500 mL of whole bloodblood
  58. 58.  Elderly patients with some cardiovascularElderly patients with some cardiovascular compromise or cerebral vascularcompromise or cerebral vascular complications should have the volumecomplications should have the volume replaced with saline solution after eachreplaced with saline solution after each procedure to avoid postural hypotensionprocedure to avoid postural hypotension TreatmentTreatment
  59. 59.  Because phlebotomy is the most efficientBecause phlebotomy is the most efficient method of lowering the hemoglobin andmethod of lowering the hemoglobin and hematocrit levels to the reference range, all newhematocrit levels to the reference range, all new patients are initially phlebotomized to decreasepatients are initially phlebotomized to decrease the risk of complications.the risk of complications.  The presence of elevated platelet counts thatThe presence of elevated platelet counts that may be exacerbated by the phlebotomy is anmay be exacerbated by the phlebotomy is an indication to use myelosuppressive agents toindication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complicationsavoid thrombotic or hemorrhagic complications TreatmentTreatment
  60. 60.  Once the patient's hemoglobin andOnce the patient's hemoglobin and hematocrit values are reduced to withinhematocrit values are reduced to within the reference range (ie, <45%), implementthe reference range (ie, <45%), implement a maintenance program either by inducinga maintenance program either by inducing iron deficiency by continuousiron deficiency by continuous phlebotomies (frequency of the procedurephlebotomies (frequency of the procedure depends on the rate of reaccumulation ofdepends on the rate of reaccumulation of red blood cells) or using ared blood cells) or using a myelosuppressive agent.myelosuppressive agent. TreatmentTreatment
  61. 61. TreatmentTreatment  The use of myelosuppressive agents such as radioactiveThe use of myelosuppressive agents such as radioactive phosphorus (32P), chlorambucil (Leukeran), busulfanphosphorus (32P), chlorambucil (Leukeran), busulfan (Myleran), pipobroman (Vercyte), and hydroxyurea(Myleran), pipobroman (Vercyte), and hydroxyurea (Hydrea) in conjunction with phlebotomy has been(Hydrea) in conjunction with phlebotomy has been studied.studied.  Chlorambucil, busulfan, and pipobroman, all alkylatingChlorambucil, busulfan, and pipobroman, all alkylating agents, have fallen out of favor because of concernsagents, have fallen out of favor because of concerns about rates of iatrogenic leukemia.about rates of iatrogenic leukemia.  The agent 32P remains in use with supplementalThe agent 32P remains in use with supplemental phlebotomy and has a reported median survival similarphlebotomy and has a reported median survival similar to that of phlebotomy alone-10.9 years according toto that of phlebotomy alone-10.9 years according to PVSG data.PVSG data.
  62. 62.  In patients treated with chlorambucil andIn patients treated with chlorambucil and 32P the PVSG demonstrated a decreased32P the PVSG demonstrated a decreased survival rate and increased mortality ratesurvival rate and increased mortality rate from acute leukemia in the first 5 years,from acute leukemia in the first 5 years, and a total of 17% of patients hadand a total of 17% of patients had leukemia after 15 years with.leukemia after 15 years with. TreatmentTreatment
  63. 63.  Hydroxyurea has been the mainstayHydroxyurea has been the mainstay therapy for PV after the PVSG resultstherapy for PV after the PVSG results indicated it is an effective agent forindicated it is an effective agent for myelosuppression; however, concernsmyelosuppression; however, concerns have been raised regarding long-termhave been raised regarding long-term risks for leukemic transformation.risks for leukemic transformation.  In the PVSG trial, HU therapy reduced theIn the PVSG trial, HU therapy reduced the risk of thrombosis compared withrisk of thrombosis compared with phlebotomy alonephlebotomy alone TreatmentTreatment
  64. 64. TreatmentTreatment  Recombinant interferon alfa-2b reducesRecombinant interferon alfa-2b reduces myeloproliferation and splenomegaly, and alleviates themyeloproliferation and splenomegaly, and alleviates the symptom of pruritus.symptom of pruritus.  It has no established mutagenic potential, and thus mayIt has no established mutagenic potential, and thus may prove a valuable option for younger patients and thoseprove a valuable option for younger patients and those with significant splenomegaly.with significant splenomegaly.  A small case series of 11 patients found that the patients'A small case series of 11 patients found that the patients' red cell indices could be normalized over six to 12red cell indices could be normalized over six to 12 months with interferon therapy alone, and withoutmonths with interferon therapy alone, and without evidence of thrombosis.evidence of thrombosis.  However, many patients discontinue interferon becauseHowever, many patients discontinue interferon because of side effects, and high cost of treatment.of side effects, and high cost of treatment.
  65. 65. TreatmentTreatment  splenectomy in patients with painfulsplenectomy in patients with painful splenomegaly or repeated episodes ofsplenomegaly or repeated episodes of thrombosis causing splenic infarctionthrombosis causing splenic infarction
  66. 66. TreatmentTreatment  Occasionally, chemotherapy may be givenOccasionally, chemotherapy may be given to suppress the bone marrow.to suppress the bone marrow.  The use of anti-platelet therapy (such asThe use of anti-platelet therapy (such as aspirin) is controversial because it mayaspirin) is controversial because it may cause gastric bleeding.cause gastric bleeding.  Allopurinol is given for hyperuricemiaAllopurinol is given for hyperuricemia (gout).(gout).
  67. 67. TreatmentTreatment  A risk-stratified approach to the management ofA risk-stratified approach to the management of PV is currently recommendedPV is currently recommended  Patients treated with phlebotomy alone benefitPatients treated with phlebotomy alone benefit from low rates of malignancy but experiencefrom low rates of malignancy but experience more thrombosis events during the first fewmore thrombosis events during the first few years of treatment.years of treatment.  Patients treated with myelosuppressive agentsPatients treated with myelosuppressive agents and supplemental phlebotomy avoid this earlyand supplemental phlebotomy avoid this early thrombotic risk but in turn have significant ratesthrombotic risk but in turn have significant rates of malignant transformation after about six yearsof malignant transformation after about six years of therapyof therapy
  68. 68.  High-risk patientsHigh-risk patients  those 60 years or olderthose 60 years or older  or those with a history of thrombosisor those with a history of thrombosis  A myelosuppressive agent with supplementalA myelosuppressive agent with supplemental phlebotomy is reasonable in this groupphlebotomy is reasonable in this group  This group's generally shorter life expectancy lessensThis group's generally shorter life expectancy lessens the threat of eventual iatrogenic malignancy.the threat of eventual iatrogenic malignancy.  Patients in this group stand to gain from the benefit ofPatients in this group stand to gain from the benefit of lower early thrombosis rates with myelosuppressivelower early thrombosis rates with myelosuppressive medications.medications. TreatmentTreatment
  69. 69.  Indeterminate riskIndeterminate risk < than age 60 and have no history of< than age 60 and have no history of thrombocytosis, but do have cardiovascular orthrombocytosis, but do have cardiovascular or other risk factorsother risk factors  Therapy in this group should beTherapy in this group should be individualized, possibly with the addition ofindividualized, possibly with the addition of agents acting on platelet function oragents acting on platelet function or number.number. TreatmentTreatment
  70. 70.  low risklow risk < than 60 years and have no thrombosis-< than 60 years and have no thrombosis- related risk factorsrelated risk factors  Phlebotomy alone may be the treatment ofPhlebotomy alone may be the treatment of choice with the goal of reducing thechoice with the goal of reducing the hematocrit level to less than 45 percenthematocrit level to less than 45 percent (0.45) or lower based on gender and race(0.45) or lower based on gender and race TreatmentTreatment
  71. 71.  Consultation with a hematologist isConsultation with a hematologist is recommended to apply such strategies,recommended to apply such strategies, and newer agents may be tailored toand newer agents may be tailored to patients on an individualized basis.patients on an individualized basis. TreatmentTreatment
  72. 72. PrognosisPrognosis  Polycythemia vera usually developsPolycythemia vera usually develops slowly, and most patients treatedslowly, and most patients treated appropriately do not experience anyappropriately do not experience any problems related to the disease.problems related to the disease.  However, the abnormal bone marrow cellsHowever, the abnormal bone marrow cells may begin to grow uncontrollably leadingmay begin to grow uncontrollably leading to acute myelogenous leukemia.to acute myelogenous leukemia.
  73. 73. PrognosisPrognosis  Patients with polycythemia vera also havePatients with polycythemia vera also have an increased tendency to form blood clotsan increased tendency to form blood clots that can result in strokes or heart attacks.that can result in strokes or heart attacks.  Some patients may experience abnormalSome patients may experience abnormal bleeding because their platelets arebleeding because their platelets are abnormal.abnormal.
  74. 74. PrognosisPrognosis  PV is a chronic disease, and its naturalPV is a chronic disease, and its natural history of 1.5-3 years of median survival inhistory of 1.5-3 years of median survival in the absence of therapy has beenthe absence of therapy has been extended to at least 10-20 years becauseextended to at least 10-20 years because of new therapeutic tools.of new therapeutic tools.
  75. 75.  The major causes of morbidity andThe major causes of morbidity and mortality are as follows:mortality are as follows: ThrombosisThrombosis Hemorrhagic complicationsHemorrhagic complications Peptic ulcer diseasePeptic ulcer disease Myelofibrosis and pancytopeniaMyelofibrosis and pancytopenia Acute leukemia or a myelodysplasticAcute leukemia or a myelodysplastic syndromesyndrome PrognosisPrognosis
  76. 76. ThrombosisThrombosis  reported in 15-60% of patientsreported in 15-60% of patients  major cause of death in 10-40% ofmajor cause of death in 10-40% of patientspatients  Venous and arterial thromboses haveVenous and arterial thromboses have resulted in pulmonary emboli, renal failureresulted in pulmonary emboli, renal failure from renal vein or artery thrombosis,from renal vein or artery thrombosis, intestinal ischemia from mesenteric veinintestinal ischemia from mesenteric vein thromboses, or peripheral arterial emboli.thromboses, or peripheral arterial emboli.
  77. 77. Hemorrhagic complicationsHemorrhagic complications  occur in 15-35% of patientsoccur in 15-35% of patients  lead to death in 6-30% of these patientslead to death in 6-30% of these patients  Bleeding is usually the consequence ofBleeding is usually the consequence of vascular compromise resulting fromvascular compromise resulting from ischemic changes from thrombosis orischemic changes from thrombosis or hyperviscosity.hyperviscosity.
  78. 78. Peptic ulcer diseasePeptic ulcer disease  Associated with PV at a 3 to 5 fold higherAssociated with PV at a 3 to 5 fold higher rate than that of the general populationrate than that of the general population  This has been attributed to increasedThis has been attributed to increased histamine serum levelshistamine serum levels
  79. 79. Myelofibrosis and pancytopeniaMyelofibrosis and pancytopenia  Occur in 3-10% of patients, usually late inOccur in 3-10% of patients, usually late in the diseasethe disease  In these patients, infections and bleedingIn these patients, infections and bleeding complications may be the most seriouscomplications may be the most serious health threatshealth threats  red blood cell transfusions may bered blood cell transfusions may be required to maintain adequate red bloodrequired to maintain adequate red blood cell counts and to improve fatigue andcell counts and to improve fatigue and other anemia-related symptoms.other anemia-related symptoms.
  80. 80. Acute leukemia or aAcute leukemia or a myelodysplastic syndromemyelodysplastic syndrome  Develops in 1.5% of patients treated withDevelops in 1.5% of patients treated with phlebotomy alonephlebotomy alone  The transformation risksThe transformation risks  increase to 13.5% within 5 years with treatment usingincrease to 13.5% within 5 years with treatment using chlorambucilchlorambucil  And 10.2% within 6-10 years in patients treated withAnd 10.2% within 6-10 years in patients treated with 32P32P  At 15 years, the transformation risk for HU isAt 15 years, the transformation risk for HU is 5.9%, which, although not statistically significant,5.9%, which, although not statistically significant, is a worrisome trendis a worrisome trend
  81. 81.  QuestionsQuestions

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