eMedicine Specialties > Hematology > Stem Cells and Disorders

Polycythemia Vera: Differential Diagnoses & Workup

Author: Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Jan 23, 2009

Differential Diagnoses

Chronic Myelogenous Leukemia
Polycythemia, Secondary

Other Problems to Be Considered

AMM with myelofibrosis
Chronic myelomonocytic leukemia
Essential thrombocythemia

Workup

Laboratory Studies

• Automated red blood cell counts and hematocrit values (including hemoglobin levels) may be deceptive with regard to the total red blood cell mass in patients with polycythemia vera (PV). 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.
• The red blood cells in patients with polycythemia vera (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).
  

  

  This blood film at 10,000X magnification shows a giant platelet and an eosinophil. Erythrocytes show signs of hypochromia as a result of repeated phlebotomies. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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  This blood film at 10,000X magnification shows a giant platelet and an eosinophil. Erythrocytes show signs of hypochromia as a result of repeated phlebotomies. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

• An elevated white blood cell count (>12,000/µL) 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 ALP score is elevated (>100 U/L) in 70% of patients. This technique is only semiquantitative and is susceptible to interobserver and laboratory errors unless it can be performed by flow cytometry, which is not routinely available.
• The platelet count is elevated to 400,000-800,000/µL in approximately 50% of patients.
  • 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, whereas the true plasma potassium level in vivo is actually within the reference range, as shown by measuring plasma levels and by the lack of electrocardiograph (ECG) changes.
  • Morphologic abnormalities in platelets include macrothrombocytes and granule-deficient platelets.
  • Abnormal platelet function (as measured by platelet aggregation tests with epinephrine, adenosine diphosphate [ADP], or collagen) may be demonstrated, but bleeding time may be normal. Some patients' platelet-rich plasma spontaneously aggregates without the addition of any of the above substances. This indicates a propensity for thromboses.
• Routine coagulation test results are normal, with a high turnover rate for fibrinogen. These test results may be reported as abnormal in patients with increased hematocrit because of an alteration of the ratio of plasma to anticoagulant in the test tube, and the results do not reflect a true coagulopathy. Thus, the volume of the ratio of anticoagulant to blood must be modified when drawing blood for coagulation tests in patients who are polycythemic.
  • The prothrombin time (PT) and activated partial thromboplastin (aPTT) time may be artifactually prolonged because of the erythrocytosis.
  • The amount of plasma collected is low in relation to the anticoagulant in the tube.
• Bone marrow studies are not necessary to establish the diagnosis, but the finding of hypercellularity and hyperplasia of the erythroid, granulocytic, and megakaryocytic cell lines or myelofibrosis supports the diagnosis of a myeloproliferative process.
• 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.
• Fibrosis is increased and detected early by silver stains for reticulin.
• 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.
• Vitamin B-12 levels are elevated to more than 900 pg/mL in approximately 30% of patients, and 75% of patients show an elevation in the unbound vitamin B-12 binding capacity greater than 2200 pg/mL. This is because of increased transcobalamin-III, a binding protein found in white blood cells, and it reflects the total white blood cell counts in the peripheral blood and bone marrow.
• Hyperuricemia occurs in 40% of patients and reflects the high turnover rate of bone marrow cells releasing DNA metabolites.
• The new genetic tests-based diagnostic algorithm for polycythemia vera (PV) includes performing reverse transcriptase (RT)-PCR for mutations involving the JAK2 mutations and measuring serum Epo levels. These studies will probably replace the main laboratory test required by the PVSG, which is measuring plasma volume and red blood cell mass due to the difficulty of obtaining⁵¹ Cr to perform the studies. Thus, evaluating patients with "increased" hemoglobin levels with or without increases in other blood counts would require initially sending for peripheral blood mutation screening for JAK2V617F (95% positive in PV) and a concomitant measurement of serum Epo levels (low in 90% of patients with PV).
  • Presence of a positive mutation and low serum Epo is suggestive or likely for diagnosis of polycythemia vera (PV) and a bone marrow examination would provide further support (but is not essential) and provide additional information on cytogenetic abnormalities and the degree of reticulin fibrosis, if present.
  • If the JAK2 mutation is negative with all the other evidences for polycythemia vera (PV), the molecular testing should be repeated and bone marrow correlated with the findings. In this regard, the JAK2 exon 12 mutation is only offered in a limited number of academic institutions and should be tested, if possible.
  • In the absence of MPD, pure erythrocytosis should be worked up for secondary causes or familial or congenital erythrocytosis.

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 polycythemia vera (PV) and no recent hemorrhage (see below). This distinguishes polycythemia from secondary causes of polycythemia in which the serum Epo level is generally within the reference range or is elevated. Each laboratory has its own reference range for serum Epo levels.
  

  

  Bone marrow film at 400X magnification demonstrating dominance of erythropoiesis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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  Bone marrow film at 400X magnification demonstrating dominance of erythropoiesis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

• Measuring arterial oxygen saturation (SaO₂) and carboxyhemoglobin (COHb) levels is important to rule out hypoxia as a secondary cause for erythrocytosis.
  • Pulse oximetry is the most convenient method for measuring SaO₂; however, in people who smoke cigarettes, the COHb must be determined directly and subtracted to give an accurate SaO₂ value. A value below 92% indicates a causal relationship with erythrocytosis. If the fall is due to increased COHb, this is less likely to cause erythrocytosis.
  • Nocturnal oxygen desaturation due to sleep apnea is observed in 20% of patients.
• Measuring spontaneous growth of erythroid progenitors in cultures (burst-forming unit, erythroid [BFU-E]) in the absence of Epo is a very sensitive test for polycythemia vera (PV) or familial erythrocytosis, but it is not routinely available for clinical use.
• The hemoglobin-oxygen dissociation curve may be useful in a rare condition to detect a congenital hemoglobinopathy with increased oxygen affinity. This can occur in families.

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