Polycythemia Vera

Disease Overview

PV (polycythemia rubra vera) is a clonal disorder characterized by the overproduction of mature RBCs, WBCs, and platelets.19,20 With the increased production of red cells, there is an increase in hemoglobin, hematocrit, and red cell mass (RCM). Erythrocytosis is the most prominent clinical manifestation of this disorder. The bone marrow is usually hypercellular with hyperplasia of all three bone marrow elements. This disorder usually occurs in the sixth or seventh decade of life. All causes of secondary erythrocytosis must be

Table 12.6 O Key Facts of

Polycythemia Vera

• Increase in all three cell lines

• Absolute increase in RCM

• Normal oxygen saturation

• Splenomegaly

• Recommended treatment is phlebotomy

• Thrombosis and hemorrhage excluded before a diagnosis of PV can be made. Table 12.6 summarizes the key facts of polycythemia.

Pathophysiology

The etiology of polycythemia has become clearer. The primary defect involves the pluripotential stem cell that has the capability of differentiating into RBCs, WBCs, and platelet. Recently the JAK2 V617F mutation has been discovered in most patients with PV18 Erythroid precursors in PV are very sensitive to erythropoietin, which leads to an increased red cell production. The increased red cell production leads to an increase in RCM and increased blood viscosity. For this reason, patients are predisposed to arterial and venous thrombosis and/or increased bleeding. The elevated hemat-ocrit and platelet counts are directly proportional to the number of thrombotic events.18

Clinical Features and Symptoms

Patients tend to be asymptomatic at the time of diagnosis. Symptoms are often insidious in onset. As the RBCs and platelet number increase, more symptoms are evident. The major symptoms are related to the hypertension, hyperviscosity, and the vascular abnormalities caused by the increased RCM. Symptoms of hypervis-cosity and increased hematocrit include headache, light-headedness, blurred vision or visual disturbances, fatigue, and plethora. Plethora is a condition of a red or ruddy complexion due to the expanded blood volume. Additionally, this manifests itself in the nail beds, hands, feet, face, and conjunctiva. Thrombosis in the small blood vessels leads to painful dilation of the vessels in the extremities. Sometimes ulceration or gangrene can occur in the fingers and toes. Thrombosis in the larger vessels can lead to myocardial infarction, transient ischemic attacks, stroke, and deep vein thrombosis (DVT).

Abnormalities in platelet function can lead to bleeding from the nose (epistaxis), easy bruising, and gingival bleeding. The increased blood cell turnover can cause hyperuricemia, gout, and stomach ulcers. As the disease progresses, the patients develop abdominal pain due to hepatomegaly and splenomegaly. Splenomegaly is present in 75% of the patients at the time of diagnosis, and hepatomegaly is present in about 30%.20,21 Pruritus, which results from increased histamine levels released from the basophil, is a common extenuating symptom.

Peripheral Blood and Bone Marrow Findings

Polycythemia is characterized by an increased cell count in all three cell lines. The major characteristics of

Red Panda Overproduction
Figure 12.3 Increased RBCs in PV.

PV are normoblastic erythroid proliferation in the bone marrow and an increased number of normocytic, normochromic RBCs in the peripheral blood. Figure 12.3 illustrates the increase in RBCs. The reticulocyte count tends to be normal or slightly increased. Neutrophilia with a "shift to the left" and basophilia are common in the blood smear.1 At disease onset, the red cell count, hemoglobin, and hematocrit are increased. The red cell distribution width (RDW) tends to be higher than normal. The granulocyte and platelet counts are found to be increased. The leukocyte alkaline phosphatase (LAP) score is usually elevated. Platelet counts are increased and have abnormal morphology and function.

Characteristically, the bone marrow biopsy is hypercellular. Pancytopenia accounts for the increased cellularity. The increase in the number of erythroid and megakaryocytic precursors is more significant. The bone marrow biopsy shows increased reticulin or fibrosis. The amount of reticulin is directly proportional to the amount of cellularity. The iron stores of the bone marrow are usually depleted.

As the disease progresses, the erythroid activity in the marrow decreases. Immature WBC and RBC precursors are found in the peripheral blood with marked morphology. Microcytes, elliptocytes, and dacryocytes (teardrop cells) develop. Granulocytes and platelet morphology is abnormal with increases in younger and younger cells.

Diagnosis

The major diagnostic issue related to PV is distinguishing it from secondary and relative erythrocytosis. Secondary erythrocytosis is an increase in the RCM without evidence of changes in the other cell lines. Table 12.7 summarizes the causes of secondary erythrocytosis.

Table 12.7 O Causes of Secondary Erythrocytosis

• Hypertension

• Arterial hypoxemia

• Impaired tissue oxygen delivery

• Renal lesions

• Renal disease

• Endocrine lesions

• Hepatic lesions

Relative erythrocytosis is due to dehydration and hemo-concentration. Elevated hematocrit and hemoglobin counts are a result of a high red cell count and a low plasma volume.

The National Polycythemia Vera Study Group (PVSG) diagnostic criteria are given in Table 12.8.1,22 PV is present when a patient demonstrates all of the major or primary criteria (elevated hematocrit or RCM, normal arterial oxygen saturation, and splenomegaly) or together with the secondary or minor criteria (thrombo-cytosis, leukocytosis, elevated LAP, and increased serum B12). In summary, the most significant finding in PV is increased RCM, splenomegaly, and the JAK2 mutation with the increase in leukocytes and platelets. Other tests that are helpful in the diagnosis of PV are a bone marrow aspirate and biopsy. However, these invasive procedures are not necessary to establish a diagnosis, but a hyper-cellular marrow with hyperplasia of erythroid, granulo-cytic, and megakaryocytic elements supports the diagnosis. Serum erythropoietin levels in patients with PV are often found to be low compared with patients with secondary and relative erythrocytosis.20,23

There is no consistent or unique cytogenetic abnormality associated with this disorder. Cytogenetic abnormalities are found in 8% to 20% of patients at the time of diagnosis.24 The most frequent cytogenetic abnormality are trisomy of1q, 8, 9 or 9p,del 3q,del 20q or interstitial deletions of 13 or 20.24

Treatment

Treatment begins with decreasing the hematocrit and hemoglobin, thereby reducing the plasma viscosity Therapy recommendations are based on age, sex, clinical manifestations, and hematological findings. Treatment recommendations for patients are phlebotomy,

194 Part III • White Cell Disorders

Table 12.8 O Diagnostic Criteria for Polycythemia Vera

A1 Elevated RCM >25% above mean normal predicated Hgb >18.5 g/dL in men or 16.5 g/dL in women

A2 No cause or absence of secondary erythrocy-

tosis

A3 Splenomegaly

A4 Prescence of JAK2 V617 F mutation or other cytogenetic abnormalities in hemopoietic cells

A5 Endogenous erythroid colony formation in vitro

B1 Thrombocytosis >400 X 109/L

B3 Bone marrow biopsy presenting with pan-

myelosis with prominent and megakaryocyte proliferation

B4 Low serum erythropoietin levels

A1 + A2 + any other category A are present, diagnose PV A1 + A2 + any two of category B are present, diagnose PV Adapted from Jaffee ES, Harris NL, Stein H, Vardiman JW eds. World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of Haematopoietic Lymphoid Tissues. Lyon: IARC Press, 2001; and Pearson TC, Messinezy M, Westwoos N, Green AR, et al. A polycythemia vera update: Diagnosis, pathobiology and treatment. Hematology 1:51-68, 2000.

radioactive phosphorus (32P), myelosuppressive agents, and interferon-alfa.25 The target goal for therapy is to decrease the hematocrit. For men, the hematocrit target value is less than 45%, and for women, it is less than 40%.26 Therapeutic phlebotomy is an immediately effective therapy and is usually the first choice of the recommended treatments.

Prognosis

PV is a chronic disease. The median survival is more than 10 years with treatment.1 The major causes of death in untreated patients are hemorrhage and thrombosis. Other causes of death are complications of myeloid metaplasia or the development of leukemia.1 The incidence of transformation into an acute leukemia is greater in patients treated with radioactive phosphate or alkylating agents.26

During the later stages of PV, a post-polycythemic myelofibrosis phase occurs, characterized by a leuko-erythroblastic peripheral blood picture with an increase in immature WBCs and RBCs. The red cells will appear in a teardrop shape, with an increase in shape changes. The spleen will increase in size due to extramedullary hematopoiesis. The main characteristics of this stage are the increase in reticulin and fibrosis in the bone marrow.27

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