In erythrocytosis (secondary polycythemia), the number of red blood cells (RBCs) and/or Hgb/Hct are increased as a result of an underlying condition.
The term primary polycythemia is used appropriately in the myeloproliferative disorder called polycythemia vera, in which there are elevated levels of all three peripheral blood cell lines — RBCs, white blood cells, and platelets.
Secondary polycythemia most often develops as a response to chronic hypoxemia, which triggers increased production of erythropoietin by the kidneys. The most common causes of secondary polycythemia include heavy cigarette smoking, chronic obstructive pulmonary disease (COPD), sleep apnea, and obesity hypoventilation syndrome. Other causes include estosterone replacement therapy. Erythropoietin-secreting tumors (eg, hepatocellular carcinoma, renal cell carcinoma, adrenal adenoma) cause some cases.
Secondary polycythemia must be differentiated from relative polycythemia (in which RBC numbers are normal but plasma volume is contracted. The reduction in plasma volume may be due to dehydration or to reduced venous compliance; the latter is also termed stress polycythemia or Gaisböck syndrome, and is typically seen in obese middle-aged men who are receiving a diuretic for treatment of hypertension.
To the extent that the increased RBCs alleviate tissue hypoxia, secondary polycythemia may in fact be beneficial. However, treatment with phlebotomy is indicated for patients with hematocrits higher than 60%-65%, who may experience symptoms such as impaired alertness, dizziness, headaches, and compromised exercise tolerance, and who may face increased risk for thrombosis, strokes, myocardial infarction, and deep venous thrombosis. Otherwise, secondary polycythemia is addressed by treating the underlying condition.
Testing for the JAK2 V617F mutation and an erythropoietin (EPO) level helps differentiate secondary polycythemia from polycythemia vera.
Positive JAK2 V617F mutation status with a low EPO level confirms the diagnosis of polycythemia vera.
If JAK2 V617F mutation testing is negative but the EPO level is low, then testing for other mutations in exon 12 and 13 of JAK2 helps identify a small minority of patients with polycythemia vera.
All the other patients with wild-type JAK2 and a normal or elevated EPO level have secondary polycythemia.
Measure red blood cell mass and plasma volume when repeated hematocrit levels exceed 52% in males and 47% in females. However, data from the Polycythemia Vera Study Group showed that if the hematocrit value is 60% or higher, the red blood cell mass is always increased; formal red blood cell mass and plasma volume studies are unnecessary in those cases. As a practical note, most nuclear medicine departments perform these tests very infrequently, which may raise questions about the reliability and validity of red blood cell mass and plasma volume measurements.
To measure red blood cell mass, calculate the total red blood cell mass from the dilution factor and a known volume of radiolabeled (chromium-51 [51 Cr]) autologous red blood cells. The red blood cell mass is increased if it exceeds 35 mg/kg in males and 31 mg/kg in females. Documentation of an increased red blood cell mass is essential to demonstrate true erythrocytosis.
To measure plasma volume, use radiolabeled albumin (iodine-131), similar to the process used with the red blood cell mass measurement. Plasma volume can also be calculated indirectly using total red blood cell mass and the hematocrit value.
Decreased plasma volume with a normal red blood cell mass indicates a relative polycythemia or erythrocytosis, similar to the increased hemoglobin and hematocrit levels associated with severe dehydration. Decreased plasma volume due to dehydration is the most common cause of elevated hemoglobin or hematocrit levels in the general population.
Measuring arterial oxygen saturation is important to exclude generalized hypoxemia as a cause of increased red blood cell mass. Further investigation may require performing the test while the patient is sleeping. Measured arterial oxygen saturations of less than 92% may be associated with the development of a secondary polycythemia.
Carboxyhemoglobin levels of greater than 8% in individuals who smoke or those who may have an occupational exposure to carbon monoxide may be associated with the development of polycythemia.
The hemoglobin-oxygen dissociation curve may be determined in patients with a lifelong history (particularly a familial history) of erythrocytosis with normal oxygen saturation and normal levels of 2,3-diphosphoglycerate.
Formulas are available in which the measured arterial and venous oxygen saturations can be used to calculate the partial pressure of oxygen (PaO2) at which hemoglobin is 50% saturated with oxygen. This partial pressure value is a good estimate of the entire oxygen dissociation curve, because the shape of the dissociation curve varies only minimally, even with very high and very low oxygen affinity hemoglobins.
Endogenous serum levels of EPO may be helpful to determine inappropriate production of EPO. Serum EPO levels also may be very helpful in distinguishing between primary and secondary polycythemias.
In polycythemia vera and congenital/familial primary polycythemias, EPO levels are usually low to low-normal. In secondary physiologic or nonphysiologic polycythemias, EPO levels are usually normal or elevated.
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Excessive polycythemia, usually defined as hematocrit levels higher than 65-70%, may result in increased whole blood viscosity. This, in turn, may lead to impaired blood flow locally, resulting in thrombosis. Hyperviscosity may also lead to generalized sluggish blood flow, resulting in impaired tissue oxygenation in multiple organs, which may lead to decreased mentation, fatigue, generalized weakness, and poor exercise tolerance.
The development of secondary erythrocytosis in response to tissue hypoxia is physiologic and probably beneficial to many patients. The expanded red blood cell mass may partially or totally compensate for the lack of oxygen delivery and result in tissue oxygenation to its normal level.
At hematocrit levels higher than 60-65%, however, the compensatory increase in red blood cells reaches the limit of benefit and begins to compromise circulation because of hyperviscosity. The latter leads to greater tissue hypoxia and erythropoietin secretion, a continued increase in red blood cells, and further impairment of circulation.
To restore viscosity and maintain circulation at its optimal level, phlebotomize or remove the offending red blood cells. Some patients with extreme secondary polycythemia have impaired alertness, dizziness, headaches, and compromised exercise tolerance. They may also be at increased risk for thrombosis, strokes, myocardial infarction, and deep venous thrombosis. These are the patients who require phlebotomy.
The optimal level of hematocrit is one that is as close as possible to normal without impairing the compensatory benefit of increased oxygen delivery. This may be determined individually by symptom relief or decompensation, depending on the viscosity level.
Repeated phlebotomies result in iron deficiency that can cause other symptoms. This may limit or retard further erythropoiesis so that additional phlebotomies may not be necessary. Proper treatment of the underlying condition in polycythemia, when possible, is important, such as the following:
Provide oxygen supplementation to patients with chronic obstructive pulmonary disease.
Recommend weight loss in patients with obesity and hypoventilation.
Recommend smoking cessation for patients with carboxyhemoglobin.
Surgically correct arteriovenous shunts.
No medications are available to treat the blood disorder of secondary polycythemia. Treat the underlying health problem.