Classification of the Polycythemias
Polycythemia, also called erythrocytosis, is an increase in the number of circulating red blood cells per volume of blood, as reflected by an elevated hematocrit or hemoglobin level. The three major categories of polycythemia are (1) relative polycythemia, (2) secondary polycythemia, and (3) primary polycythemia, or polycythemia vera.
In relative polycythemia, the red blood cell mass is normal but the plasma volume is decreased. Secondary polycythemia is caused by an elevated erythropoietin level. Polycythemia vera is a neoplastic stem cell disorder characterized by an autonomous overproduction of red blood cells and, often, of white blood cells and platelets [see 12:XVII Chronic Myelogenous Leukemia and Other Myeloproliferative Disorders].
Initial Evaluation
Patients are often asymptomatic, and the elevated hemoglobin or hematocrit level is usually discovered accidentally. When such an increase is found, it should be promptly evaluated to determine its cause [see Figure 1 ]. Any family history of polycythemia and the results of any previous hematocrit determinations should be obtained. History and physical examination findings suggestive of congenital heart disease, severe chronic obstructive pulmonary disease (COPD), or sleep apnea syndrome should be sought, and the presence or absence of splenomegaly should be determined. The results of the complete blood count, including the platelet count and white blood cell differential, should be critically reviewed for abnormalities. Findings of leukocytosis, thrombocytosis, an occasional circulating immature white blood cell, or increased basophils are suggestive of polycythemia vera and argue against secondary causes of erythrocytosis.
A hematocrit level of 60% or higher in a man or 57% or higher in a woman virtually always indicates a true increase in red blood cell mass (i.e., primary or secondary polycythemia). If the patient’s hematocrit is below these values but above normal, a red blood cell mass study is required.1 To perform this study, a sample of the patient’s red blood cells is labeled with radioactive chromium (51Cr) ex vivo and injected back into the patient. A second blood sample is then obtained to quantitate the concentration of 51Cr-labeled red blood cells among the unlabeled red blood cells. In parallel, the patient is given an injection of albumin labeled with radioactive iodine (125I) to measure the plasma volume. If a contraction of plasma volume is noted, the patient has relative polycythemia; if an increase in red blood cell mass is noted, the patient has true (i.e., primary or secondary) poly-cythemia. Once a relative or an absolute increase in red blood cell mass is documented, an exact diagnosis should be determined [see Figure 1].
Relative Polycythemia
Patients with relative polycythemia (Gaisbock syndrome) are often obese, hypertensive men who may also be heavy smokers2; they often are 45 to 55 years of age—a decade younger than typical for polycythemia vera patients [see 12:XVII Chronic Myel-ogenous Leukemia and Other Myeloproliferative Disorders]. It has been estimated that 0.5% to 0.7% of the healthy male population in the United States have relative polycythemia. Diuretic use for treatment of hypertension may exacerbate the deficit in plasma volume, and smoking-induced high carboxyhemoglobin levels or hypoxemia may also play a role.
Relative polycythemia is usually mild (hematocrit lower than 55%). In patients with a hematocrit lower than 60%, this diagnosis should be considered, and the red blood cell mass and plasma volume should be measured [see Figure 1] to avoid an extensive and ultimately frustrating workup for other causes of poly-cythemia. Patients with relative polycythemia fall into two major groups: (1) those with normal red blood cell mass and clearly decreased plasma volume and (2) those with red blood cell mass and plasma volume at the upper and lower range of normal, respectively. Behavior modification (e.g., an exercise regimen and smoking cessation) is recommended for these patients. Hematocrit returns to normal over time in approximately one third of patients.
Secondary Polycythemia
Secondary polycythemia occurs when erythropoietin production is increased as a result of chronic tissue hypoxia. Causes of tissue hypoxia include life at high altitude, high-affinity hemoglobin, cardiopulmonary disease, obstructive sleep apnea, obesity-hypoventilation syndrome, and high serum levels of carboxyhemoglobin. Polycythemia also occurs in some renal and hepatic disorders, in rare genetic disorders, and from treatment with androgens or erythropoietin. polycythemia caused by appropriate increases in erythropoietin production
Life at High Altitude
Initial human adaptation to high altitude includes increases in the respiratory rate, cardiac output, and the level of 2,3-bis-phosphoglycerate to facilitate oxygen unloading from hemoglobin to the tissues [see Figure 2]. Within 6 to 24 hours after a person has ascended to a high altitude, erythropoietin levels increase, resulting in reticulocytosis within 24 to 48 hours. Over several days, serum erythropoietin levels return to normal, but the increase in hematocrit is sustained. In addition to the increase in red blood cell mass, a modest decrease in plasma volume occurs. A patient’s travel history should be taken to determine the likelihood of high-altitude effect and thus possibly avoid having to conduct an extensive workup.
Life at high altitude, such as in the Rocky Mountains of North America or the Andes of South America, may result in chronic mountain sickness characterized by headaches, dizziness, mental slowing, dyspnea, and weakness. In such cases, individuals may have a hematocrit as high as 63% and are at risk for the development of pulmonary hypertension, early onset cardiovascular disease, and proteinuria. Treatment with low-dose an-giotensin-converting enzyme (ACE) inhibitors (e.g., enalapril, 5 mg orally each day) can improve the hematocrit and renal function over 1 to 2 years.3
Figure 1 This flowchart depicts an approach to the evaluation of a patient with polycythemia, as evidenced by an elevated hematocrit or hemoglobin level on routine complete blood count. (CBC—complete blood cell count; COPD—chronic obstructive pulmonary disease; EEC—endogenous erythroid colony; EPO—erythropoietin; RBC—red blood cell count; WBC—white blood cell count) *For coverage of polycythemia vera, see 12:XVII Chronic Myelogenous Leukemia and Other Myeloproliferative Disorders.
High-Affinity Hemoglobin
High-affinity hemoglobin is caused by an amino acid substitution in either the a chain or, more commonly, the | chain of globin that impedes the normal conformational change during oxygen loading and unloading. This condition results in an impaired ability to release oxygen in the tissues, causing tissue hy-poxia and increased erythropoietin production. More than 100 mutations causing high-affinity hemoglobin have been described. They are usually familial and are inherited in an autoso-mal dominant manner but are occasionally the result of spontaneous mutation. A review of the patient’s medical history should show evidence of lifelong polycythemia. The hematocrit is usually less than 60%, and the white blood cell and platelet counts are normal. The partial pressure of oxygen at which hemoglobin is 50% saturated (P50) should be measured; it is reduced in patients with high-affinity hemoglobin [see Figure 2].
Hemoglobin electrophoresis is usually not helpful, because many of the mutations that result in high-affinity hemoglobin are electrophoretically silent. However, the mutations can be identified by DNA sequencing. In rare instances, patients have congenital 2,3-bisphosphoglycerate mutase deficiency; the presentations of these patients are similar to those of patients with high-affinity hemoglobin. Patients with high-affinity hemoglobin or congenital 2,3-bisphosphoglycerate mutase deficiency usually have no symptoms of hyperviscosity and require no therapy. Phlebotomy decreases exercise tolerance in these patients and should not be used.
Cardiopulmonary Disease
Polycythemia caused by cardiopulmonary defects (e.g., Eisenmenger complex, univentricular heart, and tetralogy of Fallot) results from a failure to load oxygen onto hemoglobin adequately in the lungs.4,5 The hematocrit may range from 60% to 75% and cause profound symptoms of hyperviscosity, including headache, dizziness, visual disturbances, fatigue, paresthesias, irritability, and decreased mental acuity. Platelet microparticles are overproduced in cyanotic congenital heart disease, especially when the hematocrit is greater than 60%; overabundance of these microparticles may contribute to the hemostatic abnormalities in these patients.6 Some adults with cyanotic congenital heart disease have decompensated erythrocytosis, which is characterized by unstable, rising hematocrit and symptomatic hy-perviscosity; these patients may benefit from phlebotomy.
Figure 2 Depicted is the oxygen-hemoglobin dissociation curve (solid black line). The partial pressure of oxygen at which hemoglobin is 50% saturated (P50) is normally 27 mm Hg (broken blue lines). The presence of high-affinity hemoglobin shifts the curve to the left, reflecting impaired oxygen unloading in the tissues (solid blue line). An increase in the level of 2,3-bisphosphoglycerate—a feature of adaptation to high altitude—shifts the curve to the right, reflecting increased oxygen unloading in the tissues (broken black line).
Other adults with cyanotic congenital heart disease have compensated erythrocytosis, in which a stable (though elevated) hemat-ocrit is maintained without overt symptoms of hyperviscosity; these patients do not require phlebotomy.5 A practical approach is to cautiously phlebotomize patients whose hematocrits range from 60% to 65% and who have symptoms of hyperviscosity.5 The extent of phlebotomy should be guided by the patient’s symptoms. Acute dehydration, which exacerbates poly-cythemia, should be excluded from the diagnosis before phlebotomy is performed, and the volume of blood withdrawn should be replaced with isotonic saline. Iron deficiency should be avoided by the use of oral iron therapy if necessary because severe iron deficiency may alter red blood cell rheology and increase the risk of stroke.
Severe COPD can be associated with polycythemia, although the clinical features of COPD usually predominate. In patients who continue to smoke, both hypoxemia and elevated carboxy-hemoglobin levels may contribute to the development of poly-cythemia. Reduction of hematocrit in patients with significant polycythemia caused by COPD results in increased cerebral blood flow, relief from the symptoms of dizziness and headache that are associated with hyperviscosity, and dramatic improvement in mental alertness. In a study of seven patients with severe COPD and pulmonary hypertension, serial phlebotomy reduced pulmonary arterial pressure and improved exercise capacity.
Obstructive Sleep Apnea
Sleep apnea syndrome is estimated to occur in 4% of middle-aged men and 2% of women and is underdiagnosed.9 Risk factors include obesity, male sex, central body fat distribution, and a family history of obstructive sleep apnea.10 The prevalence of sleep apnea syndrome increases as the body mass index increases. Recurrent episodes of upper airway collapse during sleep obstruct air movement, resulting in intermittent nocturnal hypox-emia. Patients may have a history of loud snoring, alternating with periods of silence lasting 10 seconds to 1 minute, followed by gasping sounds. Fragmented sleep results in excessive daytime sleepiness and impaired work performance and may increase the risk of motor vehicle accidents.11 The hematocrit may be modestly increased in patients with severe obstructive sleep apnea, and this syndrome should be considered in patients with unexplained polycythemia. Nocturnal polysomnography with quantitation of the apnea-hypopnea index can establish the diagnosis. Management of this condition may include weight loss, nasal continuous positive airway pressure, and surgery12 [see 11:X1II Disorders of Sleep and 14:VI Ventilatory Control during Wakefulness and Sleep].
Obesity-Hypoventilation Syndrome
Obesity-hypoventilation syndrome is also known as pickwickian syndrome, in reference to Charles Dickens’ astute description of the obese coachboy who had excessive daytime sleepiness. Patients with this syndrome are usually morbidly obese (body mass index of 40 kg/m2) and have chronic daytime hypoxemia and hypercapnia, in part because of a blunted venti-latory response to these stimuli.13 Many of these patients also have nocturnal obstructive sleep apnea.14 Hypoxemia provides the stimulus for increased erythropoietin production and poly-cythemia. Other clinical features associated with obesity-hy-poventilation syndrome are daytime hypersomnolence and corpulmonale. Management of this condition includes weight loss and progesterone therapy to stimulate the central respiratory drive [see 14:VI Ventilatory Control during Wakefulness and Sleep].
Figure 3 (a) Binding of erythropoietin to the erythropoietin receptor on an erythroid progenitor cell triggers association and activation of the protein-tyrosine Janus kinase-2 (JAK2) and the initiation of signal transduction, stimulating growth of the erythroid progenitor cell. (b) Binding of the protein-tyrosine phosphatase SH-PTP1 results in dephosphorylation of JAK2 and termination of signal transduction.
High Carboxyhemoglobin Levels
Long-term exposure to carbon monoxide results in chronic high carboxyhemoglobin levels [see 8:I Management of Poisoning and Drug Overdose]. Carbon monoxide binds to hemoglobin with an affinity 210 times greater than that of oxygen, decreasing the quantity of hemoglobin available for oxygen transport. Carbon monoxide binding also increases the affinity of the remaining heme groups for oxygen, shifting the oxygen-hemoglobin dissociation curve to the left [see Figure 2] and impairing the unloading of oxygen in the tissues. By these mechanisms, long-term carbon monoxide exposure can cause polycythemia. Cigarette and cigar smokers and persons with long-term occupational exposure to automobile exhaust in poorly ventilated areas (e.g., toll-booth operators, underground-garage attendants, and truck loaders) are at risk. The average carboxyhemoglobin level in the blood of nonsmokers is approximately 1% or less, whereas it is 4% in smokers and as high as 15% in heavy smokers.
Symptoms may include subtle neuropsychiatric abnormalities and exacerbation of angina (likely as a result of impaired myocar-dial oxygen delivery). The diagnosis can be established by measuring the percentage of carboxyhemoglobin in the blood. Because the half-life of carboxyhemoglobin is approximately 5 hours, the test should be done late in the day, when the patient has smoked the usual number of cigarettes or spent several hours in the work environment. Polycythemic smokers usually have both elevated red blood cell mass and decreased plasma volume. For smokers, the most effective therapy is smoking cessation; abnormal blood and plasma levels revert to normal within 3 months. No therapy is available for persons with occupational polycythemia, with the exception of avoidance of the workplace.
Polycythemia caused by renal and hepatic disorders
Polycythemias arise when erythropoietin production is increased because of renal or, less often, hepatic disorders. In adults, approximately 90% of erythropoietin production occurs in the kidney, and 10% occurs in the liver. Because of the intricate regulation of erythropoietin production in the kidney, distortion of renal anatomy can result in polycythemia. Case reports document that renal cysts, hydronephrosis, focal glomeru-lonephritis, and Bartter syndrome can cause polycythemia. After renal transplantation, approximately 10% to 20% of patients have transient or persistent polycythemia. It is important to identify these patients, because they are at increased risk for arterial or venous thrombotic events and may require phlebotomy or ACE inhibitors.15 In addition, primary malignancies of the kidney or liver can cause polycythemia. Polycythemia develops in approximately 3% of patients with renal cell carcinoma. Erythro-poietin production by primary renal cell carcinoma or hepatoma tissues is the likely cause of polycythemia in these patients. In rare instances, focal nodular hyperplasia of the liver, hepatic or cerebral hemangiomas or hemangioblastomas,16 uterine fibroids, adrenal adenomas, and pheochromocytomas have been reported to cause polycythemia. Mutations in the von Hippel-Lindau gene have been associated with cerebral hemangioblastomas or renal cell cancer, either as a part of the von Hippel-Lindau syndrome or as an acquired somatic mutation.17
Familial polycythemia
The familial polycythemias are rare diseases resulting from inborn mutations affecting hematopoietic or nonhematopoietic cells. The molecular mechanisms causing familial polycythemia may be different in different families, and mutations may be inherited in an autosomal dominant or recessive fashion.
A high frequency of autosomal recessive familial poly-cythemia is found in the Chuvash region of Russia.Elegant studies have demonstrated that a point mutation in the von Hippel-Lindau gene results in enhanced stability of hypoxia-inducible factor-1a, which regulates transcription of the erythropoietin gene.19 Thus, Chuvash polycythemia is a congenital disorder of oxygen homeostasis. Chuvash polycythemia has also been identified in families of European or Asian descent.20 Patients with Chuvash polycythemia present during the teenage years with headache, dizziness, fatigue, and dyspnea on exer-tion.21 Affected members of these families have a high hemat-ocrit (approximately 60%) and elevated levels of erythropoietin, and they have thromboembolism and cerebrovascular disorders, which shorten survival. Treatment is with phlebotomy.
In autosomal dominant familial polycythemia, abnormalities in the erythropoietin receptor have been identified in a small proportion of patients.22-25 Erythropoietin initiates its biologic effects by binding to a specific receptor that is found on the surface of erythroid progenitor cells, precursor cells, and certain other types of cells. Binding triggers a cascade of events, including activation of the protein tyrosine Janus kinase-2 (JAK2) [see Figure 3]. Tyrosine phosphorylation of the erythropoietin receptor creates docking sites for other signal transduction molecules and for the protein-tyrosine phosphatase SH-PTP1, which dephos-phorylates JAK2 and terminates signal transduction. In one large Finnish family with polycythemia, a point mutation in the erythropoietin receptor affecting SH-PTP1 rendered the ery-throid progenitor cells hypersensitive to erythropoietin. Interestingly, one member of this family who had a hematocrit of 60% won three gold medals in cross-country skiing at the 1964 Winter Olympics. Another proportion of patients with autosomal dominant familial polycythemia have been found to have mutations in the erythropoietin receptor, resulting in deletion of the carboxyl terminus negative regulatory region of the receptor.23-25 Individuals with autosomal dominant familial polycythemia have erythrocytosis that remains stable over time; they do not experience leukocytosis or thrombocytosis, and no long-term clinical consequences have been described.
Polycythemia caused by drug use
Androgens (e.g., testosterone) can cause polycythemia by stimulating erythropoietin production.26 The elevation in hemat-ocrit is usually mild, and hematocrit returns to normal 2 to 3 months after discontinuance of anabolic steroid use. Since re-combinant human erythropoietin and darbepoetin have become available, concern has been raised that competitive athletes involved in endurance sports, such as bicycle racing, cross-country skiing, and long-distance running, might surreptitiously self-inject this drug to improve athletic performance.27-29 Phlebotomy followed by blood doping is known to improve performance in runners and skiers. A similar increase in hematocrit can be achieved with erythropoietin injections, which can increase maximal exercise capacity. The unmonitored increase in red blood cell production may cause significant polycythemia, which, when coupled with exercise-induced dehydration, can have tragic consequences. Erythropoietin abuse has been linked to the deaths of competitive bicyclists.27 The use of erythropoietin or darbepoetin to improve athletic performance is banned by the International Olympics Committee. Recombinant human ery-thropoietin can be detected in the urine by isoelectric focusing.30
