POLYCYTHEMIA VERA

POLYCYTHEMIA VERA

POLYCYTHEMIA VERA

Polycythemia vera is an acquired myeloproliferative disor­der that causes overproduction of all three hematopoietic cell lines, most prominently the red blood cells. Erythroid production is independent of erythropoietin, and the serum erythropoietin level is low. A mutation in exon 14 of JAK2 (V617F), a signaling molecule, has been demon­strated in 95% of cases. Additional JAK2 mutations have been identified (exon 12) and suggest that JAK2 is involved in the pathogenesis of this disease and is a potential thera­peutic target.

True erythrocytosis, with an elevated red blood cell mass, should be distinguished from spurious erythrocytosis caused by a constricted plasma volume. Primary polycythe­mia (polycythemia vera) is a bone marrow disorder charac­terized by autonomous overproduction of erythroid cells.

Symptoms and Signs

Headache, dizziness, tinnitus, blurred vision, and fatigue are common complaints related to expanded blood volume and increased blood viscosity. Generalized pruritus, espe­cially following a warm shower or bath, is related to hista­mine release from the basophilia. Epistaxis is probably related to engorgement of mucosal blood vessels in combi­nation with abnormal hemostasis. Sixty percent of patients are men, and the median age at presentation is 60 years. Polycythemia rarely occurs in persons under age 40 years.

Physical examination reveals plethora and engorged retinal veins. The spleen is palpable in 75% of cases but is nearly always enlarged when imaged. Thrombosis is the most common complication of polycythemia vera and the major cause of morbidity and death in this disorder. Thrombosis appears to be related both to increased blood viscosity and abnormal platelet function. Uncontrolled polycythemia leads to a very high incidence of thrombotic complications of surgery, and elective surgery should be deferred until the condition has been treated. Paradoxi­cally, in addition to thrombosis, increased bleeding can also occur. There is a high incidence of peptic ulcer disease.

Differential Diagnosis

Spurious polycythemia, in which an elevated hematocrit is due to contracted plasma volume rather than increased red cell mass, may be related to diuretic use or may occur with­out obvious cause.

A secondary cause of polycythemia should be suspected if splenomegaly is absent and the high hematocrit is not accom­panied by increases in other cell lines. Secondary causes of polycythemia include hypoxia and smoking; carboxyhemo­globin levels may be elevated in smokers. A renal CT scan or sonogram may be considered to look for an erythropoietin-secreting cyst or tumor. A positive family his­tory should lead to investigation for congenital high-oxygen-affinity hemoglobin. An absence of a mutation in JAK2 suggests a different diagnosis. However, JAK2 mutations are also commonly found in other myeloproliferative disorders, essential thrombocytosis, and myelofibrosis.

Polycythemia vera should be differentiated from other myeloproliferative disorders. Marked eleva­tion of the white blood count (above 30,000/mcL) suggests CML. Abnormal red blood cell morphology and nucleated red blood cells in the peripheral blood are seen in myelofi­brosis. Essential thrombocytosis is suggested when the platelet count is strikingly elevated.

Treatment

The treatment of choice is phlebotomy. One unit of blood (approximately 500 mL) is removed weekly until the hema­tocrit is less than 45%; the hematocrit is maintained at less than 45% by repeated phlebotomy as necessary. Patients for whom phlebotomy is problematic (because of poor venous access or logistical reasons) may be managed primarily with hydroxyurea. Because repeated phlebotomy intentionally produces iron deficiency, the requirement for phlebotomy should gradually decrease. It is important to avoid medicinal iron supplementation, as this can thwart the goals of a phle­botomy program. A diet low in iron also is not necessary but will increase the intervals between phlebotomies. Maintain­ing the hematocrit at normal levels has been shown to decrease the incidence of thrombotic complications.

Occasionally, myelosuppressive therapy is indicated. Indications include a high phlebotomy requirement, thrombocytosis, and intractable pruritus. There is evidence that reduction of the platelet count to less than 600,000/mcL will reduce the risk of thrombotic complications. Hydroxy­urea is widely used when myelosuppressive therapy is indicated. The usual dose is 500–1500 mg/day orally, adjusted to keep platelets less than 500,000/mcL without reducing the neutrophil count to less than 2000/mcL. The JAK2 inhibitor ruxolitinib is FDA-approved for patients resistant or intolerant to hydroxyurea. In a randomized study comparing best available therapy with ruxolitinib, treatment with ruxolitinib was 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. Studies of pegylated alfa-2 interferon have demonstrated consider­able efficacy, with hematologic responses in greater than 80%, as well as molecular responses in 20% (as measured by JAK2 mutations). Patients in whom molecular responses were not achieved had a higher frequency of mutations outside the JAK2 pathway and were more likely to acquire new mutations during therapy.

Low-dose aspirin (75–81 mg/day orally) has been shown to reduce the risk of thrombosis without excessive bleeding, and should be part of therapy for all patients without contra­indications to aspirin. Allopurinol 300 mg orally daily may be indicated for hyperuricemia. Antihistamine therapy with diphenhydramine or other H1-blockers and, rarely, selective serotonin reuptake inhibitors are used to manage pruritus.

Reference

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