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PolycythemiaPolycythemia

Victor Politi, M.D., FACPVictor Politi, M.D., FACPMedical Director, SVCMC, School of Medical Director, SVCMC, School of Allied Health Professions, Physician Allied Health Professions, Physician

Assistant ProgramAssistant Program

IntroductionIntroduction

Polycythemia vera is a chronic Polycythemia vera is a chronic myeloproliferative disorder characterized myeloproliferative disorder characterized by increased red blood cell mass (RCM), by increased red blood cell mass (RCM), or erythrocytosis or erythrocytosis

The resultant hyperviscosity of the blood The resultant hyperviscosity of the blood predisposes such patients to thrombosis predisposes such patients to thrombosis


Increased RCM is accompanied by Increased RCM is accompanied by increased white blood cell (myeloid) and increased white blood cell (myeloid) and platelet (megakaryocytic) production, platelet (megakaryocytic) production, which is due to an abnormal clone of the which is due to an abnormal clone of the hematopoietic stem cells with increased hematopoietic stem cells with increased sensitivity to the different growth factors sensitivity to the different growth factors for maturation. for maturation.

Its etiology is not fully established, but Its etiology is not fully established, but hypersensitivity to interleukin-3 may play a hypersensitivity to interleukin-3 may play a role in the sustained erythrocytosis role in the sustained erythrocytosis observed in this disease. observed in this disease.



Polycythemia vera should be suspected in Polycythemia vera should be suspected in patients with elevated hemoglobin or patients with elevated hemoglobin or hematocrit levels, splenomegaly, or portal hematocrit levels, splenomegaly, or portal venous thrombosis. venous thrombosis.


Secondary causes of increased red blood Secondary causes of increased red blood cell mass (e.g., heavy smoking, chronic cell mass (e.g., heavy smoking, chronic pulmonary disease, renal disease) are pulmonary disease, renal disease) are more common than polycythemia vera and more common than polycythemia vera and must be excluded must be excluded


Patients may present with complaints of pruritus Patients may present with complaints of pruritus after bathing, burning pains in the distal after bathing, burning pains in the distal extremities (erythromelalgia), gastrointestinal extremities (erythromelalgia), gastrointestinal disturbances, or nonspecific complaints such as disturbances, or nonspecific complaints such as weakness, headaches, or dizziness. weakness, headaches, or dizziness.

Other patients are diagnosed after an incidental Other patients are diagnosed after an incidental finding of an elevated hemoglobin and/or finding of an elevated hemoglobin and/or hematocrit level on a complete blood count. hematocrit level on a complete blood count.


Diagnosis is made using criteria Diagnosis is made using criteria developed by the Polycythemia Vera developed by the Polycythemia Vera Study Group; major criteria include Study Group; major criteria include elevated red blood cell mass, normal elevated red blood cell mass, normal oxygen saturation, and palpable oxygen saturation, and palpable splenomegaly. splenomegaly.


Untreated patients may survive for six to Untreated patients may survive for six to 18 months, whereas adequate treatment 18 months, whereas adequate treatment may extend life expectancy to more than may extend life expectancy to more than 10 years. 10 years.


Treatment includes phlebotomy with the Treatment includes phlebotomy with the possible addition of myelosuppressive possible addition of myelosuppressive agents based on a risk-stratified approach. agents based on a risk-stratified approach.

Agents under investigation include Agents under investigation include interferon alfa-2b, anagrelide, and aspirin. interferon alfa-2b, anagrelide, and aspirin. Consultation with a hematologist is Consultation with a hematologist is recommended.recommended.

IntroductionIntroduction Alternative Names:Alternative Names:

Primary polycythemia Primary 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 polycythemia Cryptogenic polycythemia

PathophysiologyPathophysiology

Normal stem cells are present in the bone Normal stem cells are present in the bone marrow of patients with PV. marrow of patients with PV.

Also present are abnormal clonal stem Also present are abnormal clonal stem cells that interfere with or suppress normal cells that interfere with or suppress normal stem cell growth and maturation. stem cell growth and maturation.

Evidence indicates that the etiology of Evidence indicates that the etiology of panmyelosis is unregulated neoplastic panmyelosis is unregulated neoplastic proliferation. proliferation.

The origin of the stem cell transformation The origin of the stem cell transformation remains unknownremains unknown


Polycythemia veraPolycythemia vera

Bone marrow film at 100X magnification Bone marrow film at 100X magnification demonstrating hypercellularity and demonstrating hypercellularity and increased number of megakaryocytes increased number of megakaryocytes


Thromboses and bleeding are frequent in Thromboses and bleeding are frequent in persons with PV and myeloproliferative persons with PV and myeloproliferative disease (MPD), and they result from the disease (MPD), and they result from the disruption of hemostatic mechanisms disruption of hemostatic mechanisms because of because of an increased level of red blood cells an increased level of red blood cells an elevation of the platelet countan elevation of the platelet count

Tissue factor is also synthesized by blood Tissue factor is also synthesized by blood leukocytes, the level of which is increased leukocytes, the level of which is increased in persons with MPD, which can contribute in persons with MPD, which can contribute to thrombosis. to thrombosis.


Hyperhomocystinemia is a risk factor for Hyperhomocystinemia is a risk factor for thrombosis and is also widely prevalent in thrombosis 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).


Polycythemia vera is a rare diseasePolycythemia vera is a rare diseaseThe peak incidence of PV is age 50-70 The peak incidence of PV is age 50-70

yearsyearsHowever, it occurs in persons of all age However, it occurs in persons of all age

groups, including those in early adulthood and groups, including those in early adulthood and childhood, albeit rarely. childhood, albeit rarely.

The disease is slightly more common in The disease is slightly more common in males than in females.males than in females.

StatisticsStatistics

The disease usually develops slowlyThe disease usually develops slowlySymptoms are often insidious in onsetSymptoms are often insidious in onset

They are often related to blood hyperviscosity They are often related to blood hyperviscosity secondary to a marked increase in the cellular secondary to a marked increase in the cellular elements of blood, which impairs elements of blood, which impairs microcirculation. microcirculation.

HistoryHistory

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 and which lead to poor oxygen delivery and symptoms that include:symptoms that include:headache, dizziness, vertigo, tinnitus, visual headache, dizziness, vertigo, tinnitus, visual

disturbances, angina pectoris, or intermittent disturbances, angina pectoris, or intermittent claudications claudications

HistoryHistory

Bleeding complications ,, include epistaxis, Bleeding complications ,, include epistaxis, gum bleeding, ecchymoses, and GI gum bleeding, ecchymoses, and GI bleeding.bleeding.

Thrombotic complications ,, include Thrombotic complications ,, include venous thrombosis or thromboembolism venous thrombosis or thromboembolism and an increased prevalence of stroke and and an increased prevalence of stroke and other arterial thromboses.other arterial thromboses.

HistoryHistory

Abdominal pain due to peptic ulcer Abdominal pain due to peptic ulcer disease is present because PV is disease is present because PV is associated with increased histamine levels associated with increased histamine levels and gastric acidity or possible Budd-Chiari and 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

Splenomegaly, when present, can cause Splenomegaly, when present, can cause early satiety because of early satiety because of gastric filling being impaired by the enlarged gastric filling being impaired by the enlarged

spleen or, rarely, symptoms of splenic spleen or, rarely, symptoms of splenic infarction. infarction.

Weight loss may result from early satiety Weight loss may result from early satiety or from the increased myeloproliferative or from the increased myeloproliferative activity of the abnormal clone. activity of the abnormal clone.

HistoryHistory

Pruritus results from increased histamine Pruritus results from increased histamine levels released from increased basophils levels released from increased basophils and mast cells and can be exacerbated by and 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

The following symptoms are due to the The following symptoms are due to the manifestations of myeloproliferative manifestations of myeloproliferative disorders with extramedullary disorders with extramedullary hematopoiesis:hematopoiesis:Splenomegaly - Present in 75% of patients at Splenomegaly - Present in 75% of patients at

the time of diagnosisthe time of diagnosisHepatomegaly - Present in approximately Hepatomegaly - Present in approximately

30% of patients with PV30% of patients with PV

PhysicalPhysical

Hypertension is common in patients with Hypertension is common in patients with PV. The red blood cell mass should PV. The red blood cell mass should differentiate PV from Gaisbock syndrome, differentiate PV from Gaisbock syndrome, which is hypertension and which is hypertension and pseudopolycythemia (ie, high hemoglobin pseudopolycythemia (ie, high hemoglobin levels due to low plasma volume). levels due to low plasma volume).

PhysicalPhysical

Polycythemia is characterized by Polycythemia is characterized by increased cell counts in all cell lines in the increased cell counts in all cell lines in the myeloid series (ie, red blood cells, white myeloid series (ie, red blood cells, white blood cells [preferentially granulocytes], blood cells [preferentially granulocytes], and platelets). and platelets).

PhysicalPhysical

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 to conditions that increase red blood cells secondary to

systemic hypoxic conditions or an artificial condition systemic hypoxic conditions or an artificial condition stimulating Epo secretion in the kidneysstimulating Epo secretion in the kidneys

granulocytosis from infections or mobilization by granulocytosis 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

Secondary Causes of Increased Secondary Causes of Increased Red Cell Mass (Erythrocytosis)Red Cell Mass (Erythrocytosis)

Chronic pulmonary or cardiac disease Chronic pulmonary or cardiac disease Decreased 2,3-diphosphoglycerate Decreased 2,3-diphosphoglycerate High oxygen affinity hemoglobinopathy High oxygen affinity hemoglobinopathy Increased carboxyhemoglobin (in smokers) and Increased carboxyhemoglobin (in smokers) and

methemoglobin methemoglobin Residence at high altitude Residence at high altitude Adrenal cortical hypersecretion Adrenal cortical hypersecretion Hydronephrosis Hydronephrosis Tumors producing erythropoietin or anabolic steroids Tumors producing erythropoietin or anabolic steroids Relative (stress) Relative (stress) Disorders associated with decreased plasma volume Disorders associated with decreased plasma volume

(e.g., diarrhea, emesis, renal diseases) (e.g., diarrhea, emesis, renal diseases)

DiagnosisDiagnosis

PV should be suspected when hemoglobin PV 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 blacks and > than 16 g per dL [160 g per L] in blacks and women)and women)

hematocrit level greater than 52 percent hematocrit 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 women in blacks and women

DiagnosisDiagnosis

PV also should be suspected in patients PV also should be suspected in patients with portal venous thrombosis and with portal venous thrombosis and splenomegaly with or without splenomegaly with or without thrombocytosis and leukocytosis.thrombocytosis and leukocytosis.

Diagnosis: Diagnosis: Other Signs and Symptoms of Other Signs and Symptoms of

Polycythemia VeraPolycythemia Vera More CommonMore Common Hematocrit level >52 percent Hematocrit level >52 percent

(0.52) in white men, >47 (0.52) in white men, >47 percent (0.47) in blacks and percent (0.47) in blacks and women women

Hemoglobin level >18 g per dL Hemoglobin 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)

Plethora Plethora Pruritus after bathing Pruritus after bathing Splenomegaly Splenomegaly Weight loss Weight loss Weakness Weakness Sweating Sweating

Less CommonLess Common Bruising/epistaxis Bruising/epistaxis Budd-Chiari syndrome Budd-Chiari syndrome Erythromelalgia Erythromelalgia Gout Gout Hemorrhagic events Hemorrhagic events Hepatomegaly Hepatomegaly Ischemic digits Ischemic digits Thrombotic events Thrombotic events Transient neurologic Transient neurologic

complaints (headache, tinnitus, complaints (headache, tinnitus, dizziness, blurred vision, dizziness, blurred vision, paresthesias) paresthesias)

Atypical chest pain Atypical chest pain

In making the diagnosis of PV, once a In making the diagnosis of PV, once a secondary cause is ruled out, the secondary cause is ruled out, the diagnosis of PV is made using a diagnosis of PV is made using a combination of major and minor criteria combination of major and minor criteria defined by the Polycythemia Vera Study defined by the Polycythemia Vera Study Group (PVSG). Group (PVSG).

Although new diagnostic modalities have Although new diagnostic modalities have been developed, these criteria remain the been developed, these criteria remain the standard method to diagnose PV standard method to diagnose PV

DiagnosisDiagnosis

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 Criteria Major Criteria total RBC vol total 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% Splenomegaly Splenomegaly

Minor Criteria Minor Criteria Thrombocytosis with platelet count > 400,000/mL Thrombocytosis with platelet count > 400,000/mL Leukocytosis with WBC > 12,000/mL Leukocytosis 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/mL Serum B12 > 900 pg/mL or binding capacity UB12 BC > 2200 pg/mL

Serum Epo assaySerum Epo assay

Epo levels in patients with PV are often Epo levels in patients with PV are often below the lower limit of normal compared below the lower limit of normal compared with patients with secondary erythrocytosis with patients with secondary erythrocytosis and pseudoerythrocytosisand pseudoerythrocytosisbut the levels for PV and secondary but the levels for PV and secondary

erythrocytosis or pseudoerythrocytosis erythrocytosis or pseudoerythrocytosis overlap and are nonspecific for differentiating overlap and are nonspecific for differentiating these conditions. these conditions.

Bone marrow morphology and Bone marrow morphology and histologyhistology

Overall hypercellularity with expansion of all cell Overall hypercellularity with expansion of all cell lines with megakaryocytic proliferation and the lines with megakaryocytic proliferation and the presence of myelofibrosis can help diagnose PV presence of myelofibrosis can help diagnose PV and MPDand MPD

PV patients may have normal bone marrow PV patients may have normal bone marrow findingsfindings

These results are nonspecific and may be These results are nonspecific and may be observed in the other Philadelphia observed in the other Philadelphia chromosome–negative MPDs. chromosome–negative MPDs.

Bone marrow findings for Bone marrow findings for Polycythemia vera include Polycythemia vera include

Moderate to marked hypercellularity Moderate to marked hypercellularity trilineage hyperplasia trilineage hyperplasia megakaryocytes increased; megakaryocytes increased;

hyperlobulated hyperlobulated dilated sinusoids with intravascular dilated sinusoids with intravascular

hematopoiesis hematopoiesis decreased or absent iron stores decreased or absent iron stores increased reticulin (only in a minority of increased reticulin (only in a minority of

patients) patients)

LabsLabs

Peripheral blood findings Peripheral blood findings Increased hemoglobin & hematocrit Increased hemoglobin & hematocrit Normal red blood cell morphology, unless iron Normal red blood cell morphology, unless iron

deficient or spent phasedeficient or spent phase Normoblasts may be present Normoblasts may be present Mild to moderate leukocytosis Mild to moderate leukocytosis Mild neutrophilia and/or basophilia Mild neutrophilia and/or basophilia Thrombocytosis Thrombocytosis

This disease may also alter the results of the This disease may also alter the results of the following tests: following tests: Lactate dehydrogenase Lactate dehydrogenase u/a u/a Serum uric acid Serum uric acid T- wbc T- wbc RBC count RBC count Platelet aggregation test Platelet aggregation test Leukocyte alkaline phosphatase Leukocyte alkaline phosphatase Hemoglobin Hemoglobin ESRESR Erythropoietin Erythropoietin

LabsLabs

Automated red blood cell counts and hematocrit values Automated 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 should Direct measurement of the red blood cell mass should show an increase with a normal or slightly decreased show an increase with a normal or slightly decreased plasma volume. plasma volume. This is a nuclear medicine test that uses radiochromium-labeled This is a nuclear medicine test that uses radiochromium-labeled

red blood cells to measure actual red blood cell and plasma red blood cells to measure actual red blood cell and plasma volume. volume.

However, patients with hemoglobin concentrations of at However, patients with hemoglobin concentrations of at least 20 g/dL or hematocrit values of at least 60% in least 20 g/dL or hematocrit values of at least 60% in males and 56% in females always have an elevated red males and 56% in females always have an elevated red blood cell mass. blood cell mass.

LabsLabs

The red blood cells in patients with PV are The red blood cells in patients with PV are usually normochromic normocytic unless usually normochromic normocytic unless the patient has been bleeding from the patient has been bleeding from underlying peptic ulcer disease or underlying peptic ulcer disease or phlebotomy treatment (wherein the cells phlebotomy treatment (wherein the cells may be hypochromic and microcytic, may be hypochromic and microcytic, reflecting low iron stores). reflecting low iron stores).

LabsLabs

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 is occurs in approximately 60% of patients. It is mainly composed of neutrophils with a left shift mainly 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 elevated The 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 is This technique is only semiquantitative and is

susceptible to laboratory errors unless it can be susceptible to laboratory errors unless it can be performed by flow cytometry, which is not routinely performed by flow cytometry, which is not routinely availableavailable

LabsLabs

The platelet count is elevated to 400,000-The platelet count is elevated to 400,000-800,000/mL in approximately 50% of 800,000/mL in approximately 50% of patients. patients.

LabsLabs

The release of potassium into the serum The release of potassium into the serum caused by the increased number of caused by the increased number of platelets during in vitro coagulation may platelets during in vitro coagulation may cause a pseudohyperkalemia in the cause a pseudohyperkalemia in the serum, while the true plasma potassium serum, while the true plasma potassium level in vivo is actually within the reference level in vivo is actually within the reference range, as shown by measuring plasma range, as shown by measuring plasma levels and the lack of ECG changes. levels and the lack of ECG changes.

LabsLabs

Abnormal platelet function (as measured Abnormal platelet function (as measured by platelet aggregation tests with by platelet aggregation tests with epinephrine, adenosine diphosphate, or epinephrine, adenosine diphosphate, or collagen) may be demonstrated, but collagen) may be demonstrated, but bleeding time may be normal. bleeding time may be normal.

Some patients' platelet-rich plasma Some patients' platelet-rich plasma aggregates spontaneously without the aggregates spontaneously without the addition of any of the above substances. addition of any of the above substances.

This indicates a propensity for thromboses This indicates a propensity for thromboses

LabsLabs

Bone marrow studies are not necessary to Bone marrow studies are not necessary to establish the diagnosis but the findings of:establish the diagnosis but the findings of:hypercellularityhypercellularityhyperplasia of the erythroid, granulocytic and hyperplasia of the erythroid, granulocytic and

megakaryocytic cell linesmegakaryocytic cell linesmyelofibrosis myelofibrosis

support the diagnosis of a support the diagnosis of a myeloproliferative process. myeloproliferative process.

LabsLabs

Iron stores are decreased or absent Iron stores are decreased or absent because of the increased red blood cell because of the increased red blood cell mass, and macrophages may be masked mass, and macrophages may be masked in the myeloid hyperplasia that is present. in the myeloid hyperplasia that is present.

LabsLabs

Fibrosis is increased and detected early by Fibrosis is increased and detected early by silver stains for reticulin silver stains for reticulin

LabsLabs

Cytogenetics of the bone marrow cells Cytogenetics of the bone marrow cells show a clonal abnormality in show a clonal abnormality in 30% of patients who are not treated and in 30% of patients who are not treated and in

50% of patients who are treated with 50% of patients who are treated with alkylating or myelosuppressive agents.alkylating or myelosuppressive agents.These chromosomal abnormalities include These chromosomal abnormalities include

deletions of the long arm of chromosome 5 or 20 deletions 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 with Leukemic transformation is usually associated with multiple or complex abnormalities.multiple or complex abnormalities.

LabsLabs

Hyperuricemia occurs in 40% of patients Hyperuricemia occurs in 40% of patients and reflects the high turnover rate of bone and reflects the high turnover rate of bone marrow cells releasing DNA metabolites. marrow cells releasing DNA metabolites.

LabsLabs

Imaging StudiesImaging Studies

An enlarged spleen is often palpable and An enlarged spleen is often palpable and does not require any imaging studies. does not require any imaging studies.

In some patients with posteriorly enlarged In some patients with posteriorly enlarged spleens or in those who are obese, spleens or in those who are obese, ultrasonography or CT scanning may be ultrasonography or CT scanning may be able to detect an enlargement missed able to detect an enlargement missed during the physical examination.during the physical examination.

Other TestsOther Tests

The serum Epo level should be decreased The serum Epo level should be decreased in nearly all patients with PV and no recent in nearly all patients with PV and no recent hemorrhage. hemorrhage.

This distinguishes polycythemia from This distinguishes polycythemia from secondary causes of polycythemia in secondary causes of polycythemia in which the serum Epo level is generally which 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 for Each lab has its own reference range for

serum Epo level serum Epo level

TreatmentTreatment

The objective of treatment is to reduce the The objective of treatment is to reduce the high blood viscosity (thickness of the high blood viscosity (thickness of the blood) due to the increased red blood cell blood) due to the increased red blood cell mass and to prevent hemorrhage and mass 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 of Thrombosis accounts for the majority of

morbidity and mortality. The major goal of morbidity and mortality. The major goal of treatment is to prevent thrombotic events. treatment is to prevent thrombotic events.

Examples of thrombotic events include Examples of thrombotic events include arterial and venous thrombosis, arterial and venous thrombosis, cerebrovascular accident, deep venous cerebrovascular accident, deep venous thrombosis, myocardial infarction, thrombosis, myocardial infarction, peripheral arterial occlusion, and peripheral arterial occlusion, and pulmonary infarctpulmonary infarct

TreatmentTreatment

TreatmentTreatment

The mainstay of treatment for PV is The mainstay of treatment for PV is phlebotomy, which is aimed at reducing phlebotomy, which is aimed at reducing hyperviscosity by decreasing the venous hyperviscosity by decreasing the venous hematocrit level to less than 45 percent hematocrit 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 median The PVSG reported the best median survival, 12.6 years, for this type of survival, 12.6 years, for this type of treatment. treatment.

Phlebotomy is a simple procedure without Phlebotomy is a simple procedure without many risks, except for the eventual many risks, except for the eventual development of iron deficiency development of iron deficiency

TreatmentTreatment

Patients with hematocrit values of less Patients with hematocrit values of less than 70% may be bled twice a week to than 70% may be bled twice a week to reduce the hematocrit to the range of 40%. reduce the hematocrit to the range of 40%.

Patients with severe plethora who have Patients with severe plethora who have altered mentation or associated vascular altered mentation or associated vascular compromise can be bled more vigorously, compromise can be bled more vigorously, with daily removal of 500 mL of whole with daily removal of 500 mL of whole bloodblood

Elderly patients with some cardiovascular Elderly patients with some cardiovascular compromise or cerebral vascular compromise or cerebral vascular complications should have the volume complications should have the volume replaced with saline solution after each replaced with saline solution after each procedure to avoid postural hypotension procedure to avoid postural hypotension

TreatmentTreatment

Because phlebotomy is the most efficient Because phlebotomy is the most efficient method of lowering the hemoglobin and method of lowering the hemoglobin and hematocrit levels to the reference range, all new hematocrit levels to the reference range, all new patients are initially phlebotomized to decrease patients are initially phlebotomized to decrease the risk of complications. the risk of complications.

The presence of elevated platelet counts that The presence of elevated platelet counts that may be exacerbated by the phlebotomy is an may be exacerbated by the phlebotomy is an indication to use myelosuppressive agents to indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications avoid thrombotic or hemorrhagic complications

TreatmentTreatment

Once the patient's hemoglobin and Once the patient's hemoglobin and hematocrit values are reduced to within hematocrit values are reduced to within the reference range (ie, <45%), implement the reference range (ie, <45%), implement a maintenance program either by inducing a maintenance program either by inducing iron deficiency by continuous iron deficiency by continuous phlebotomies (frequency of the procedure phlebotomies (frequency of the procedure depends on the rate of reaccumulation of depends on the rate of reaccumulation of red blood cells) or using a red blood cells) or using a myelosuppressive agent. myelosuppressive agent.

TreatmentTreatment

TreatmentTreatment The use of myelosuppressive agents such as radioactive The use of myelosuppressive agents such as radioactive

phosphorus (32P), chlorambucil (Leukeran), busulfan phosphorus (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 alkylating Chlorambucil, busulfan, and pipobroman, all alkylating agents, have fallen out of favor because of concerns agents, 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 supplemental The agent 32P remains in use with supplemental phlebotomy and has a reported median survival similar phlebotomy and has a reported median survival similar to that of phlebotomy alone-10.9 years according to to that of phlebotomy alone-10.9 years according to PVSG data. PVSG data.

In patients treated with chlorambucil and In patients treated with chlorambucil and 32P the PVSG demonstrated a decreased 32P the PVSG demonstrated a decreased survival rate and increased mortality rate survival 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 had and a total of 17% of patients had leukemia after 15 years with. leukemia after 15 years with.

TreatmentTreatment

Hydroxyurea has been the mainstay Hydroxyurea has been the mainstay therapy for PV after the PVSG results therapy for PV after the PVSG results indicated it is an effective agent for indicated it is an effective agent for myelosuppression; however, concerns myelosuppression; however, concerns have been raised regarding long-term have been raised regarding long-term risks for leukemic transformation. risks for leukemic transformation.

In the PVSG trial, HU therapy reduced the In the PVSG trial, HU therapy reduced the risk of thrombosis compared with risk of thrombosis compared with phlebotomy alone phlebotomy alone

TreatmentTreatment

TreatmentTreatment Recombinant interferon alfa-2b reduces Recombinant interferon alfa-2b reduces

myeloproliferation and splenomegaly, and alleviates the myeloproliferation and splenomegaly, and alleviates the symptom of pruritus.symptom of pruritus.

It has no established mutagenic potential, and thus may It has no established mutagenic potential, and thus may prove a valuable option for younger patients and those prove 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 12 red cell indices could be normalized over six to 12 months with interferon therapy alone, and without months with interferon therapy alone, and without evidence of thrombosis.evidence of thrombosis.

However, many patients discontinue interferon because However, many patients discontinue interferon because of side effects, and high cost of treatment. of side effects, and high cost of treatment.

TreatmentTreatment

splenectomy in patients with painful splenectomy in patients with painful splenomegaly or repeated episodes of splenomegaly or repeated episodes of thrombosis causing splenic infarction thrombosis causing splenic infarction

TreatmentTreatment

Occasionally, chemotherapy may be given Occasionally, chemotherapy may be given to suppress the bone marrow.to suppress the bone marrow.

The use of anti-platelet therapy (such as The use of anti-platelet therapy (such as aspirin) is controversial because it may aspirin) is controversial because it may cause gastric bleeding.cause gastric bleeding.

Allopurinol is given for hyperuricemia Allopurinol is given for hyperuricemia (gout).(gout).

TreatmentTreatment

A risk-stratified approach to the management of A risk-stratified approach to the management of PV is currently recommended PV is currently recommended

Patients treated with phlebotomy alone benefit Patients treated with phlebotomy alone benefit from low rates of malignancy but experience from low rates of malignancy but experience more thrombosis events during the first few more thrombosis events during the first few years of treatment. years of treatment.

Patients treated with myelosuppressive agents Patients treated with myelosuppressive agents and supplemental phlebotomy avoid this early and supplemental phlebotomy avoid this early thrombotic risk but in turn have significant rates thrombotic risk but in turn have significant rates of malignant transformation after about six years of malignant transformation after about six years of therapy of therapy

High-risk patients High-risk patients those 60 years or olderthose 60 years or older or those with a history of thrombosis or those with a history of thrombosis A myelosuppressive agent with supplemental A myelosuppressive agent with supplemental

phlebotomy is reasonable in this groupphlebotomy is reasonable in this group This group's generally shorter life expectancy lessens This 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 of Patients in this group stand to gain from the benefit of

lower early thrombosis rates with myelosuppressive lower early thrombosis rates with myelosuppressive medications. medications.

TreatmentTreatment

Indeterminate riskIndeterminate risk < than age 60 and have no history of < than age 60 and have no history of

thrombocytosis, but do have cardiovascular or thrombocytosis, but do have cardiovascular or other risk factorsother risk factors

Therapy in this group should be Therapy in this group should be individualized, possibly with the addition of individualized, possibly with the addition of agents acting on platelet function or agents acting on platelet function or number. number.

TreatmentTreatment

low risk low risk < than 60 years and have no thrombosis-< than 60 years and have no thrombosis-

related risk factorsrelated risk factorsPhlebotomy alone may be the treatment of Phlebotomy alone may be the treatment of

choice with the goal of reducing the choice with the goal of reducing the hematocrit level to less than 45 percent hematocrit 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

Consultation with a hematologist is Consultation with a hematologist is recommended to apply such strategies, recommended to apply such strategies, and newer agents may be tailored to and newer agents may be tailored to patients on an individualized basis. patients on an individualized basis.

TreatmentTreatment

PrognosisPrognosis

Polycythemia vera usually develops Polycythemia vera usually develops slowly, and most patients treated slowly, and most patients treated appropriately do not experience any appropriately do not experience any problems related to the disease. problems related to the disease.

However, the abnormal bone marrow cells However, the abnormal bone marrow cells may begin to grow uncontrollably leading may begin to grow uncontrollably leading to acute myelogenous leukemia.to acute myelogenous leukemia.

PrognosisPrognosis

Patients with polycythemia vera also have Patients with polycythemia vera also have an increased tendency to form blood clots an 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 abnormal Some patients may experience abnormal bleeding because their platelets are bleeding because their platelets are abnormal.abnormal.

PrognosisPrognosis

PV is a chronic disease, and its natural PV is a chronic disease, and its natural history of 1.5-3 years of median survival in history of 1.5-3 years of median survival in the absence of therapy has been extended the absence of therapy has been extended to at least 10-20 years because of new to at least 10-20 years because of new therapeutic tools. therapeutic tools.

The major causes of morbidity and The major causes of morbidity and mortality are as follows:mortality are as follows:ThrombosisThrombosisHemorrhagic complicationsHemorrhagic complicationsPeptic ulcer diseasePeptic ulcer diseaseMyelofibrosis and pancytopeniaMyelofibrosis and pancytopeniaAcute leukemia or a myelodysplastic Acute leukemia or a myelodysplastic

syndrome syndrome

PrognosisPrognosis

ThrombosisThrombosis

reported in 15-60% of patients reported in 15-60% of patients major cause of death in 10-40% of major cause of death in 10-40% of

patientspatientsVenous and arterial thromboses have Venous and arterial thromboses have

resulted in pulmonary emboli, renal failure resulted in pulmonary emboli, renal failure from renal vein or artery thrombosis, from renal vein or artery thrombosis, intestinal ischemia from mesenteric vein intestinal ischemia from mesenteric vein thromboses, or peripheral arterial emboli. thromboses, or peripheral arterial emboli.

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 of Bleeding is usually the consequence of vascular compromise resulting from vascular compromise resulting from ischemic changes from thrombosis or ischemic changes from thrombosis or hyperviscosity. hyperviscosity.

Peptic ulcer diseasePeptic ulcer disease

Associated with PV at a 3 to 5 fold higher Associated 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 increased This has been attributed to increased histamine serum levels histamine serum levels

Myelofibrosis and pancytopeniaMyelofibrosis and pancytopenia

Occur in 3-10% of patients, usually late in Occur in 3-10% of patients, usually late in the disease the disease

In these patients, infections and bleeding In these patients, infections and bleeding complications may be the most serious complications may be the most serious health threatshealth threats

red blood cell transfusions may be red blood cell transfusions may be required to maintain adequate red blood required to maintain adequate red blood cell counts and to improve fatigue and cell counts and to improve fatigue and other anemia-related symptoms. other anemia-related symptoms.

Acute leukemia or a Acute leukemia or a myelodysplastic syndromemyelodysplastic syndrome

Develops in 1.5% of patients treated with Develops in 1.5% of patients treated with phlebotomy alonephlebotomy alone

The transformation risks The transformation risks increase to 13.5% within 5 years with treatment using increase to 13.5% within 5 years with treatment using

chlorambucil chlorambucil And 10.2% within 6-10 years in patients treated with And 10.2% within 6-10 years in patients treated with

32P32P

At 15 years, the transformation risk for HU is At 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 trend is a worrisome trend

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polycythemia victor

elevated red blood cell

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