IM Board Review

Erythrocytosis due to presumed polycythemia vera

Author and Disclosure Information

 

References

A 40-year-old woman with hypertrophic   obstructive cardiomyopathy presents to the hematology clinic for a second opinion regarding a history of headaches and fatigue for the past 10 years. She has been diagnosed with idiopathic erythrocytosis, presumed to be due to polycythemia vera. She periodically undergoes phlebotomy to keep her hematocrit below 41%, and this markedly improves her headaches. She denies shortness of breath, cough, fever, weight loss, joint pain, and visual or other neurologic symptoms. She has never reported pruritus related to bathing or exposure to water.

She does not smoke, drink alcohol, or use illicit drugs. She works as a pharmacy technician. She says her father died of cancer (no further details available) and describes a family history of gastrointestinal malignancy in her grandfather and paternal aunt. She takes aspirin, metoprolol, and spironolactone for her cardiomyopathy.

Physical examination reveals generalized plethora, more marked on her cheeks and face, and mild bilateral pitting pedal edema. No lymphadenopathy or hepatosplenomegaly can be palpated. Other systems, including the cardiac, respiratory, and nervous systems, are normal.

ERYTHROCYTOSIS AND POLYCYTHEMIA VERA

1. In patients with erythrocytosis, which of the following is not characteristic of polycythemia vera?

  • Erythromelalgia and postbathing pruritus
  • Splenomegaly
  • History of thrombosis
  • Gout
  • Hematuria

Erythrocytosis—an abnormally high concentration of red blood cells in the peripheral blood—is a laboratory finding. It often reflects an increase in the total quantity or mass of red blood cells in the body (polycythemia) but can sometimes be due to decreased plasma volume (spurious polycythemia).1 Erythrocytosis can be caused by a number of diseases, hereditary and acquired, and can be classified as primary or secondary (Table 1).

Symptoms arise from an increase in the total blood volume and red blood cell mass, often leading to dilated capillaries and other blood vessels. Symptoms can occur regardless of the cause and classically include headache (often described as diffuse heaviness), dizziness, and a tendency for bleeding or thrombosis.2 Symptoms are relieved when the hematocrit is lowered.

Several features in the history and physical examination of a patient being evaluated for erythrocytosis can suggest an underlying cause. Smoking, chronic respiratory insufficiency, and congenital cyanotic heart disease point to secondary erythrocytosis and can usually be identified at the outset. A history of occupational exposure to carbon monoxide (such as engine exhaust) should be elicited carefully. A family history of erythrocytosis should raise suspicion of a heritable condition such as a hemoglobinopathy associated with increased oxygen affinity or rare forms of primary erythrocytosis associated with endogenous overproduction of erythropoietin or activating mutations of the erythropoietin receptor.3 Iatrogenic causes such as androgen supplementation, erythropoietin abuse, and postrenal-transplant erythrocytosis should also be considered.

Secretion of erythropoietin or erythropoietinlike proteins by a malignant neoplasm is a rare but important cause of erythrocytosis. For example, renal cell carcinoma may present with erythrocytosis secondary to excessive erythropoietin production, and hematuria can be an early symptom.

Polycythemia vera

Polycythemia vera, a myeloproliferative neoplasm, is characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. The bone marrow shows a panmyelosis that is often accompanied by leukocytosis or thrombocytosis, or both, in the peripheral blood.

Symptoms such as severe itching after exposure to hot water (aquagenic pruritus) and periodic attacks of redness, swelling, and pain in the hands or feet, or both (erythromelalgia), have been described in patients with polycythemia vera. Splenomegaly is relatively common, seen in approximately two-thirds of patients.4 Hyperuricemia (from increased cell turnover) and gout are also associated with polycythemia vera, as is a history of arterial and venous thrombosis.5

Hematuria is not commonly seen in polycythemia vera, although bleeding from the bladder, vagina, or uterus has been described.

CASE RESUMED: INITIAL LABORATORY TESTS

Results of our patient’s initial laboratory tests are:

  • Hemoglobin 16.9 g/dL (reference range 11.5–15.5)
  • Hematocrit 48.8% (36.0–46.0)
  • Mean corpuscular volume 85.2 fL (80–100)
  • Platelet count 328 × 109/L (150–400)
  • White blood cell count 9.14 × 109/L (3.7–11.0)
  • Absolute neutrophil count 5.95 × 109/L (1.45–7.5)
  • Blood urea nitrogen 12 mg/dL (8–25)
  • Creatinine 0.5 mg/dL (0.7–1.4)
  • Lactate dehydrogenase 180 U/L (100–220)
  • Uric acid 3.0 mg/dL (2.0–7.0)
  • Thyroid-stimulating hormone 2.2 µU/mL (0.4–5.5).

The patient undergoes additional tests, including a serum erythropoietin level and hemoglobinopathy screen. Bone marrow aspiration and biopsy are performed, with cytogenetic analysis, chromosomal microarray analysis, and molecular testing for mutation of the Janus kinase 2 (JAK2) gene.

CONFIRMING SUSPECTED POLYCYTHEMIA VERA

2. In patients with suspected polycythemia vera, which of the following laboratory tests is most useful in making the diagnosis?

  • Hemoglobin, hematocrit, and red blood cell mass
  • Serum erythropoietin level
  • Arterial blood gases with co-oximetry
  • Testing for the JAK2 mutation
  • Bone marrow aspiration and biopsy

The aim of the initial workup of erythrocytosis is to differentiate polycythemia vera from secondary causes of erythrocytosis.

Hemoglobin, hematocrit, red cell mass

Erythrocytosis is defined by an abnormal elevation in the hematocrit (> 48% in women or > 49% in men), hemoglobin concentration (> 16.0 g/dL in women or > 16.5 g/dL in men), or red blood cell mass. The red blood cell count should not be used as a surrogate for red blood cell mass, since some anemias (especially thalassemia minor) can be associated with an increase in the number of red blood cells but a low hemoglobin concentration.

Isotope dilution techniques to determine the red cell mass and plasma volume can differentiate true erythrocytosis from a spurious elevation due to a decrease in plasma volume.6,7 However, this is an expensive, time-consuming test that is not widely available and so is rarely performed.8

JAK2 mutation testing

The initial evaluation of a patient with erythrocytosis has changed significantly in the past 10 years with the discovery of the JAK2 gene and its role in the pathogenesis of polycythemia vera and other myeloproliferative neoplasms.

JAK2, located at 9p24, codes for a tyrosine kinase important for signal transduction in hematopoietic cells. Mutations in this gene have been shown to promote hypersensitivity to cytokines, including erythropoietin.9 The most common somatic mutation occurs within exon 14 at base pair 1849 and results in a phenylalanine-for-valine amino acid substitution in the JAK2 protein, designated V617F. Less commonly, mutations occur elsewhere in exons 12 to 15, with more than 50 different mutations described; nonpolymorphic mutations are assumed to have biologic effects similar to those of V617F.

Taken together, the JAK2 V617F and non-V617F mutations have a diagnostic sensitivity of 98% to 100% for polycythemia vera. For practical purposes, this means that the presence of a JAK2 mutation can be used as a clonal marker to distinguish polycythemia vera from reactive secondary causes of erythrocytosis. A JAK2 mutation is one of three major diagnostic criteria for polycythemia vera in the 2016 revision to the 2008 World Health Organization criteria (Table 2).10 Of note, this mutation is not specific for polycythemia vera and can also be found in other myeloproliferative neoplasms, including primary myelofibrosis and essential thrombocythemia.

Absence of a JAK2 mutation makes polycythemia vera unlikely, so this test is most useful in making the diagnosis.

Serum erythropoietin

Serum erythropoietin testing can be very useful to distinguish polycythemia vera from secondary erythrocytosis. Low levels suggest polycythemia vera, while high levels are seen in secondary processes.11

This test is best used along with JAK2 V617F mutation analysis as an initial step in evaluating patients with erythrocytosis. When JAK2 V617F mutation analysis is negative, a low serum erythropoietin level should prompt further testing for non-V617F JAK2 mutations, whereas a normal or elevated erythropoietin level should be evaluated further with tests to distinguish hereditary from acquired secondary causes of erythrocytosis.

Arterial blood gas analysis and co-oximetry

Arterial blood gas analysis can reveal hypoxemia, pointing to a cardiorespiratory process driving the erythrocytosis, whereas co-oximetry can be used to identify the presence and amount of carboxyhemoglobin in the blood.

Bone marrow biopsy

An increase in pleomorphic megakaryocytes in the bone marrow without stainable iron is often described as characteristic in polycythemia vera patients, but it is not diagnostic. Panmyelosis with increased cellularity is the norm but can be seen in other myeloproliferative neoplasms. The morphologic features of bone marrow are now included as one of the major diagnostic criteria for polycythemia vera (Table 2).

Next Article:

Your patient has chronic leukemia: Now what?

Related Articles