LabMed

Polycythemia Vera (PV)

At a Glance

Most patients being evaluated for polycythemia vera (PV) are incidentally discovered to have an increased hematocrit (>48% in women and >52% in men, respectively) and/or hemoglobin (>15 g/dL in women and >17 g/dL in men, respectively). Sustained expansion of the red cell mass, as seen in PV and other erythrocytoses, typically takes weeks or months to occur; thus, most PV patients are initially asymptomatic.

PV should also be suspected when the complete blood count (CBC) shows somewhat lower hematocrit/hemoglobin levels (either just outside the reference range or near the top of the reference range) accompanied by an elevated white blood cell count (>10,000/uL), especially with increased basophils on differential and/or platelet count (>450,000/uL) in the absence of infectious or inflammatory illness that could cause a reactive increase in these counts.

However, once the hemoglobin rises to 18-20 g/dL, patients generally become symptomatic and report:

  • chronic headaches

  • general malaise

  • easy fatigability

  • pruritus (often after showering)

Physical examination may demonstrate:

  • facial plethora (prominent and bloodshot eyes with red-purple mucous membranes)

  • dilated blood vessels of the conjunctiva and ocular fundus

  • splenomegaly

When the hemoglobin is greater than 20 g/dL, life-threatening conditions may occur, including:

  • venous and/or arterial thrombosis

  • hemorrhage (especially gastrointestinal (GI) when taking aspirin/NSAIDs)

Rarely, PV patients with chronic and sustained GI bleeding develop iron deficiency; such patients may have leukocytosis and/or thrombocytosis but a relatively normal hematocrit/hemoglobin. The laboratory clues to this situation are the hypochromia seen on peripheral smear and the low mean corpuscular volume (MCV). When such patients are not suspected of having PV, well-meaning but mistaken iron replacement therapy can rapidly cause symptomatic erythrocytosis.

Clinical findings or situations that would point the clinician away from PV and toward other causes of high hemoglobin/hematocrit include:

  • hypoxic diseases (especially pulmonary illness)

  • erythrocytosis at a younger age (especially in children)

  • patients living at high-altitudes

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Diagnostic criteria (World Health Organization (WHO) revised) for PV requires both major criteria and one minor criterion or one major criterion plus two minor criteria.

Major criteria:

  1. Hemoglobin greater than 18.5 g/dL in men, greater than 16.5 g/dL in women, or increased red cell volume

  2. JAK2 V617F mutation present or similar mutation in JAK2 exon 12

Minor criteria:

  1. Blood—prominent leukocytosis or thrombocytosis and/or Marrow—hypercellularity of all cell lines with abnormal megakaryocytes

  2. Serum Erythropoietin less than 4 mU/mL (or lower than reference range)

  3. In vitro demonstration of endogenous erythroid colony (EEC) formation

Note that not all PV patients will have such an extreme elevation in hemoglobin as seen in Major Criterion 1. If there is a sustained increase of at least 2 g/dL from baseline values, hemoglobin values greater than 17 g/dL in men and greater than 15 g/dL in women fulfill the major criterion. Similarly, a red cell mass greater than 25% above the mean predicted normal value also suffices.

(Table 1)

Table 1

Test Results Indicative of the Disorder
JAK2 V617F mutation Red cell mass Endogenous erythroid colony formation
present >25% above the mean predicted normal value present

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Caveats on laboratory testing for PV

Hemoglobin/hematocrit is not high enough to meet criteria.

  • Microcytosis (MCV < 70-80) is present (e.g., iron deficiency).

JAK2 V617F mutation is highly sensitive (present in 90-95% of patients with a clinical PV profile) but nonspecific.

  • Mutation is also present in upwards of 50-70% of patients with essential thrombocytosis or primary myelofibrosis (marrow examination may help).

JAK2 V617F mutation is not present.

  • Other JAK2 exon 12 mutations may exist.

Erythropoietin value is in the normal range.

  • EPO levels rise after phlebotomy or with iron deficiency (check MCV).

Stem cell assay—normal expansion of burst-forming unit-erythroid (BFU-E) does not occur without added erythropoietin. EEC formation is not as sensitive for PV as the presence of the JAK2 mutation.

  • False positive—EEC formation is present with erythropoietin receptor defects.

What Lab Results Are Absolutely Confirmatory?

If reactive or physiologic etiologies for polycythemia are not present, early measurement of the JAK2 V617F mutation is justified. Presence of this mutation outweighs the relative importance of other clinical criteria.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

Other scenarios

PV is clinically present but in the absence of any JAK2 mutation:

  • marrow aspirate and biopsy to look for hypercellularity/dysplasia

  • transcobalamin III increased (hard-to-find reference lab test)

Secondary polycythemia is possible based on clinical history/exam:

  • pediatric patients—hemoglobin analysis, hemoglobin P50, intracellular 2,3-DPG levels

  • cardiac studies—imaging, catheterization

  • lung function studies—blood gases, pulse oximetry, carbon monoxide

  • erythropoietin-producing tumors—EPO level, imaging of the head and abdomen, intravenous pyelogram

Iron deficiency:

  • serum iron, total iron-binding capacity, and serum ferritin—iron deficiency criteria are met but with hemoglobin greater than 10-11 g/dL

What Factors, If Any, Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Other genetic studies for related myeloproliferative diseases that, generally, used to rule out PV include:

  • BCRABL1 for chronic myelogenous leukemia

  • MPL W515K/L for a tiny subset of essential thrombocytosis

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