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Polycythemia

Victor Politi, M.D., FACP Medical Director, SVCMC, School of Allied Health Professions, Physician Assistant Program

Introduction
Polycythemia vera is a chronic myeloproliferative disorder characterized by increased red blood cell mass (RCM), or erythrocytosis The resultant hyperviscosity of the blood predisposes such patients to thrombosis

Introduction

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

Introduction

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

Introduction

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

Introduction

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

Introduction

Patients may present with complaints of pruritus after bathing, burning pains in the distal extremities (erythromelalgia), gastrointestinal disturbances, or nonspecific complaints such as weakness, headaches, or dizziness. Other patients are diagnosed after an incidental finding of an elevated hemoglobin and/or hematocrit level on a complete blood count.

Introduction

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

Introduction

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

Introduction
Treatment includes phlebotomy with the possible addition of myelosuppressive agents based on a risk-stratified approach. Agents under investigation include interferon alfa-2b, anagrelide, and aspirin. Consultation with a hematologist is recommended.

Introduction

Alternative Names:

Primary polycythemia Polycythemia rubra vera Myeloproliferative disorder Erythremia Splenomegalic polycythemia Vaquez's disease Osler's disease Polycythemia with chronic cyanosis Myelopathic polycythemia Erythrocytosis megalosplenica Cryptogenic polycythemia

Pathophysiology
Normal stem cells are present in the bone marrow of patients with PV. Also present are abnormal clonal stem cells that interfere with or suppress normal stem cell growth and maturation.

Pathophysiology
Evidence indicates that the etiology of panmyelosis is unregulated neoplastic proliferation. The origin of the stem cell transformation remains unknown

Polycythemia vera

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

Pathophysiology

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

Pathophysiology

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

Pathophysiology

Hyperhomocystinemia is a risk factor for thrombosis and is also widely prevalent in patients with MPD (35% in controls, 56% in persons with PV).

Statistics
Polycythemia vera is a rare disease The peak incidence of PV is age 50-70 years

However, it occurs in persons of all age groups, including those in early adulthood and childhood, albeit rarely.

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

History
The disease usually develops slowly Symptoms are often insidious in onset

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

History

Symptoms are related to hyperviscosity, sludging of blood flow, and thromboses, which lead to poor oxygen delivery and symptoms that include:

headache, dizziness, vertigo, tinnitus, visual disturbances, angina pectoris, or intermittent claudications

History

Bleeding complications ,, include epistaxis, gum bleeding, ecchymoses, and GI bleeding. Thrombotic complications ,, include venous thrombosis or thromboembolism and an increased prevalence of stroke and other arterial thromboses.

History

Abdominal pain due to peptic ulcer disease is present because PV is associated with increased histamine levels and gastric acidity or possible Budd-Chiari syndrome (hepatic portal vein thrombosis) or mesenteric vein thrombosis.

History

Splenomegaly, when present, can cause early satiety because of

gastric filling being impaired by the enlarged spleen or, rarely, symptoms of splenic infarction.

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

History
Pruritus results from increased histamine levels released from increased basophils and mast cells and can be exacerbated by a warm bath or shower. This occurs in up to 40% of patients.

Physical

The following symptoms are due to the manifestations of myeloproliferative disorders with extramedullary hematopoiesis:
Splenomegaly - Present in 75% of patients at the time of diagnosis Hepatomegaly - Present in approximately 30% of patients with PV

Physical

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

Physical

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

Physical

However, if red blood cell levels are increased, several conditions must be excluded, including:

conditions that increase red blood cells secondary to systemic hypoxic conditions or an artificial condition stimulating Epo secretion in the kidneys granulocytosis from infections or mobilization by secondary causes, as in leukemoid reactions thrombocytosis from bleeding and iron deficiency.

Secondary Causes of Increased Red Cell Mass (Erythrocytosis)


Chronic pulmonary or cardiac disease Decreased 2,3-diphosphoglycerate High oxygen affinity hemoglobinopathy Increased carboxyhemoglobin (in smokers) and methemoglobin Residence at high altitude Adrenal cortical hypersecretion Hydronephrosis Tumors producing erythropoietin or anabolic steroids Relative (stress) Disorders associated with decreased plasma volume (e.g., diarrhea, emesis, renal diseases)

Diagnosis

PV should be suspected when hemoglobin and/or hematocrit levels are elevated

(> 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 women)

hematocrit level greater than 52 percent (0.52) in white men and 47 percent (0.47) in blacks and women

Diagnosis

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

Diagnosis: Other Signs and Symptoms of


Polycythemia Vera

More Common Hematocrit level >52 percent (0.52) in white men, >47 percent (0.47) in blacks and women Hemoglobin level >18 g per dL (180 g per L) in white men, >16 g per dL (160 g per L) in blacks and women) Plethora Pruritus after bathing Splenomegaly Weight loss Weakness Sweating

Less Common Bruising/epistaxis Budd-Chiari syndrome Erythromelalgia Gout Hemorrhagic events Hepatomegaly Ischemic digits Thrombotic events Transient neurologic complaints (headache, tinnitus, dizziness, blurred vision, paresthesias) Atypical chest pain

Diagnosis
In making the diagnosis of PV, once a secondary cause is ruled out, the diagnosis of PV is made using a combination of major and minor criteria defined by the Polycythemia Vera Study Group (PVSG). Although new diagnostic modalities have been developed, these criteria remain the standard method to diagnose PV

A diagnosis of polycythemia vera is made when a patent fulfills

all three of the major criteria any two major and any two minor criteria

Or

Major Criteria

total RBC vol


Men > or = to 36 mL/kg Women > or = to 32 mL/kg

arterial 02 saturation > or = to 92% Splenomegaly Thrombocytosis with platelet count > 400,000/mL Leukocytosis with WBC > 12,000/mL Increased leukocyte alkaline phosphatase LAP > 100U/L (no infection) Serum B12 > 900 pg/mL or binding capacity UB12 BC > 2200 pg/mL

Minor Criteria

Serum Epo assay

Epo levels in patients with PV are often below the lower limit of normal compared with patients with secondary erythrocytosis and pseudoerythrocytosis

but the levels for PV and secondary erythrocytosis or pseudoerythrocytosis overlap and are nonspecific for differentiating these conditions.

Bone marrow morphology and histology

Overall hypercellularity with expansion of all cell lines with megakaryocytic proliferation and the presence of myelofibrosis can help diagnose PV and MPD PV patients may have normal bone marrow findings These results are nonspecific and may be observed in the other Philadelphia chromosomenegative MPDs.

Bone marrow findings for Polycythemia vera include


Moderate to marked hypercellularity trilineage hyperplasia megakaryocytes increased; hyperlobulated dilated sinusoids with intravascular hematopoiesis decreased or absent iron stores increased reticulin (only in a minority of patients)

Labs

Peripheral blood findings


Increased hemoglobin & hematocrit Normal red blood cell morphology, unless iron deficient or spent phase Normoblasts may be present Mild to moderate leukocytosis Mild neutrophilia and/or basophilia Thrombocytosis

Labs

This disease may also alter the results of the following tests:

Lactate dehydrogenase u/a Serum uric acid T- wbc RBC count Platelet aggregation test Leukocyte alkaline phosphatase Hemoglobin ESR Erythropoietin

Labs

Automated red blood cell counts and hematocrit values (including hemoglobin levels) may be deceptive with regard to the total red blood cell mass. Direct measurement of the red blood cell mass should show an increase with a normal or slightly decreased plasma volume.

This is a nuclear medicine test that uses radiochromium-labeled red blood cells to measure actual red blood cell and plasma volume.

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

Labs

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

Labs

An elevated white blood cell count (>12,000/L) occurs in approximately 60% of patients. It is mainly composed of neutrophils with a left shift and a few immature cells.

Mild basophilia occurs in 60% of patients. The leukocyte alkaline phosphatase score is elevated (>100 U/L) in 70% of patients. This technique is only semiquantitative and is susceptible to laboratory errors unless it can be performed by flow cytometry, which is not routinely available

Labs

The platelet count is elevated to 400,000800,000/mL in approximately 50% of patients.

Labs

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

Labs
Abnormal platelet function (as measured by platelet aggregation tests with epinephrine, adenosine diphosphate, or collagen) may be demonstrated, but bleeding time may be normal. Some patients' platelet-rich plasma aggregates spontaneously without the addition of any of the above substances. This indicates a propensity for thromboses

Labs

Bone marrow studies are not necessary to establish the diagnosis but the findings of:
hypercellularity hyperplasia of the erythroid, granulocytic and megakaryocytic cell lines myelofibrosis

support the diagnosis of a myeloproliferative process.

Labs

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

Labs

Fibrosis is increased and detected early by silver stains for reticulin

Labs

Cytogenetics of the bone marrow cells show a clonal abnormality in

30% of patients who are not treated and in 50% of patients who are treated with alkylating or myelosuppressive agents.
These

chromosomal abnormalities include deletions of the long arm of chromosome 5 or 20 (5q-, 20q-) and trisomy 8 (+8) or 9 (+9). Leukemic transformation is usually associated with multiple or complex abnormalities.

Labs

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

Imaging Studies
An enlarged spleen is often palpable and does not require any imaging studies. In some patients with posteriorly enlarged spleens or in those who are obese, ultrasonography or CT scanning may be able to detect an enlargement missed during the physical examination.

Other Tests
The serum Epo level should be decreased in nearly all patients with PV and no recent hemorrhage. This distinguishes polycythemia from secondary causes of polycythemia in which the serum Epo level is generally within the reference range or is elevated.

Each lab has its own reference range for serum Epo level

Treatment
The objective of treatment is to reduce the high blood viscosity (thickness of the blood) due to the increased red blood cell mass and to prevent hemorrhage and thrombosis. No single treatment is available for PV. Thrombosis accounts for the majority of morbidity and mortality. The major goal of treatment is to prevent thrombotic events.

Treatment

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

Treatment
The mainstay of treatment for PV is phlebotomy, which is aimed at reducing hyperviscosity by decreasing the venous hematocrit level to less than 45 percent (0.45) in white men and 42 percent (0.42) in blacks and women. The PVSG reported the best median survival, 12.6 years, for this type of treatment.

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

Treatment
Patients with hematocrit values of less than 70% may be bled twice a week to reduce the hematocrit to the range of 40%. Patients with severe plethora who have altered mentation or associated vascular compromise can be bled more vigorously, with daily removal of 500 mL of whole blood

Treatment

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

Treatment

Because phlebotomy is the most efficient method of lowering the hemoglobin and hematocrit levels to the reference range, all new patients are initially phlebotomized to decrease the risk of complications. The presence of elevated platelet counts that may be exacerbated by the phlebotomy is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications

Treatment

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

Treatment

The use of myelosuppressive agents such as radioactive phosphorus (32P), chlorambucil (Leukeran), busulfan (Myleran), pipobroman (Vercyte), and hydroxyurea (Hydrea) in conjunction with phlebotomy has been studied. Chlorambucil, busulfan, and pipobroman, all alkylating agents, have fallen out of favor because of concerns about rates of iatrogenic leukemia. The agent 32P remains in use with supplemental phlebotomy and has a reported median survival similar to that of phlebotomy alone-10.9 years according to PVSG data.

Treatment

In patients treated with chlorambucil and 32P the PVSG demonstrated a decreased survival rate and increased mortality rate from acute leukemia in the first 5 years, and a total of 17% of patients had leukemia after 15 years with.

Treatment
Hydroxyurea has been the mainstay therapy for PV after the PVSG results indicated it is an effective agent for myelosuppression; however, concerns have been raised regarding long-term risks for leukemic transformation. In the PVSG trial, HU therapy reduced the risk of thrombosis compared with phlebotomy alone

Treatment

Recombinant interferon alfa-2b reduces myeloproliferation and splenomegaly, and alleviates the symptom of pruritus. It has no established mutagenic potential, and thus may prove a valuable option for younger patients and those with significant splenomegaly. A small case series of 11 patients found that the patients' red cell indices could be normalized over six to 12 months with interferon therapy alone, and without evidence of thrombosis. However, many patients discontinue interferon because of side effects, and high cost of treatment.

Treatment

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

Treatment
Occasionally, chemotherapy may be given to suppress the bone marrow. The use of anti-platelet therapy (such as aspirin) is controversial because it may cause gastric bleeding. Allopurinol is given for hyperuricemia (gout).

Treatment

A risk-stratified approach to the management of PV is currently recommended Patients treated with phlebotomy alone benefit from low rates of malignancy but experience more thrombosis events during the first few years of treatment. Patients treated with myelosuppressive agents and supplemental phlebotomy avoid this early thrombotic risk but in turn have significant rates of malignant transformation after about six years of therapy

Treatment

High-risk patients

those 60 years or older or those with a history of thrombosis A myelosuppressive agent with supplemental phlebotomy is reasonable in this group This group's generally shorter life expectancy lessens the threat of eventual iatrogenic malignancy. Patients in this group stand to gain from the benefit of lower early thrombosis rates with myelosuppressive medications.

Treatment

Indeterminate risk

< than age 60 and have no history of thrombocytosis, but do have cardiovascular or other risk factors

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

Treatment

low risk

< than 60 years and have no thrombosisrelated risk factors

Phlebotomy alone may be the treatment of choice with the goal of reducing the hematocrit level to less than 45 percent (0.45) or lower based on gender and race

Treatment

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

Prognosis
Polycythemia vera usually develops slowly, and most patients treated appropriately do not experience any problems related to the disease. However, the abnormal bone marrow cells may begin to grow uncontrollably leading to acute myelogenous leukemia.

Prognosis
Patients with polycythemia vera also have an increased tendency to form blood clots that can result in strokes or heart attacks. Some patients may experience abnormal bleeding because their platelets are abnormal.

Prognosis

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

Prognosis

The major causes of morbidity and mortality are as follows:


Thrombosis Hemorrhagic complications Peptic ulcer disease Myelofibrosis and pancytopenia Acute leukemia or a myelodysplastic syndrome

Thrombosis
reported in 15-60% of patients major cause of death in 10-40% of patients Venous and arterial thromboses have resulted in pulmonary emboli, renal failure from renal vein or artery thrombosis, intestinal ischemia from mesenteric vein thromboses, or peripheral arterial emboli.

Hemorrhagic complications
occur in 15-35% of patients lead to death in 6-30% of these patients

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

Peptic ulcer disease


Associated with PV at a 3 to 5 fold higher rate than that of the general population This has been attributed to increased histamine serum levels

Myelofibrosis and pancytopenia


Occur in 3-10% of patients, usually late in the disease In these patients, infections and bleeding complications may be the most serious health threats red blood cell transfusions may be required to maintain adequate red blood cell counts and to improve fatigue and other anemia-related symptoms.

Acute leukemia or a myelodysplastic syndrome


Develops in 1.5% of patients treated with phlebotomy alone The transformation risks

increase to 13.5% within 5 years with treatment using chlorambucil And 10.2% within 6-10 years in patients treated with 32P

At 15 years, the transformation risk for HU is 5.9%, which, although not statistically significant, is a worrisome trend

Questions