Acquired Secondary Polycythemia

Polycythemia may be present in clinical situations associated with chronic arterial oxygen desaturation. Cardiovascular defects involving right-to-left shunts and pulmonary diseases interfering with proper oxygenation are the most common causes of hypoxic polycythemia. Clinical findings usually include cyanosis, hyperemia of the sclerae and mucous membranes, and clubbing of the fingers. As the hematocrit rises to > 65%, clinical manifestations of hyperviscosity, such as headache and hypertension, may require phlebotomy (Chapter 97.3). Living at high altitudes also causes hypoxic polycythemia; the hemoglobin level increases approximately 4% for each rise of 1,000 m in altitude. Partial obstruction of a renal artery rarely results in polycythemia. Polycythemia has also been associated with benign and malignant tumors that secrete erythropoietin. Exogenous or endogenous excess of anabolic steroids also may cause polycythemia.

Congenital Secondary Polycythemia

Lifelong or familial polycythemia should trigger a search for a congenital etiology. Inherited polycythemias may be transmitted as dominant or recessive disorders. Autosomal dominant polycythemia is caused by hemoglobins that have increased oxygen affinity (P₅₀ [partial pressure of oxygen in the blood at which the hemoglobin is 50% saturated] < 20 mm Hg). Other congential forms of polycythemia include erythropoietin receptor mutations resulting in an enhanced effect of erythropoietin or mutations in the von Hippel–Lindau gene that result in altered intracellular oxygen sensing. Another rare cause is autosomal recessive 2,3-ddiphosphoglyceric acid (2,3-DPG) deficiency, which leads to a left shift of the oxygen dissociation curve, increased oxygen affinity, and consequent polycythemia.

Subtle decreases in oxygen delivery to tissues may cause polycythemia. Congenital methemoglobinemia resulting from an autosomal recessive deficiency of cytochrome b5 reductase may cause cyanosis and polycythemia (Chapter 456.7). Most affected individuals are asymptomatic. Neurologic abnormalities may be present in patients whose enzyme deficits are not limited to hematopoietic cells. Hemoglobin M disease (autosomal dominant) causes methemoglobinemia and can lead to polycythemia. Cyanosis may occur in the presence of as little as 1.5 g/dL of methemoglobin but is uncommon in other hemoglobin variants unless hyperviscosity results in localized hypoxemia (Chapter 97.3).