Secondary erythrocytosis is erythrocytosis that develops secondary to disorders that cause tissue hypoxia, inappropriately increased erythropoietin production, or increased sensitivity to erythropoietin.
(See also Overview of Myeloproliferative Neoplasms.)
In secondary erythrocytosis, only red blood cells (RBCs) are increased, whereas in polycythemia vera, RBCs, white blood cells (WBCs), and platelets will usually be increased. Any elevation of hemoglobin or hematocrit above normal values for age and sex is considered erythrocytosis.
Etiology of Secondary Erythrocytosis
Common causes of secondary erythrocytosis include
Smoking
Chronic arterial hypoxemia
Tumors (tumor-associated erythrocytosis)
Use of androgenic steroids
Surreptitious erythropoietin use
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 and increases in erythropoietin production.)
Right to left arteriovenous shunts in the lungs
Proline hydroxylase 2 and hypoxia-inducible factor 2 alpha (HIF-2α) mutations
Spurious erythrocytosis may occur with hemoconcentration (eg, due to burns, diarrhea, or diuretic use).
In patients who smoke cigarettes, reversible erythrocytosis results mainly from tissue hypoxia due to elevation of blood carboxyhemoglobin concentration, and there is usually plasma volume reduction. Levels will normalize with smoking cessation.
Patients with chronic hypoxemia (arterial hemoglobin 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 hematocrit 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 hemoglobin becomes 50% saturated) and, if possible, determining the complete oxyhemoglobin dissociation curve (see figure Oxyhemoglobin Dissociation Curve). Standard hemoglobin electrophoresis may be normal and cannot reliably exclude this cause of erythrocytosis.
Evaluation of Secondary Erythrocytosis
Tests done when isolated erythrocytosis is present include (see figure Algorithm for the Diagnosis of Erythrocytosis)
Arterial oxygen saturation
Serum erythropoietin levels
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 evaluated as for polycythemia vera.
Serum erythropoietin level is elevated in patients with hypoxia-induced erythrocytosis (or level is inappropriately normal for their elevated hematocrit) and in patients with tumor-associated erythrocytosis. Patients with elevated erythropoietin levels (and no indication of hypoxia) or microscopic hematuria should undergo abdominal imaging, central nervous system imaging, or both to seek a renal lesion or other tumor sources of erythropoietin.
Algorithm for the Diagnosis of Erythrocytosis
P50 measures the affinity of hemoglobin for oxygen; a normal result excludes a high oxygen-affinity hemoglobinopathy (a familial abnormality) as the cause of erythrocytosis.
Treatment of Secondary Erythrocytosis
Treatment of secondary erythrocytosis is directed at the underlying disorder. For example, secondary erythrocytosis that is caused by oxygen deprivation may be treated with oxygen. People who smoke are advised to quit and are offered treatments to assist quitting.
In some people, phlebotomy is used to lower the number of red blood cells, but phlebotomy is rarely needed in secondary erythrocytosis.
