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Secondary Erythrocytosis

(Secondary Polycythemia)

By Jane Liesveld, MD, Professor, Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center ; Patrick Reagan, MD, Fellow in Hematology and Medical Oncology, University of Rochester Medical Center

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Patient Education

Secondary erythrocytosis is erythrocytosis that develops secondary to disorders that cause tissue hypoxia, inappropriately increase erythropoietin production, or increase sensitivity to erythropoietin.

In secondary erythrocytosis, only RBCs are increased, whereas in polycythemia vera, RBCs, WBCs, and platelets may be increased. Any elevation of Hb or Hct above normal values for age and sex is considered erythrocytosis.

Common causes of secondary erythrocytosis include

  • Smoking

  • Chronic arterial hypoxemia

  • Tumors (tumor-associated erythrocytosis)

  • Use of androgenic steroids

  • Surreptitious erythropoietinuse

Less common causes include certain congenital disorders such as

  • High oxygen-affinity hemoglobinopathies

  • Erythropoietin receptor mutations

  • Chuvash polycythemia (in which a mutation in the VHL gene affects the hypoxia-sensing pathway)

  • Proline hydroxylase 2 and hypoxia-inducible factor 2 alpha (HIF-2α) mutations

Spurious erythrocytosis may occur with hemoconcentration (eg, due to burns, diarrhea, or diuretics).

In patients who smoke, reversible erythrocytosis results mainly from tissue hypoxia due to elevation of blood carboxyhemoglobin concentration; levels often normalize with smoking cessation.

Patients with chronic hypoxemia (arterial Hb oxygen concentration < 92%), typically due to lung disease, right-to-left intracardiac shunts, renal transplantation, prolonged exposure to high altitudes, or hypoventilation syndromes, often develop erythrocytosis. The primary treatment is to alleviate the underlying condition, but oxygen therapy may help, and phlebotomy may decrease viscosity and alleviate symptoms. Because in some cases the elevated Hct is physiologic, phlebotomy should be limited to the extent necessary to relieve symptoms (in contrast to polycythemia vera, where the goal is to normalize the hematocrit).

Tumor-associated erythrocytosis can occur when renal tumors, cysts, hepatomas, cerebellar hemangioblastomas, or uterine leiomyomas secrete erythropoietin. Removal of the lesion is curative.

High oxygen–affinity hemoglobinopathies are very rare. This diagnosis is suggested by a family history of erythrocytosis; it is established by measuring the P50 (the partial pressure of oxygen at which Hb becomes 50% saturated) and, if possible, determining the complete oxyhemoglobin dissociation curve. Standard Hb electrophoresis may be normal and cannot reliably exclude this cause of erythrocytosis.

Evaluation

Tests done when isolated erythrocytosis is present include

  • Arterial oxygen saturation

  • Serum erythropoietinlevels

  • P50 to rule out a high oxygen-affinity hemoglobinopathy

A low or normal serum erythropoietin level is diagnostically nonspecific. If polycythemia vera is suspected, the patient should be worked up as for polycythemia vera and other causes for inappropriate erythropoietin production such as renal dysfunction should be sought.

Serum erythropoietin level is elevated in patients with hypoxia-induced erythrocytosis (or level is inappropriately normal for their elevated Hct) and patients with tumor-associated erythrocytosis. Patients with elevated erythropoietin levels (and no indication of hypoxia) or microscopic hematuria should undergo abdominal imaging, CNS imaging, or both to seek a renal lesion or other tumor sources of erythropoietin.

P50 measures the affinity of Hb for oxygen; a normal result excludes a high-affinity Hb (a familial abnormality) as the cause of erythrocytosis.