JAK2 V617F mutation is present in 97% of patients with polycythemia vera

Test your medicine knowledge with the MKSAP challenge, in partnership with the American College of Physicians.

An 81-year-old woman is evaluated for a 1-year history of headaches, redness of the face, and itching. She indicates being otherwise capable of performing her daily activities on her farm. She reports no shortness of breath, chest pain, or difficulty sleeping. Medical history is significant for hypertension; she has never smoked and does not drink alcohol. Her only medication is hydrochlorothiazide.

On physical examination, vital signs are normal except for a blood pressure of 160/90 mm Hg; BMI is 19. Abdominal examination shows splenomegaly.

Laboratory studies:

Erythropoietin	Undetectable
Hemoglobin	17.5 g/dL (175 g/L)
Leukocyte count	11,000/µL (11 × 10⁹/L)
Platelet count	400,000/µL (400 × 10⁹/L)

Which of the following is the most appropriate diagnostic test to perform next?

A. Calreticulin mutation testing
B. JAK2 V617F mutation testing
C. Polymerase chain reaction for BCR-ABL
D. Sleep study

MKSAP Answer and Critique

The correct answer is B. JAK2 V617F mutation testing.

The most appropriate diagnostic test to perform is for the JAK2 V617Fmutation. Polycythemia vera (PV) is a disorder of the myeloid and erythroid stem cells that causes erythropoietin-independent proliferation of erythrocytes. This older adult patient has an elevated hematocrit level, a low erythropoietin level, and splenomegaly, indicating a likely diagnosis of PV. More than 97% of patients with PV have the JAK2 mutation. The 2016 World Health Organization major criteria for PV include increased hemoglobin level (>16.5 g/dL [165 g/L] in men and >16 g/dL [160 g/L] in women), a bone marrow biopsy specimen showing hypercellularity and increased reticulin and collagen fibrosis, and positive findings for JAK2 or exon 12 mutation. JAK2 mutation testing can be done on peripheral blood granulocytes.

Calreticulin mutation has been recently found in JAK2-negative myeloproliferative disorders such as essential thrombocythemia and myelofibrosis. Evaluation for the calreticulin mutation would not be indicated in the absence of thrombocytosis or cytopenia.

Translocation of chromosomes 9 and 22, resulting in a BCR-ABL fusion gene, is seen in patients with chronic myeloid leukemia (CML). CML can present with elevated leukocyte and platelet counts, but polycythemia is not a typical presentation.

Most causes of secondary erythrocytosis share the mechanism of an elevated erythropoietin level, which is most commonly driven by hypoxemia. Polycythemia can be the presenting symptom of undiagnosed sleep apnea, and all patients with polycythemia should be screened for symptoms and signs of sleep apnea. However, in this patient with no symptoms, a low erythropoietin level, and splenomegaly, PV is much more likely, and JAK2 mutational analysis should be performed first.

Key Point

JAK2 V617F mutation is present in 97% of patients with polycythemia vera, so testing should be performed in patients in whom the disease is suspected.

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