Polycythemia Vera

Essentials of Diagnosis

• Autonomous overproduction of erythroid cells

• Elevated RBC mass

• Hematocrit > 49% in males or > 48% in females

• JAK2 V617F mutation

• Splenomegaly

• Normal arterial oxygen saturation

• Usually elevated white blood count and platelet count

General Considerations

• Although characterized by autonomous overproduction of erythroid cells, there is overproduction of all hematopoietic cell lines

Demographics

• 60% of patients are men

• Median age at presentation is 60 years

• Rarely occurs in persons under age 40 years

Symptoms and Signs

• Common complaints related to expanded blood volume and increased blood viscosity include

  • Headache

  • Dizziness

  • Tinnitus

  • Blurred vision

  • Fatigue

• Generalized pruritus is related to histamine release from basophils

• Epistaxis is probably related to engorgement of mucosal blood vessels in combination with abnormal hemostasis

• Thrombosis

  • Appears to be related both to increased blood viscosity and abnormal platelet function

  • Incidence of thrombotic complications of surgery is very high if polycythemia is uncontrolled; elective surgery should be deferred until the condition has been treated

• Increased bleeding can also occur

• Physical examination reveals plethora and engorged retinal veins

Differential Diagnosis

• Spurious polycythemia may be related to diuretic use or may occur without obvious cause

• Suspect secondary causes of polycythemia if

  • Splenomegaly is absent

  • Elevated hematocrit is not accompanied by increases in other cell lines

• Secondary causes of polycythemia include

  • Hypoxia: cardiac disease, pulmonary disease, high altitude

  • Carboxyhemoglobin: smoking

  • Kidney lesions

  • Erythropoietin-secreting tumors (rare)

  • Abnormal hemoglobins (rare)

• Polycythemia vera should be differentiated from other myeloproliferative disorders (Table 13–14)

Laboratory Findings

• Hematocrit (at sea level) that exceeds 49% in males or 48% in females

• RBCs

  • RBC morphology is normal at presentation (Table 13–14)

    • However, microcytosis, hypochromia, and poikilocytosis may result from iron deficiency following treatment by phlebotomy

  • RBC mass is elevated

• White blood cells

  • Usually normal morphology, though basophilia and eosinophilia are frequently present

  • Count is usually elevated to 10,000–20,000/mcL

• Platelets

  • Morphology is usually normal

  • Count is variably increased, sometimes to counts exceeding 1,000,000/mcL

• Erythropoietin levels are suppressed

• Bone marrow

  • Hypercellular, with hyperplasia of all hematopoietic elements

  • Iron stores are usually absent

• Vitamin B₁₂ levels are strikingly elevated because of increased levels of transcobalamin III

• Overproduction of uric acid may lead to hyperuricemia

• Progressive hypersplenism may also lead to elliptocytosis

• Confirm diagnosis with JAK2 mutation testing

• Phlebotomy is treatment of choice

  • One unit of blood (approximately 500 mL) is removed weekly until the hematocrit is < 45%

  • Hematocrit is maintained at < 45% by repeated phlebotomy as necessary

  • Avoid medicinal iron supplementation

  • A diet low in iron-containing foods is not necessary but will increase the intervals between phlebotomies

• Indications for myelosuppressive therapy

  • High phlebotomy requirement

  • Thrombocytosis

  • Intractable pruritus

• Hydroxyurea

  • Used for patients in whom phlebotomy is problematic and when myelosuppressive therapy is indicated

  • Usual dose is 500–1500 mg/day orally, adjusted to keep platelets < 500,000/mcL without reducing the neutrophil count to < 2000/mcL

• Ruxolitinib

  • JAK2 inhibitor

  • Approved by FDA for patients resistant to or intolerant or hydroxyurea

  • Associated with greater benefit for both hematocrit control without phlebotomy (60%) and splenic volume reduction (38%)

  • Symptom burden improved by greater than 50% in 49% of patients

• Pegylated alfa-2 interferon

  • Has demonstrated considerable efficacy, with hematologic response rates > 80%, as well as molecular responses in 20% (as measured by JAK2 mutations)

  • Patients failing to achieve molecular responses had a higher frequency of mutations outside the JAK2 pathway and were more likely to acquire new mutations during therapy

  • Side effects were generally acceptable and much less significant than with nonpegylated forms of interferon

• Low-dose aspirin (75–81 mg/day orally)

  • Has been shown to reduce the risk of thrombosis without excessive bleeding

  • Should be part of therapy for all patients without contraindications to aspirin

• Avoid alkylating agents because of increased risk of conversion to acute leukemia

• Lastly, a new and promising therapeutic strategy is induction of apoptosis via the p53 pathway through pharmacologic inhibition of human double minute 2 (mdm2)

Complication

• Peptic ulcer disease

Prognosis

• Median survival of > 15 years

• Arterial thrombosis is major cause of morbidity and mortality

• Over time, polycythemia vera may convert to myelofibrosis or to chronic myeloid leukemia (CML)

• In approximately 5% of cases, the disorder progresses to acute myeloid leukemia (AML), which is usually refractory to therapy

When to Refer

• Patients with polycythemia vera should be referred to a hematologist

When to Admit

• Inpatient care is rarely required