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872 Part VI: The Erythrocyte Chapter 57: Primary and Secondary Erythrocytoses 873

first popularized in 1956 with the classic description of the pickwickian OSA. 24,25 The total number of hours of hypoxia per day may dictate
syndrome by Burwell and colleagues. Polycythemia associated with whether the stimulus to erythropoietin production is sufficient to cause
14
carboxyhemoglobinemia resulting in hypoxemia as a result of smoking erythrocytosis.
and with tissue hypoxia because of inherited abnormal hemoglobins
with high-affinity oxygen binding to hemoglobin was recognized sub- Polycythemia Associated with Smoking
15
sequently (Chaps. 49 and 50). Erythrocytosis associated with abnor- Smoking clearly increases hematocrit in COPD compared to controls of
mal hemoglobins with an increased affinity for oxygen also represents comparable pulmonary function. In a study of 2524 patients with severe
an appropriate response to hypoxia first noted by Charache and col- COPD, 10.2 percent of patients reported as current smokers had sig-
15
leagues in 1966 when they described hemoglobin Chesapeake. nificantly higher hematocrit values than did ex-smokers or nonsmokers
Relative erythrocytosis is the term used to depict enhanced red of comparable pulmonary impairment of both genders, with p <0.02. 20
cell count or blood hemoglobin values resulting from reduced plasma Even young male smokers without pulmonary impairment have
volume, not increased red cell mass. The disorder is, therefore, not a higher hematocrits. In one study, 1169 subjects (age range: 18.6 to
true polycythemia and is designated apparent, spurious, or relative poly- 22.8 years; mean: 19.4 years) were recruited and 25 percent were smokers.
cythemia. The cause of the reduced plasma volume and hence relative Predictably, carboxyhemoglobin was much higher in smokers than in
erythrocytosis is often known, that is, diuretic use, dehydration from nonsmokers (r = 0.958, p <0.001) and both hemoglobin and hematocrits
excessive sweating, etc. However, there are some patients with mild ery- were also markedly higher in smokers (hemoglobin (p = 0.001), hema-
throcytosis in which neither the cause nor the clinical significance is tocrit (p = 0.004). 26
clear. In 1905, Gaisbock reported that a number of hypertensive patients
had plethora and an elevated red cell count but no splenomegaly, a con-
dition he termed polycythemia hypertonica, sometimes called Gaisbock High Oxygen Affinity and Hemoglobins
16
syndrome. In 1952, direct measurement of blood volume in patients These disorders are reviewed in detail in Chaps. 49 and 50. High oxygen-
with polycythemia led Lawrence and Berlin to identify a subgroup of affinity hemoglobins deliver less oxygen to tissues, which is appropri-
patients with a normal red cell volume but reduced plasma volume. ately compensated by increased erythropoiesis and a higher steady-state
Although some members of this group were hypertensive, the authors hemoglobin concentration. While considered rare, high oxygen affinity
were more impressed by their tense and anxious behavior and coined has been found, according to one report, in approximately 20 percent of
27
the term stress polycythemia. 17 70 unrelated subjects with otherwise idiopathic polycythemia.
Polycythemia of Eisenmenger Complex
EPIDEMIOLOGY Eisenmenger syndrome, characterized by elevated pulmonary vascular
resistance and right-to-left shunting of blood, is usually accompanied
PRIMARY POLYCYTHEMIAS by polycythemia. Most patients with the syndrome survive for 20 to
28
Primary Familial and Congenital Polycythemia 30 years.
This autosomal dominant disorder (designated PFCP) is uncommon but
more prevalent than is generally appreciated, as many affected subjects are Polycythemia of Endocrine Disorders and from Iatrogenic or
initially misdiagnosed as having polycythemia vera. Its prevalence is sim- Self-Administration of Androgens
29
ilar to congenital polycythemias because of high oxygen-affinity hemo- Erythrocytosis has been reported in Cushing syndrome, primary
30
globin mutants, and far more common than 2,3-bisphosphoglycerate aldosteronism, and Bartter syndrome (Chap. 38). 31
(2,3-BPG) deficiency. 18 In a prospective trial of testosterone use in older men, erythrocy-
tosis (defined as a hematocrit greater than 50 or 52 percent) was three
times more likely to occur in the testosterone-treated group compared
32
SECONDARY POLYCYTHEMIAS to placebo. (Refer to Chap. 38 for more details.)
Pulmonary Disease with Hypoxia Inappropriate Tissue Elaboration of Erythropoietin
In one study of 2524 patients with severe chronic obstructive pul- The prevalence of various types of secondary polycythemia is a func-
monary disease (COPD), 8.4 percent had a hematocrit higher than tion of underlying causes, such as geographical location of the patient
55 percent. In this study, hematocrit was an independent predictor or presence of a causative neoplasm. Approximately 1 to 3 percent of
of longer survival, decreased hospital admission rate, and decreased all patients with pheochromocytoma or paraganglioma have erythro-
cumulative duration of hospitalization. In another, smaller study of cytosis. Rare patients with congenital erythrocytosis will develop
19
33
309 subjects with COPD and chronic respiratory failure, 67 percent had pheochromocytoma or paraganglioma. Uterine leiomyomas in pre-
34
normal hemoglobin levels, 20 percent had anemia, and 18 percent had menopausal women are very common, estimated at 20 to 40 percent,
polycythemia. 20 and the occurrence of erythrocytosis ranges from 0.02 to 0.5 percent of
cases. Isolated instances of polycythemia have been attributed to myx-
35
36
37
Obstructive Sleep Apnea oma of the atrium, hamartoma of the liver, and focal hyperplasia of
38
21
Although the evidence is largely anecdotal, secondary polycythemia the liver. Erythrocytosis and inappropriate secretion of erythropoietin
is a widely recognized complication of longstanding obstructive sleep may be found in approximately 15 percent of patients with cerebellar
apnea (OSA), being found in 5 to 10 percent of those with nocturnal hemangioma. 39,40
22
apnea and hypopnea. The published studies remain controversial; in
a study of 263 patients (189 men and 74 women), patients with severe Self-Administration of Erythropoietin
sleep apnea had significantly higher hematocrit values than did patients Athletes have attempted for decades to manipulate their blood to gain
with mild to moderate sleep apnea or nonapneic controls (p <0.01). a competitive advantage either by blood transfusions or erythropoie-
23
In contrast, in other studies, there were no significant differences in tin. This evolving, but continuous, problem has been the subject of a
hemoglobin levels or hematocrit between subjects with and without review. 41

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