A 52-year-old man comes to the physician complaining of dizziness, headaches, and pruritus after showering. He has smoked half a pack of cigarettes daily for the past fifteen years and drinks alcohol socially. Physical examination shows a reddish facial complexion and mild splenomegaly. Laboratory results are as follows:
Complete blood count Hemoglobin 19 g/dL Hematocrit 59% Erythrocytes 7.5 million/µL Platelets 550,000 /µL Leukocytes 15,600 /µL
Which of the following is the most likely cause of this patient’s findings?
Causes of polycythemia | ||||||
Etiology | Plasma | RBC | SaO2 | EPO | ||
Relative | Dehydration | ↓ | Normal | Normal | Normal | |
Absolute | Primary | Polycythemia vera | Normal | ↑ | Normal | ↓ |
Secondary | Physiologic response to hypoxemia | Normal | ↑ | ↓ | ↑ | |
Inappropriate (eg, EPO-producing | Normal | ↑ | Normal | ↑ | ||
*Polycythemia vera accounts for ~95% of primary polycythemia cases, with rare mutations other than JAK2 accounting for the remainder. EPO = erythropoietin; RBC = red blood cell; SaO2 = oxygen saturation. | ||||||
Polycythemia vera (PV) is a clonal myeloproliferative disease of pluripotent hematopoietic stem cells. Approximately 95% of patients with PV have a V617F mutation involving the JAK2 gene, a signal transduction molecule that stimulates cell growth. This mutation replaces a valine with phenylalanine, allowing constitutive proliferation of hematopoietic cells independent of circulating growth factor (eg, erythropoietin, thrombopoietin) levels.
PV presents with increased RBC mass and low erythropoietin levels. Additional manifestations can include an elevated platelet and/or WBC count, thrombotic events (from blood hyperviscosity), peptic ulceration and aquagenic pruritus (due to histamine release from basophils), and gouty arthritis (from increased cell turnover).
Physical examination typically shows a plethoric, reddened face and splenomegaly. Diagnosis is established by confirming low serum erythropoietin levels and cytogenetic studies showing a JAK2 mutation. Treatment involves serial phlebotomy as necessary to keep the hematocrit < 45%.
(Choice A) Dehydration or excessive diuresis can also cause elevated hematocrit, mild leukocytosis, and thrombocytosis due to low effective circulating volume. However, splenomegaly and symptoms such as pruritus would not be seen.
(Choice B) Hypoxia is a strong stimulus for erythropoietin production. SaO2 < 92% (PaO2 < 65 mm Hg) appears to be the threshold for the development of (physiologic) secondary polycythemia. Conditions such as chronic obstructive pulmonary disease and obstructive sleep apnea can cause secondary polycythemia. However, these will not cause leukocytosis, thrombocytosis, or splenomegaly.
(Choice D) Increased red cell life span would not be expected to cause leukocytosis and thrombocytosis.
(Choice E) EPO-producing tumors (eg, renal cell carcinoma, hepatocellular carcinoma) can cause secondary polycythemia due to abnormal erythropoietin production. Workup will show an elevated erythropoietin level. However, the combination of multiple elevated cell lines and splenomegaly is unlikely to result from a process causing secondary polycythemia.
Educational objective:
Polycythemia vera (PV) is a clonal myeloproliferative disease characterized by an increased RBC mass and low erythropoietin levels. PV can be differentiated from secondary polycythemia by the presence of leukocytosis, thrombocytosis, and/or splenomegaly. The majority of patients with PV have a JAK2 mutation causing hematopoietic stem cells to proliferate uncontrollably.