Polycythemia Vera

Polycythemia vera involves increased production of red blood cells (RBCs), white blood cells (WBCs), and platelets. Thus, polycythemia vera is a panmyelosis because of elevations of all 3 peripheral blood components. Increased production confined to the RBC line is termed erythrocytosis; isolated erythrocytosis may occur with polycythemia vera but is more commonly due to other causes (see secondary erythrocytosis Secondary Erythrocytosis Secondary erythrocytosis is erythrocytosis that develops secondary to disorders that cause tissue hypoxia, inappropriately increased erythropoietin production, or increased sensitivity to erythropoietin... read more ). In polycythemia vera, RBC production proceeds independently of the serum erythropoietin level, which is usually low but can be normal.

Extramedullary hematopoiesis may occur in the spleen, liver, and other sites that have the potential for blood cell formation. In polycythemia vera, in contrast to the secondary erythrocytoses, the red cell mass increase is often initially masked by an increase in the plasma volume that leaves the hematocrit in the normal range. This is particularly the case in women, who can present with hepatic vein thrombosis and a normal hematocrit.

Iron deficiency Iron Deficiency Anemia Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as occurs in celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more may eventually occur because of the increased need for iron to produce RBCs. In the presence of iron deficiency of any kind, RBCs become increasingly smaller (microcytic erythrocytosis) because the red cell hemoglobin concentration (MCHC) is defended at the expense of red cell volume (mean corpuscular volume [MCV]). Although patients with iron deficiency from other causes become anemic, patients with polycythemia vera have increased RBC production and thus even when iron-deficient initially have a normal hematocrit level but an elevated red cell count and microcytic RBC indices; this combination of findings is a hallmark of polycythemia vera.

Eventually, about 10 to 15% of patients progress to a syndrome similar to primary myelofibrosis Primary Myelofibrosis Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis... read more but with a better survival.

Transformation to acute leukemia Acute leukemias Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more is rare and may take many years to develop. The risk of transformation is increased with exposure to alkylating agents, such as chlorambucil, radioactive phosphorus (mostly of historic significance), and hydroxyurea. Acute leukemia is more common in men, particularly after age 60.

Polycythemia vera itself is often asymptomatic, but eventually the increased red cell volume and viscosity cause weakness, headache, light-headedness, visual disturbances, fatigue, and dyspnea. Pruritus often occurs, particularly after a hot bath or shower (aquagenic pruritus) and may be the earliest symptom. The face may be red and the retinal veins engorged. The palms and feet may be red, warm, and painful, sometimes with digital ischemia (erythromelalgia). Over 30% of patients have splenomegaly.

Thrombosis may cause symptoms in the affected site (eg, neurologic deficits with stroke or transient ischemic attack; leg pain, swelling, or both with lower extremity thrombosis; unilateral vision loss with retinal vascular occlusion).

Bleeding, typically from the gastrointestinal tract, occurs in about 10% of patients.

Hypermetabolism can cause low-grade fevers and weight loss and suggests progression to secondary myelofibrosis, which is clinically indistinguishable from primary myelofibrosis Primary Myelofibrosis Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis... read more but has a better prognosis.

Polycythemia vera is often first suspected because of an abnormal CBC (eg, hemoglobin > 16.5 g/dL [> 165 g/L] in men or >16.0 g/dL [> 160 g/L] in women). However, hemoglobin and hematocrit levels may be misleading. The hematocrit may be normal because of plasma volume expansion, and the hemoglobin may be normal if there is concurrent iron deficiency. Thus, an elevated red cell count is the most useful measure of erythrocytosis. Along with erythrocytosis, the neutrophil and platelet counts are usually, but not invariably, increased.

In patients with only an elevated hematocrit, polycythemia vera may be present, but secondary erythrocytosis Secondary Erythrocytosis Secondary erythrocytosis is erythrocytosis that develops secondary to disorders that cause tissue hypoxia, inappropriately increased erythropoietin production, or increased sensitivity to erythropoietin... read more , a much more common cause of elevated hematocrit, must be considered first. Polycythemia vera should always be considered in patients with a normal hematocrit but microcytic erythrocytosis and evidence of iron deficiency Diagnosis Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as occurs in celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more ; this combination of findings is a hallmark of polycythemia vera.

Polycythemia vera may also be suspected based on clinical findings, including thrombosis in an unusual site, such as Budd-Chiari syndrome in women or portal vein thrombosis in men.

The challenge in diagnosing polycythemia vera is that several other myeloproliferative neoplasms can have the same genetic mutations and bone marrow findings. Although the hallmark of polycythemia vera is erythrocytosis, some patients present with isolated leukocytosis or isolated thrombocytosis and do not initially manifest an elevated hematocrit level. Thus, multiple findings must be integrated.

Patients suspected of having polycythemia vera typically should have testing for JAK2V617F (exon 14) and JAK2 exon12 mutations. If these results are negative, testing for CALR and LNK mutations is done. The presence of a known causative mutation in a patient with clear erythrocytosis is strongly suggestive of polycythemia vera. If erythrocytosis is not clearly present, direct measurement of red cell mass and plasma volume is done (eg, with chromium-labeled RBCs, although this test is usually available only at specialized centers) to help differentiate between true and relative polycythemia and between polycythemia vera and other myeloproliferative disorders (which do not have an increased red cell mass). If erythrocytosis is present but secondary causes have not been excluded, serum erythropoietin level should be measured; patients with polycythemia vera typically have low or low-normal serum erythropoietin levels; elevated levels suggest secondary erythrocytosis.

Bone marrow aspirate and biopsy is not diagnostic of polycythemia vera. When done, bone marrow aspirate and biopsy typically shows panmyelosis, large and clumped megakaryocytes, and sometimes an increase in reticulin fibers. However, no bone marrow findings absolutely differentiate polycythemia vera from other disorders of excessive erythrocytosis (eg, congenital familial polycythemia) or from other myeloproliferative neoplasms, of which polycythemia vera is the most common.

Acquired von Willebrand disease Von Willebrand Disease Von Willebrand disease (VWD) is a hereditary quantitative deficiency or functional abnormality of von Willebrand factor (VWF), which causes platelet dysfunction. Bleeding tendency is usually... read more (as a cause of bleeding) may be diagnosed by showing decreased plasma von Willebrand factor antigen using the ristocetin cofactor test.

Nonspecific laboratory abnormalities that may occur in polycythemia vera include elevated vitamin B12 and B12-binding capacity, hyperuricemia and hyperuricosuria (present in ≥ 80% of patients), and decreased expression of MPL (the receptor for thrombopoietin) in megakaryocytes and platelets. These tests are not needed for diagnosis.

The World Health Organization diagnostic guidelines are based on hemoglobin and hematocrit levels and red cell mass determination, but these guidelines are limited because they ignore leukocytosis, thrombocytosis, and splenomegaly and characterize polycythemia vera as having isolated erythrocytosis, which is rarely the case (1, 2 Diagnosis references Polycythemia vera is a chronic myeloproliferative neoplasm characterized by an increase in morphologically normal red cells (its hallmark), but also white cells and platelets. Ten to 15% of... read more ). Actually, < 10% of patients with polycythemia vera present with erythrocytosis alone, and neither a bone marrow aspirate and biopsy nor a serum erythropoietin assay is useful diagnostically.

Some studies cite a median survival of 24 years, but many patients live much longer, even when myelofibrosis develops. Survival is anticipated to improve further as newer therapies become more widely used.

Thrombosis is the most common cause of morbidity and death, followed by the complications of myelofibrosis and development of leukemia. Gene expression profiling or other characteristics may aid in the identification of prognostic subgroups.

Therapy must be individualized according to age, sex, medical status, clinical manifestations, and hematologic findings. However, previous criteria used to stratify treatment by high- or low-risk classification such as age and extreme thrombocytosis (1,000,000/mcL [1000 × 10⁹/L]) have not been prospectively validated and are not recommended to guide therapy.

Although very high leukocyte counts (> 30,000/mcL [> 30 × 10⁹/L]) have been correlated with disease acceleration, there is no evidence that lowering the leukocyte count with chemotherapy prolongs survival. In fact, the polycythemia vera stem cell is resistant to conventional chemotherapy, and lowering the leukocyte or platelet count to normal does not prevent thrombosis if the red cell mass is not normalized by phlebotomy.