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880 Part VI: The Erythrocyte Chapter 57: Primary and Secondary Erythrocytoses 881

SECONDARY ACQUIRED POLYCYTHEMIA may be as high as 8 × 10 cells/L and associated with hypertension and
12
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High-Altitude Erythrocytosis congestive failure. At higher hematocrit levels (usually >60 percent),
46,47,182
Comorbid-
thrombotic events may complicate the clinical course.
Tolerance to high altitudes varies greatly, but most normal individu- ities that are associated with or causative of renal failure are frequently
als have no discomfort at altitudes of up to 2130 m (7000 ft). Above also factors predisposing to thrombosis, and the risk of erythrocyto-
this level, and especially if the ascent is rapid, some manifestations of sis-associated thrombosis has not been submitted to rigorous multivar-
cerebral hypoxia are common. Headaches, sleeplessness, and palpita- iate rigorous statistical analyses. Thus, reports of increased thrombotic
tions are frequently encountered, and weakness, nausea, vomiting, and risks must be viewed with great caution.
mental dullness may be present. More-severe manifestations include
pulmonary and cerebral edema that may lead to death. Cheyne-Stokes Tumors
respiration commonly occurs, especially during sleep. These symptoms The erythrocytosis that occurs with erythropoietin-secreting tumors
constitute the syndrome of acute mountain sickness. 168 is generally mild, and the predominating clinical manifestations are
136
Ruddy cyanosis and physiologic emphysema are the two character- those of the tumor itself. Even moderate elevations to a hematocrit of
istic features of some humans living at high altitudes. Venous and cap- 64 percent have been encountered without symptoms referable to the
illary engorgement can be observed readily in the conjunctiva, mucous polycythemia. Resection of the erythropoietin-secreting tumor cures
38
membranes, and skin, and may contribute to the remarkable capacity of the associated polycythemia. 105
Tibetan Sherpas to walk barefoot and sleep on ice and snow. Asymp- In the syndrome of congenital polycythemia and pheochromocy-
169
tomatic retinal hemorrhages are seen frequently at high altitudes, but toma or paraganglioma (see description in “Etiology” earlier) tumor
rarely at altitudes of 3000 m (9000 ft) or less. Splenomegaly and jaun- resection does not lead to normalization of elevated hematocrit.
170
dice are unusual, although the sustained erythrocytosis is associated with
an increased fractional rate of red cell destruction and bilirubin genera- Neonatal Polycythemia
tion. It has been stated that Monge disease includes low fertility, 42,66 but Of 55 infants with neonatal polycythemia, 47 (85 percent) had signs
this may not be universally so. It has been suggested that high-altitude and symptoms attributed to this disorder. These included “feeding
native-resident Tibetans exhibit two distinct genotypes for increased problems” (21.8 percent), plethora (20 percent), lethargy (14.5 percent),
oxygen affinity of hemoglobin, and that women with genotypes for cyanosis (14.5 percent), respiratory distress (9.1 percent), jitteriness
high oxygen saturation have more surviving children suggesting (7.3 percent), and hypotonia (7.3 percent). Other findings included
171
natural selection on the locus for oxygen saturation of hemoglobin. 72,171 hypoglycemia (40 percent) and hyperbilirubinemia (21.8 percent). In a
However, these conclusions have been based not on measurement of larger group of nearly 1000 infants, six had intracranial hemorrhage. 151
the hemoglobin-oxygen dissociation curve, but on assumptions based
on arterial oxygen saturation. In point of fact, when properly mea- LABORATORY FEATURES
sured, Tibetans have normal oxygen affinity of hemoglobin when the
hemoglobin-oxygen dissociation curve is rigorously determined. 63 PRIMARY POLYCYTHEMIA

Erythrocytosis Associated with Pulmonary Disease Primary Familial and Congenital Polycythemia
The erythrocytosis associated with smoking is generally asymptomatic. Characteristic laboratory findings of PFCP are: (1) increased red blood
There may be an increase in thrombotic events, but this may be from cell mass without increased leukocyte or platelet counts; (2) normal
smoking rather than erythrocytosis. hemoglobin–oxygen dissociation curve; (3) invariably low serum ery-
When erythrocytosis is present in patients with COPD, with or thropoietin levels; and (4) in vitro hypersensitivity of erythroid progen-
without smoking, elevated hematocrit is associated with higher survival itors to erythropoietin. PFCP is often misdiagnosed as polycythemia
5
rates than anemic and normocythemic subjects. 19,20,175 Furthermore, vera, although with the advent of a reliable polymerase chain reac-
moderate erythrocytosis has no adverse effect on vascular function in tion-based test for the JAK2 V617F mutation, this should no longer ever
COPD and is not associated with venous thromboembolism. 177 happen. Whereas leukocytes are typically normal, platelet counts are
176
Large studies of patients with Eisenmenger syndrome and other often mildly decreased, presumably by dilution of the normal platelet
28
patients with cyanotic heart disease caution against routine phlebot- mass by an often-dramatic increase of red cell and whole-blood vol-
178
omy for asymptomatic elevation of the hematocrit; in fact, thrombotic umes. Some patients come to attention because of concurrent medical
complications were not observed in these studies. Transgenic mice with problems that may cause leukocytosis and secondary thrombocytosis,
extreme polycythemia (hematocrit 85 percent) from constitutive overex- falsely suggesting the phenotype of polycythemia vera.
pression of erythropoietin did not develop the expected thrombotic com-
plications. Adults with cyanotic congenital heart disease are at risk of Chuvash Polycythemia
179
having cerebrovascular events. This risk is increased in the presence of Blood profiling in patients with Chuvash polycythemia indicates
hypertension, atrial fibrillation, history of phlebotomy, and microcyto- increased hemoglobin and hematocrit and lower white blood cell and
sis, the latter condition having the strongest significance (p <0.005). The platelet counts than in controls. Erythropoietin ranges from normal (but
authors of these findings endorsed a more conservative approach toward never close to the lower limits of normal) to elevated, at times exceed-
phlebotomy and more aggressive approach toward treating microcytosis ing 10 times the mean normal value. In larger studies, hemoglobin-
with iron preparations in adults with cyanotic congenital heart disease. 180 adjusted serum erythropoietin concentrations were approximately
In a prospective cohort of U.S. Veterans Health Administration 10-fold higher in VHL 598C>T homozygotes than in controls. 4,5, 99
outpatients with stable COPD (n = 683), polycythemia prevalence was Affected subjects have lower CD4 counts, elevated levels of both
low and, unlike anemia, had no association with worsened outcomes. 175 proinflammatory and antiinflammatory cytokines, and altered plasma
thiol levels, with elevated homocysteine and glutathione and low
Renal Polycythemia and Post–Renal Transplant cysteine concentrations. 164,183,184 Their serum PAI-1 and VEGF lev-
Erythrocytosis els are also increased. 4,95,99 Circulating transferrin receptor levels are
Although most patients with kidney failure are anemic, a fraction (often higher in Chuvash polycythemia homozygotes as compared to their
with polycystic kidney disease) display erythrocytosis, which, like the unaffected relatives and spouses. 4,5,99 Ferritin-adjusted transferrin
post–renal transplant state, can be very severe. Erythrocyte counts receptor concentrations were approximately threefold higher in VHL

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