Wintrobe’s Clinical Hematology
11th Edition

POLYCYTHEMIA (ABSOLUTE ERYTHROCYTOSIS)
Primary Polycythemia
POLYCYTHEMIA VERA
Polycythemia vera is discussed in Chapter 85.
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PRIMARY FAMILIAL POLYCYTHEMIA (“CHUVASH POLYCYTHEMIA”)
Familial erythrocytosis or polycythemia is a term used to describe instances in which two or more members of a family have polycythemia, do not have polycythemia vera, and have no identifiable “secondary” causes (62,64). This finding can result from a constellation of pathophysiologic mechanisms, including abnormalities of oxygen-Hb interaction, or idiopathic constitutive erythropoietin secretion. These syndromes are discussed under etiologies of secondary polycythemia, below.
Primary familial polycythemia is a term used to describe a syndrome observed in families with abnormalities of the erythropoietin receptor, resulting in hypersensitivity to erythropoietin and consequent erythrocytosis (65,66 and 67). This particular autosomal-dominant trait does not necessarily confer an adverse prognosis early in life: The propositus of the first such family described was an Olympic gold medallist in cross-country skiing (65). However, these individuals are at increased risk for thrombotic and vascular mortality later on (68,69). A variant of this syndrome occurs with high frequency among the people of the Chuvashia region of the former Soviet Union. These individuals appear to have a mutation in the oxygen-sensing pathway regulating erythropoietin production and also in the response of erythroid progenitors to erythropoietin (70,71 and 72).
Secondary Polycythemia [Physiologically Appropriate (Hypoxic)]
Insufficient oxygen supply to the tissues may result from any of the following, alone or in combination: (a) decreased ambient oxygen pressure (e.g., high altitude); (b) pulmonary diffusion or mixing abnormalities; (c) right-to-left cardiopulmonary shunts, as in cyanotic congenital heart disease; (d) hypoventilation; or (e) altered oxygen-carrying affinity of Hb. In all of these disorders, insufficient tissue oxygenation leads to increased erythropoietin production and a consequent increase in red cell mass (see Chapter 7).
HIGH-ALTITUDE ERYTHROCYTOSIS
In 1890, Viault showed that erythrocytosis develops during sojourn at high altitude (73). He found erythrocyte counts of 7.5 to 8.0 × 1012 cells/L not only in natives of the Peruvian Andes working in a mine at an altitude of 4392 m above sea level, but also in himself and in a traveling companion, although his blood count in Lima (160 m above sea level) had been normal. On a Mt. Everest expedition, researchers demonstrated that red cell volume and values of total Hb rose progressively as higher altitudes were attained; at 19,000 feet (5800 m), mean values were 49% above those at sea level. The increase in total blood volume was partially masked by reductions in plasma volume (74). Recent investigations of the control of erythropoiesis at high altitudes indicate that a sharp increase in erythropoietin production occurs within the first week of high-altitude exposure and is associated with mobilization of iron stores and evidence of iron-deficient erythropoiesis (75). Mechanisms of adaptation to living at high altitude apparently are multiple and differ between ethnic groups (76,77).
The rapid ascent to high altitude is accompanied by symptoms of fatigue, dizziness, pulsating headache, anorexia, nausea, vomiting, insomnia, and irritability—a syndrome well known to mountain climbers and residents of high altitudes and referred to as acute mountain sickness (78,79 and 80). The symptoms first appear some 4 to 6 hours after reaching a high altitude but may be delayed for as many as 96 hours, suggesting that the pathogenesis represents more than simple hypoxia. The incidence is greatest in younger persons, in those flying to high altitude, or in those who climb fast and spend few nights acclimatizing. Gender, the weight of the load carried, and recent respiratory infection do not appear to affect the incidence (81). Severity is greatest in the young and correlates with the speed of ascent and the altitude reached (81). Thus, all persons develop symptoms if they are suddenly transported from sea level to 15,000 feet (4570 m) or higher, whereas a few develop symptoms at 8000 to 10,000 feet (2400 to 3000 m) (74). After 4 to 8 days, acclimatization usually occurs, and symptoms remit spontaneously (78,81). In some individuals, however, symptoms may progress to cerebral confusion, coma, and even death related to pulmonary edema unless the subject is returned to low altitude (79,82).
The pathogenesis of acute mountain sickness may involve hypoxia and subsequent excessive secretion of antidiuretic hormone and adrenal steroids with resulting fluid retention, increased blood volume, and finally cerebral edema, pulmonary congestion, or both (79,83). The incidence and severity of symptoms can be considerably reduced by administering diuretics, such as acetazolamide or furosemide (79,80 and 81). The administration of dexamethasone has also proven effective in the prevention and treatment of this disorder (84).
The events associated with acclimatization after arrival at high altitude are not understood completely but probably include the following:
An increase in erythrocyte 2,3-diphosphoglycerate (DPG) levels and a shift to the right in the oxygen-Hb dissociation curve, thus allowing better tissue delivery of oxygen despite decreased arterial oxygen saturation (77,82,85). The increase in 2,3-DPG appears to compensate for the left shift in the curve that results from the initial hypocapnia and increase in arterial pH (79,82).
Increased erythropoietin production with subsequent increase in iron mobilization (discussed above), reticulocytosis (86), and increase in red cell mass and blood volume.
Correction of the initial excessive antidiuretic hormone and adrenal steroid secretion and return to the normal diurnal variation of plasma steroid levels (79).
The final result is a new equilibrium at decreased oxygen saturation and carbon dioxide tension with increases in alveolar ventilation, respiratory frequency, and red cell mass (78,84). These manifestations of acclimatization are quickly lost on descent to sea level, even after many years of residence at high altitude.
At an altitude of 15,000 feet, well-acclimated individuals had hematocrit values of approximately 0.60 and, although cyanotic, had no significant limitations of physical activity (87). This physiologic state is accomplished by hematologic adjustments and alterations in ventilatory rate, the diffusing capacity of the lungs, and the anatomic relation of capillaries to muscles (76), as well as increased levels of myoglobin (76) and altered enzymes within the muscle cell (88). Cardiac output remains normal despite the increase in blood viscosity imposed by polycythemia.
In some individuals, however, after a few or many years of good adaptation, excessive erythrocytosis develops, and arterial oxygen saturation may fall to as low as 60% (normal, 81%). An incapacitating illness characterized by alveolar hypoventilation develops. This entity is known as chronic mountain sickness or Monge disease (88). Diminished mental acuity, headaches, dyspnea, fatigue, reduced physical fitness, nausea, vomiting, diminution of visual acuity, dizziness, tinnitus, vague or even excruciating pains in the extremities, paresthesias, and cough are characteristic symptoms. If the condition advances, symptoms include incessant dyspnea, aphonia, profound lethargy, and even coma. The face is bluish violet or almost black, the eyelids are edematous and bluish, the sclerae are intensely colored by distended capillaries, the tongue is thick, the hands are
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enlarged and turgid, the fingers are clubbed, and dependent edema may be observed. The thorax is more barrel shaped than in healthy inhabitants of the same region and altitude. Hypotension is often present. The spleen and the liver are infrequently enlarged, unless cardiac failure ensues.
Erythrocytosis is more marked than in normal residents of high altitudes, with VPRC up to 0.84 L/L and Hb values as high as 28.0 g/dl. MCV is normal or slightly increased, and the mean corpuscular Hb concentration (MCHC) is normal (87). Normal reticulocyte and leukocyte counts are usually observed (88,89). Hyperbilirubinemia owing to unconjugated bilirubin may be pronounced. Red cell turnover is greater in these individuals than in normal residents of high altitudes (90). Platelet counts usually are normal or high, yet epistaxis is common, and hemoptysis, bleeding of the gums, and purpura may occur. Red cell volume is greatly increased (88 to 95 ml/kg body weight) (90).
Affected individuals usually are in the fourth to sixth decade of life. Remissions and relapses are described. Ascent to still higher altitudes aggravates symptoms, whereas descent to sea level relieves them. Cardiac impairment does not appear until late in the disease course, and death occurs more often from hemorrhage, pulmonary tuberculosis, or bronchopneumonia than from cardiac insufficiency.
At first, the disease was considered a distinct entity. It has been suggested that the disease is an exaggeration of the process of acclimatization and aging, because patients with chronic mountain sickness had Hb concentrations within the normally distributed values for large groups of native residents. Support for this suggestion comes from the observation that chronic lung disease increases the likelihood of chronic mountain sickness (91). Chronic mountain sickness has not been reported to occur in natives of the Himalayas (92,93). This may reflect in part occupational differences, namely mining, and a consequently high incidence of chronic lung disease in the Andes as compared with the pastoral occupation of the Sherpas.
Differentiation of chronic mountain sickness from other causes of hypoxic polycythemia should not be difficult. Cases of congenital or acquired cyanotic heart disease can be distinguished by the cardiac findings. Polycythemia vera is not altered by increased ambient oxygen tension, whereas in Monge disease, descent to sea level produces complete relief of symptoms, together with a pronounced reduction in the blood volume and restoration of normal blood counts (87). Medroxyprogesterone also produces clinical and laboratory improvement, apparently by decreasing the frequency of periods of sleep apnea and accompanying arterial oxygen desaturation (94,95).
PULMONARY DISEASE
A variety of diseases, such as chronic obstructive pulmonary disease, diffuse pulmonary infiltrates (fibrous or granulomatous), kyphoscoliosis, and multiple pulmonary emboli, lead to erythrocytosis as the result of inadequate oxygenation of the blood circulating through the lungs. Not all patients with lung disease and decreased arterial oxygen saturation, however, have elevated Hb or hematocrit levels (96,97), and only in approximately 50% is an increase in red cell mass noted (98). The reason for this suboptimal response to hypoxia is not clear, but it does not appear to result from a decrease in erythropoietin production or the presence of chronic infection (96,97 and 98). When polycythemia occurs, it usually is associated with increased MCV, reduced MCHC (99), and normal MCH (96) values. The red cell changes have been attributed to increased water uptake by the cell, which in turn may result from carbon dioxide retention (96). It has been suggested that carbon dioxide retention may inhibit the marrow response, but no confirmatory evidence is available (96). If polycythemia is present, it is corrected by chronic oxygen administration (100).
Cavernous hemangiomas of the lung may be associated with erythrocytosis (101). Pulmonary arteriovenous fistulae should be suspected when a murmur is heard in a lung field in association with erythrocytosis, cyanosis, and other symptoms suggestive of a pulmonary disorder (102,103 and 104).
Chronic Cor Pulmonale
The clinical picture of chronic cor pulmonale varies, but oxygen deficiency with arterial desaturation and elevated pulmonary artery pressure are of central importance (105,106). Polycythemia with its associated increase in blood viscosity and volume appears to be the physiologic price of a compensatory mechanism progressively extended to the point at which it is more injurious than beneficial (107). As in less severe pulmonary disease, the MCV of the red cells tends to be elevated, whereas the MCHC generally is decreased (108).
Ayerza syndrome (Primary Pulmonary Hypertension)
Ayerza syndrome, characterized clinically by slowly developing asthma, bronchitis, dyspnea, and cyanosis (“black cardiacs”) with associated polycythemia, was described by Ayerza in 1901. The syndrome probably represents right-sided heart failure consequent to primary pulmonary hypertension (109,110 and 111).
CYANOTIC HEART DISEASE
Red cell counts of 7.0 to 8.5 × 1012/L are common in persons with congenital heart disease; counts as high as 10.0 to 13.9 × 1012/L have been reported (112). Polycythemia occurs in patients with a partial shunt of the blood from the pulmonary circuit. The most common defects producing such polycythemia are pulmonary stenosis (usually with defective ventricular or atrial septum, patent foramen ovale, or patent ductus arteriosus), persistent truncus arteriosus, complete transposition of the great vessels, and the tetralogy of Fallot (pulmonary stenosis, defective ventricular septum, dextroposition of the aorta, right ventricular hypertrophy). Individuals with such defects exhibit evidence of disturbed cardiorespiratory function, marked cyanosis, clubbing of the fingers and toes, and sometimes stunted growth.
The total plasma volume may be reduced to below normal levels, but the increase in the size of the red cell mass is so great that the total blood volume usually is higher than normal (113,114). Erythroid hyperplasia is observed in the marrow (112,115).
The general consensus is that low oxygen tension resulting from shunting of unoxygenated blood through or around the lungs with consequent desaturation of the arterial blood stimulates erythropoietin production. The arterial oxygen saturation often is as low as 30 to 35%. With successful operative intervention, this value may be significantly corrected, with resolution of polycythemia.
ACQUIRED HEART DISEASE
In acquired heart disease, such erythrocytosis as may develop is of minor degree and is correlated to some extent with the degree of cardiopulmonary decompensation. Polycythemia is reportedly accompanied by evidence of intensified erythropoiesis in the bone marrow, an increase in red cell mass, and some macrocytosis (116).
HYPOVENTILATION SYNDROMES
Polycythemia is found occasionally in patients who exhibit no evidence of pulmonary disease or cardiovascular shunts. The primary defect in at least some of this group appears to be an inadequate ventilatory drive from the respiratory center in the brain (105,117). Such a defect has been reported in patients with the Pickwickian syndrome, so called because of the description of
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Joe, the hypersomnolent fat boy, in Dickens’s The Pickwick Papers (118). In the setting of extreme obesity, these patients exhibit somnolence, cyanosis, and hypercapnia and may develop periodic respiration, ultimately with right ventricular failure. Voluntary hyperventilation alleviates the hypercapnia, and in many patients, loss of weight restores normal alveolar ventilation and reverses the syndrome (105). Alveolar hypoventilation and erythrocytosis, however, do not develop in all obese individuals; it appears that only in the presence of an insensitive respiratory center does a massive panniculus limit respiratory function and result in alveolar hypoventilation, hypoxemia, and hypercapnia (119). In some patients, the decreased ventilatory drive is of unknown cause or is a result of idiopathic disease of the medullary respiratory center (Ondine curse) (117,120); other etiologies include bulbar poliomyelitis, vascular thrombosis, or previous encephalitis (105,117). In any case, the consequent hypoxemia results in elevated levels of erythropoietin and erythrocytosis, with hematocrits reported as high as 0.75 (121). Medroxyprogesterone acetate has been reported to be an effective treatment for the Pickwickian syndrome (122).
Patients with polycythemia and positional arterial oxygen desaturation have also been reported (123). Whether this results from alveolar hypoventilation while supine or from shunting through an arteriovenous malformation while upright (124) is unclear. Obstructive sleep apnea has been associated with polycythemia (presumably due to episodic erythropoietin secretion during apneic episodes) in some (125) but not all (126) reports.
ABNORMAL HEMOGLOBINS
Inherited Abnormalities of Hemoglobin
Certain mutant Hbs are characterized by increased oxygen, and patients who carry such Hbs tend to develop erythrocytosis (127,128,129,130 and 131). Oxygen-Hb dissociation curves are shifted dramatically to the left in individuals carrying these abnormal Hbs. The degree of left shift can be quantified by determining the P50 (i.e., the oxygen pressure at which Hb is half-saturated). The normal value in whole blood is 23 to 29 mm Hg at standard pH, temperature, CO2 content, and barometric pressure. The whole-blood P50 is almost invariably decreased in patients with a high-affinity Hb; most values fall between 9 and 21 mm Hg. In a few instances, the P50 has been normal, or nearly so, in whole blood (e.g., HbG Norfolk), necessitating the measurement of the oxygen dissociation curve of the purified Hb to demonstrate the defect.
The most important physiologic consequence of increased oxygen affinity is that release of oxygen is impaired at partial pressure of oxygen values normally found in tissues. Uptake of oxygen in the lungs is enhanced, but this effect is relatively unimportant, because normal Hb is nearly completely saturated in the lungs under the usual physiologic circumstances. As previously noted, however, the increased affinity may confer some advantages when environmental oxygen is low, such as at high altitudes.
The first described high-affinity Hb, Hb Chesapeake, was reported in 1966 (132). By 2000, more than 115 high-affinity Hbs had been characterized. Most result from amino acid substitutions in the β-chain. Some unstable Hbs (see Chapter 41) and M Hbs (see Chapter 49) also have increased affinity for oxygen but do not cause erythrocytosis.
Most of the high-affinity Hb variants associated with erythrocytosis are found in single subjects or in small family clusters. However, studies of the few large kindreds available suggest that the inheritance pattern is autosomal-dominant (132,133). No apparent predilections for any racial group or geographic area have been observed.
The severity of reported erythrocytosis varies considerably. With some of the variants (particularly those involving the α-chain), the associated blood Hb levels were within normal limits. In other variants (e.g., Hb British Columbia), the abnormality in oxygen binding was relatively mild and was demonstrable only by careful laboratory studies. In most patients, a mild, stable erythrocytosis (Hb, 17 to 20 g/dl) is found. The finding of erythrocytosis is often incidental. Patients may have noticed that their complexions are ruddy, but they usually have no other symptoms, and the clinical course is benign. Somewhat more severe erythrocytosis has been noted with a few variants: Hb Vanderbilt, Hb Malmö, Hb Wood, Hb Kempsey, Hb Yakima, Hb Heathrow, Hb Little Rock, Hb Syracuse, Hb Osler, and Hb Villaverde. Many of these patients were symptomatic, but some complained of the nonspecific symptoms of expanded blood volume and erythrocytosis: headaches, dizziness, a feeling of “fullness” in the head, and fatigue. Leukocyte and platelet counts were rarely abnormal (131).
Individuals with high-affinity Hbs are not at a disadvantage under hypoxic conditions. They tolerate ascent to high altitudes as well as or better than normal subjects and thus appear to be preadapted to hypoxic stresses. Under such conditions, the enhanced oxygen loading seems more important than the impaired delivery. Similarly, exercise tolerance appears unimpaired (134). There is no evidence that oxygen delivery to the heart is defective in patients with high-affinity Hbs. Although myocardial infarctions and other findings of atherosclerotic cardiovascular disease are reported in these patients, it is unclear whether this is an actual association or simply reflects the high frequency of atherosclerosis in the general population (135,136,137 and 138).
High-affinity Hbs appear to exert no adverse effects on fetal development in utero. Theoretically, oxygen delivery to a developing, noncarrier fetus might be impaired when the mother is a carrier, because the normal differential in oxygen affinity between fetal and adult Hb (which is in favor of the developing fetus) would be narrowed. However, only in the family with Hb Yakima was there a suggestion that spontaneous abortions occurred at an increased rate (139). In contrast, normal pregnancy outcomes were recorded for mothers carrying the severe high-affinity variants Hb Bethesda, Hb Osler, and Hb Little Rock (140,141). Evidently, maternal and fetal polycythemia and increased uterine and fetal blood flow compensate for the theoretic deficit in placental oxygen transport. There are no data addressing whether carrier fetuses have a developmental advantage over noncarriers born to these mothers; however, in dizygotic twins born to a mother with Hb Osler, the carrier twin developed more fully than the noncarrier as measured by the ponderal index (weight/length3) (140).
It has been suggested that the homozygous state for high-affinity Hbs would be incompatible with life because of insufficient oxygen release to tissue. This may be true; however, at least four patients with abnormal Hb levels approximating those that would be observed in homozygotes have been described with no apparent ill effects [Hb Abruzzo (142), Hb Crete (143), and Hb Headlington (144)]. The unusually high proportion of abnormal Hb was clearly due to concurrent β-thalassemia in two cases (144) and probably in the others as well.
Routine electrophoresis at alkaline pH on cellulose acetate detects approximately one-half of the stable high-affinity Hbs. An additional 10 to 15% can be detected by electrophoresis on citrate agar at acidic pH, and a further 10% are detectable by isoelectric focusing. This leaves 20 to 25% electrophoretically silent. The detection of an abnormal Hb in these circumstances requires determination of P50 under conditions controlled for
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pH and DPG concentration. The steps used to identify Hbs with altered oxygen affinity have been outlined (129). Some high-affinity Hbs interfere with detection of glycated Hb and lead to falsely elevated HbA1c levels in diabetics (145).
Most patients fully compensate for the reduced tissue oxygen delivery by developing erythrocytosis. Levels of serum erythropoietin and erythrocyte 2,3-DPG are typically normal, indicating that compensation is complete. It may be assumed that a new homeostatic equilibrium has been achieved by the mechanism reviewed in the discussion on erythropoietin levels in the classification of polycythemia. The situation is precisely analogous (146).
No treatment is indicated for most patients with high-affinity Hbs. Their erythrocytosis is a compensation for a physiologic state and should be regarded as “normal for them.” In the rare patient with erythrocytosis and associated symptoms, phlebotomy may be used, but caution must be used to avoid lowering the hematocrit to a point at which oxygen delivery is impaired. A reasonable approach is probably to phlebotomize the individual patient to the highest hematocrit at which he or she is no longer symptomatic rather than to a specific number (129,134,136,147). Certainly, reducing blood Hb concentrations to normal levels would be undesirable. Under no circumstances should cytoreductive agents be used for treatment. A partial listing of high-affinity Hbs associated with erythrocytosis is shown in Table 50.5.
TABLE 50.5. A Selection of Stable Hemoglobins with Increased Oxygen Affinity

Name Reference Structure Molecular Abnormality Amount (%) Electrophoresis P50 Bohr Hill na

Milledgeville 148 α44(CD2)Pro→Leu α1β2 15 NSb 11.0 N 1.10
Fort de France 128,149 α45(CD3)His→Arg ?Heme 20 8.6s 27.5 N 2.70
G-Norfolk 150 α85(F6)Asp→Asn ? 20 8.6s 30.0 N 2.60
Chesapeake 132 α92(FG4)Arg→Leu α1β2 23 8.6f 19.0 N 1.40
Denmark Hill 135 α95(G2)Pro→Ala α1β2 19 8.6s D D 1.90
Nunobiki 151 α141(HC3)Arg→Cys Salt bridge 13 IF D D 1.25
Rouen 152 α140(HC2)Ty→His ? 19 IF 12.1 D 1.50
Okayama 153 β2(HA2)His→Glu 2,3-DPG 47 IF 23.0
Olympia 154 β20(B2)Val→Met ? 40 NS 19.0 N 2.60
Pitie-Saltpetriere 155 β34(B16)Val→Phe α1β1 37 IF 17.0
Hirose 140,148,156,180 β37(C3)Ty→Ser α1β2 41 8.6s D 2.60
Great Lakes 157 β68(E12)Leu→His Heme 39 NS 16.0 D 1.50
Olomouc 158 β86(E2)Ala→Asp ? 47 8.6f 12.0 ?D
Rahere 159 β82(EF6)Lys→Thr 2,3-DPG 50 6.2f 18.0 N
Creteil 147,160 β89(F5)Ser→Asn ? IF 18.0 D 1.30
Vanderbilt 161 β89(F5)Ser→Arg ? 8.8s 14.5
Barcelona 162 β94(FG1)Asp→His Salt bridge 37 8.6s 21.0 D 2.40
Malmö 163 β97(FG4)His→Gln α1β2 50 IF 14.0 N 1.50
Wood 164 β97(FG4)His→Leu α1β2 50 IF 9.0 N 1.50
Kempsey 165,166 β99(G1)Asp→Asn α1β2 48 8.6s D 1.10
Yakima 139,167 β99(G1)Asp→His α1β2 38 8.6s 12.0 N 1.10
Ypsilanti 168 β99(G1)Asp→Tyr α1β2 50 8.6s 17.0
Brigham 138 β100(G2)Pro→Leu α1β2 50 NS 20.0 N
New Mexico 169 β100(G2)Pro→Arg α1β2 54 8.5s D D 1.20
British Columbia 170 β101(G3)Glu→Lys α1β2 23.0 N
Heathrow 171 β103(G5)Phe→Leu ?Heme 50 NS 10.0 N 1.20
Crete 143 β129(H7)Ala→Pro α1β1 85c 8.6s 11.0 D
Abruzzo 142 β143(H21)His→Arg 2,3-DPG 95c 9.0s D N 2.00
Little Rock 172,173 β143(H21)His→Gln 2,3-DPG 50 6.2f D N 2.90
Syracuse 174 β143(H21)His→Pro 2,3-DPG 40 IF 11.0 D 1.10
Mito 175 β144(HC1)Lys→Glu Salt bridge 42 IF D D N
Osler 176,177 β145(HC2)Tyr→Asp α1β2 28 8.6f 13.0 D 1.40
McKees Rocks 178 β145(HC2)Tyr→Stop α1β2 46 6.0f 10.0 D 1.00
Hiroshima 179 β146(HC3)His→Asp Salt bridge, Bohr, α1β2 50 8.6f 5.0 D 2.00
Cowtown 180,181 and 182 β145(HC3)His→Leu Salt bridge, Bohr α1β2 40 6.0f 19.0 D N
Headlington 144 β72(E16)Ser→Arg ? 83c 8.6s 8.8 N 2.70
Gambara 183 β82(EF6)Lys→Glu ? 52 f 19.3 D
Villaverde 184 β89(F5)Ser→Thr ? NS 1.3 D 1.20
Saint Nazaire 185 β130(G5)Phe→Ile ? IF 9.0 N 2.10
D, decreased; DPG, diphosphoglycerate; f, migrating faster than hemoglobin A; IF, demonstrable only by isoelectric focusing; N, normal; NS, not separable; s, migrating slower than hemoglobin A.
NOTE: Variants are grouped by α-chain and β-chain abnormalities. Within each group, they are listed in order of the position in the polypeptide chain at which amino acid substitution has occurred. See Chapter 35 for an explanation of the notation for structure.
aHill n is a measure of subunit interaction. Normal range, 27 to 31.
bValue for pH at which separation was detected.
cHigh values probably occurring in individuals with coexisting thalassemia.

Molecular Pathology
Most of the changes in the oxygen affinity of Hb can be accounted for by effects on the equilibrium between a low-affinity molecular configuration, designated T, and a high-affinity configuration, designated R (see Chapter 7). Normally, the Hb molecule shifts from T to R as oxygen is bound, accounting for the phenomenon of subunit interaction. The usual measure of subunit interaction is the value n in Hill’s equation. With no subunit interaction, n is 1.0; the value for HbA is 2.7 to 3.1. Most high oxygen-affinity variants are characterized by a reduced value for n; 16 of the 29 variants in Table 50.5
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with reported n values are 1.5 or less. Biphasic Hill plots are observed when Hbs of different oxygen affinities are mixed.
The high oxygen-affinity variants result from molecular alterations that either stabilize the R form or destabilize the T form. The most common known sites for amino acid substitutions involve the α1β2 interface, which destabilize the T form. Substitutions at 2,3-DPG binding sites or at residues involving intrachain salt bridges also destabilize the T form. In contrast, certain Hbs result from amino acid substitutions that stabilize the R form, such as Hb Little Rock (172), Hb Chesapeake (186), and Hb Creteil (159). The mechanisms by which several other substitutions produce altered oxygen affinity are unclear.
Acquired Abnormalities of Hemoglobin
Moderate elevations of carboxyhemoglobin in erythrocytes shift the oxygen dissociation curve. In heavy smokers, carboxyhemoglobin concentration may reach sufficiently high levels (4.0 to 6.8%) to produce polycythemia (187). In the older literature, polycythemia in association with phosphorus poisoning has been described, although it may have been merely relative erythrocytosis resulting from acute liver damage. Although certain drugs and chemicals (e.g., nitrites, nitrates, aniline dyes, sulfonamides, and nitrobenzene) produce toxic levels of methemoglobin, sulfhemoglobin, or both in the blood of even normal persons (188,189,190 and 191), erythrocytosis apparently has not been described in patients with toxic methemoglobinemia.
FAMILIAL POLYCYTHEMIA (PHYSIOLOGICALLY APPROPRIATE)
Familial defects in 2,3-DPG metabolism [e.g., DPG mutase deficiency (192) or elevated erythrocyte adenosine triphosphate (193)], which would have the effect of shifting the oxygen dissociation curve, provide other physiologically appropriate (tissue hypoxia) reasons for polycythemia.
Secondary Polycythemia [Physiologically Inappropriate (Normoxic)]
ABERRANT ERYTHROPOIETIN SECRETION
Erythrocytosis has been described in association with a variety of neoplasms, cysts, vascular abnormalities, and endocrinologic disorders. In the syndromes discussed in the preceding section, erythrocytosis was secondary (i.e., driven by increased erythropoietin); however, this erythropoietin secretion and the consequent erythrocytosis were physiologic responses to tissue hypoxia. In this section, disorders in which erythropoietin-driven erythrocytosis bears no relation to physiologic requirements are reviewed (Table 50.6).
TABLE 50.6. Disorders Associated with Normoxic Secondary Polycythemia

Renal disease Other neoplasms
   Renal cell carcinoma    Uterine leiomyomata
   Renal sarcomaa    Uterine fibroid tumorsa
   Renal adenomaa    Cutaneous leiomyomataa
   Renal hemangiomaa    Meningiomaa
   Wilms tumora    Placental trophoblastic tumorsa
   Solitary renal cysts    Chronic lymphocytic leukemiaa
   Polycystic kidney disease    Systemic amyloidosisa
   Hydronephrosis    Atrial myxomaa
   Horseshoe kidneya Endocrine disorders
   Renal artery stenosisa    Cushing syndrome
   Postrenal transplantation    Primary aldosteronism
Hepatic disease    Virilizing ovarian tumors
   Hepatocellular carcinoma    Bartter syndromea
   Hepatic hamartomaa    Pheochromocytomaa
   Hepatic metastasesa Other
   Hepatic angiosarcomaa    Human immunodeficiency virus infectiona
   Hepatic angiomaa  
   Viral hepatitisa  
   Vascular cerebellar tumors  
aPolycythemia infrequently reported.

Renal Disorders
Renal cell carcinoma (hypernephroma) is one of the disorders most frequently associated with erythrocytosis. Erythrocytosis is observed in 0.9 to 1.6% of patients with renal cell carcinoma (approximately one-fourth as frequent a finding as anemia) (194). Elevated serum erythropoietin levels, however, are observed in more than 60% of patients (195). Erythrocytosis also has been reported in patients with renal sarcoma, hemangioma, adenoma (196), Wilms tumor (197), renal cysts, hydronephrosis (198,199), horseshoe kidney (199), and polycystic kidneys (196). Renal artery stenosis has also been reported in association with erythrocytosis (200).
Erythrocytosis in renal cell carcinoma is attributed to constitutive erythropoietin production by the tumor. Erythropoietin messenger RNA can be demonstrated in renal carcinoma cells (201). It is assumed that this is also the mechanism by which other parenchymal renal diseases produce erythrocytosis. Hydronephrosis and anatomic abnormalities probably produce erythrocytosis by increasing pressure on erythropoietin-producing cells in the renal parenchyma (202). Significant and measurable concentrations of erythropoietin (sometimes >100 mU/ml) can be detected in fluid aspirated from renal cysts associated with polycythemia. Production of erythropoietin in renal cell carcinoma is said to predict a good response to therapy (203). Management of erythrocytosis in these patients should be directed at treatment of the responsible renal lesion with phlebotomy as an adjunct, when necessary.
Erythrocytosis is also observed in patients after renal transplantation (204). This phenomenon is associated with elevated serum erythropoietin; the source of erythropoietin is presumed to be the transplant recipient’s native kidneys (205,206). Effective therapeutic modalities include phlebotomy, angiotensin-converting enzyme inhibitors, and theophylline (207,208 and 209).
Liver Diseases
During fetal development, the liver contributes to erythropoietin production (Chapter 6); hepatic disease, like renal disease, may be associated with erythropoietin production and polycythemia. Erythrocytosis has been identified in persons with hepatocellular carcinoma with incidence 2.5 to 10.0% (210,211,212 and 213). When measured, red cell mass has been shown to be increased (211), and elevated serum erythropoietin levels have also been described (213). As with renal cell carcinoma, erythropoietin production by the tumor has been demonstrated (214,215 and 216). Remission of erythrocytosis may be observed after successful tumor treatment (215,216).
Erythrocytosis has also been reported with hepatic hamartomas and tumors metastatic to liver (196), as well as hepatic angiomas (217) and hemangiosarcomas (218). Polycythemia has been reported in the early stages of viral hepatitis (219,220). Cirrhosis is occasionally listed in texts as associated with erythrocytosis, but this apparently does not occur except in the setting of another disease, such as cirrhosis with hepatocellular carcinoma.
Cerebellar Vascular Tumors
The association of erythrocytosis with vascular tumors of the cerebellum is well established (196,221). Elevated serum erythropoietin levels and tumor production of erythropoietin have been demonstrated (222,223). Correction of erythrocytosis may be observed after effective therapy and erythrocytosis may return with recurrence of the tumor (196).
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Leiomyoma and Fibroid Tumors of the Uterus
Several cases in which large leiomyomas and fibroid tumors of the uterus were associated with erythrocytosis have been reported (224,225). Erythrocytosis tends to subside after effective therapy and is also associated with production of erythropoietin by tumor (226,227). Cutaneous leiomyomata have also been associated with erythrocytosis (228).
Other Neoplasms
Rare instances of erythrocytosis in association with a variety of other tumors have been reported, but some of these associations may be coincidental (196). However, erythropoietin synthesis by tumor cells has been clearly demonstrated in a patient with meningioma (229). Erythrocytosis has also been reported in rare patients with chronic lymphocytic leukemia (230), systemic amyloidosis (231), placental trophoblastic tumors (232), and atrial myxomas (233).
Endocrinologic and Other Disorders
Erythrocytosis has been reported in association with a number of endocrinologic disorders, including Cushing syndrome, primary aldosteronism (234), virilizing ovarian tumors (235), Bartter syndrome (236), and pheochromocytoma (237). In the latter disorder, tumor erythropoietin production has been reported (237).
There have been a number of reports describing small numbers of patients with human immunodeficiency virus infection and polycythemia (238,239,240,241,242 and 243). It is unclear if there is an actual pathophysiologic association or if this is coincidental.
DRUG-INDUCED ERYTHROCYTOSIS
Anabolic and androgenic steroids may be abused by both recreational and professional athletes for purposes of improving performance (244,245). A consequence of androgen administration, either medicinal or extralegal, may be erythrocytosis (246). In some cases, the degree of erythrocytosis may be severe.
Recombinant human erythropoietin has also been abused by athletes (particularly those in endurance sports) to increase the red cell mass and thus oxygen-carrying capacity (244,247,248). As indicated earlier, this may backfire if the athlete becomes hypovolemic as a result of exertion. Cases of surreptitious erythropoietin self-administration resulting in accelerated hypertension and unstable angina have been reported (249). A perceived advantage of erythropoietin over androgens for this purpose is the inability to distinguish endogenous from exogenous erythropoietin as well as the lack of hepatic toxicity. More recently developed techniques that allow discrimination between exogenous recombinant erythropoietin and endogenous erythropoietin may make this practice less frequent (250).
FAMILIAL POLYCYTHEMIA (PHYSIOLOGICALLY INAPPROPRIATE)
Kindreds that exhibit an autosomal-recessive erythrocytosis associated with increased erythropoietin production have been described (251).
Idiopathic Polycythemia
The term idiopathic polycythemia (or erythrocytosis) refers to patients who have an elevated red cell mass of unknown etiology after appropriate investigation. It would include most of the patients formerly categorized as “benign erythrocytosis.” The existence of this group, which is estimated to contain 20 to 30% of patients evaluated for polycythemia (125), essentially represents a failure to correctly categorize all polycythemic patients.
Of 25 patients reported in one series, 12 were found to have elevated erythropoietin levels and were therefore assumed to represent patients with secondary polycythemia; these patients tended to be younger than the patients with normal erythropoietin levels (123). Progenitor culture studies were not helpful in subcategorizing the group in this particular study (123). Some studies have reported endogenous colony-formation studies to be useful and serum erythropoietin levels not helpful (42), whereas others have reported the opposite (252).
Kiladjian and colleagues treated 39 patients with idiopathic erythrocytosis with pipbroman and compared their clinical course to 140 concurrently treated polycythemia vera patients (253). The risk of leukemia, thrombosis, and myelofibrosis was the same in the two groups. This study confirms that the idiopathic erythrocytosis group contains a certain number of polycythemia vera patients; however, it does not provide a way to identify individuals who do not have a myeloproliferative disorder and therefore should not be exposed to leukemogenic agents (253).
Because this category probably represents a mixed bag, including early polycythemia vera, mild secondary polycythemia, and normal individuals at the higher end of the bell-shaped curve for red cell mass (61), a cautious approach is warranted. Observation may be the most reasonable intervention; this may be the patient subset in whom otherwise low-yield studies, such as erythropoietin levels, and erythroid progenitor studies are likely to be useful.