Polycythemia vera (PCV) is a clonal stem cell disorder associated with excessive proliferation of erythroid, granulocytic, and megakaryocytic cells from a single neoplastic stem cell. Even though all cell lines are affected, erythroid precursors dominate and thus result in the characteristic increase in red cell mass. The diagnosis should be considered when patients have an elevated hemoglobin/hematocrit above the 95th percentile or there is a significant increase from the patients prior documentated baseline, or the patient displays PCV-related features (thrombocytosis, leukocytosis, microcytosis, splenomegaly, aquagenic pruritus, thrombosis, or erythromelalgia) and a high normal hematocrit. Unlike secondary forms of absolute erythrocytosis, which occur secondary to normal or increased erythropoietin levels, PCV results from the above-mentioned neoplastic stem cell, and serum erythropoietin levels are depressed. When the diagnosis is in doubt, screening peripheral blood samples for the Janus-Kinase 2 (JAK-2) mutation or bone marrow examination may be necessary.
Once secondary disease is diagnosed, an ABG to determine if the patient is hypoxic would be the next step. The presence of hypoxia would indicate COPD, right-to-left cardiopulmonary shunting of blood, persons living in high altitudes, carbon monoxide poisoning, smoker's polycythemia, or sleep apnea as the potential underlying etiology. Peripheral hypoxic processes not associated with hypoxia on ABG testing include high oxygen-affinity hemoglobinopathies, 2,3-diphosphoglycerate mutase deficiency, and renal artery stenosis. Both high oxygen-affinity hemoglobinopathies and 2,3-diphophoglycerate mutase deficiency are associated with a low Pa 50 level on ABG testing. Other secondary causes not associated with hypoxia of any kind include malignant tumors (hepatocellular carcinoma, renal cell carcinoma, cerebellar hemangioblastomas, and parathyroid cancers), uterine leiomyomas, renal cysts, pheochromocytoma, obesity, diuretic use, and meningiomas Before beginning a long arduous work-up, the history should include questions about androgen useage, erythropoietin doping and smoking. Smokers should abstain for three months and have a reevaluation of their hemoglobin and hematocrit values. Post-renal transplant erythrocytosis may be associated with thrombosis and responds to ACEI or ARB therapy.
Polycythemia vera usually occurs during the fifth through sixth decades of life. Males are affected more often than females, and whites are affected more often than African Americans and Asians. Symptoms result from increased blood volume, viscosity, vascular stasis, and either a thrombotic tendency or hemorrhagic diathesis, and include headache, dizziness, hematemesis, melena, gout, abdominal pain, and pruritus (especially after a hot shower or bath). Abdominal pain is secondary to splenic or renal infarcts or peptic ulcer disease. Increased release of histamine from basophils is believed to be the cause of the characteristic pruritus and peptic ulcer disease. Secondary gout is the result of hyperuricemia,which results from increased cell turnover.
Splenomegaly is a helpful finding. Splenomegaly is not a feature of secondary erythrocytosis, and unexplained splenomegaly in the presence of erythrocytosis is virtually diagnostic of polycythemia vera. The leukocyte alkaline phosphatase (LAP) level and Philadelphia chromosome help to exclude chronic myelogenous leukemia (CML) from the differential diagnosis. CML is associated with an extremely low LAP level and the presence of the Philadelphia chromosome.
As mentioned previously, an elevated erythropoietin level is diagnostic of secondary absolute erythrocytosis and its various causes, and its presence virtually excludes PCV. With a normal value, PCV is still possible so evaluation for the presence of JAK-2 mutation or bone marrow biopsy would be the next step in the evaluation. A low serum erythropoietin level is consistent with a diagnosis of PCV. In confusing cases, bone marrow biopsy is often helpful.
Therapy for PCV includes phlebotomy or phlebotomy followed by hydroxyurea or interferon-alpha therapy. Phlebotomy is the preferred therapy for young patients especially women of child bearing age. The goal of therapy is a hematocrit less than 45%. Patients should be phlebotomized 500 mL with volume replacement every other day until the hematocrit is less than 45% in caucasian males and less than 42% in females and persons of African heritage. After patients have been phlebotomized initially, patients may undergo either monthly phlebotomy or hydroxyurea therapy. Once the diagnosis of PCV has been made and therapy begun, it is important to counsel the patient not to allow other physicians to mistakenly place the patient on iron therapy. Patients with PCV sometimes progress to myelofibrosis (10% of cases) and no longer require phlebotomy. Postpolycythemic myeloid metaplasia is characterized by progressive splenomegaly, the appearance of dacryocytes on the peripheral smear and marrow fibrosis. The development of acute leukemia occurs in 25% of these patients. Patients who progress to myelofibrosis may require transfusions to treat the resultant anemia.
If thrombosis continues even after phlebotomy therapy has been instituted, treatment with either anagrelide, interferon or low dose aspirin (81 mg/day) should begin. For patients suffering from refractory pruritus, either hydroxyurea therapy or cyproheptadine (4-16 mg/day) plus ranitidine (300 mg/day) may prove helpful. Selective serotonin reuptake inhibitors are also helpful in treating associated pruritus.