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882 Part VI: The Erythrocyte Chapter 57: Primary and Secondary Erythrocytoses 883

598C>T homozygotes than in unaffected participants (p <0.0005), TABLE 57–3. VHL Mutations Associated with Congenital
which is consistent with upregulation by HIF-1.
Chuvash polycythemia is a relatively recently described disor- Polycythemia
der; thus, additional laboratory findings as a result of augmentation of Clinical
hypoxia sensing are expected to be described. VHL Genotype Ethnicities References Features
235 C>T/586 C>G White 101
Other Congenital Polycythemias from Augmented Hypoxia 598 C>T/598 C>T Chuvash, 101, 102, Frequent
Sensing Danish, U.S. 104, 105, thrombotic
At present, a paucity of data precludes any reliable description of other (white), 231 complications
congenital polycythemias from augmented hypoxia sensing. Some Bangladeshi,,
affected subjects have unexpectedly low-normal erythropoietin levels. Pakistani,
Russian,
Turkish
SECONDARY ERYTHROCYTOSIS 598 C>T/574 C>T U.S. (white) 104
Characteristically, only the number of erythrocytes in the blood is 598 C>T/562 C>G U.S. (white) 104
increased in secondary erythrocytosis. An increase in the leukocyte
count and/or splenomegaly may be present as features of the underlying 598 C>T/388 G>C U.S. (white) 105
disease, for example, pulmonary infection in COPD with cor pulmon- 571 C>G/571 C>G Croatian 104 Failure to
ale, or as seen in Monge disease among Andean high-altitude dwellers thrive
or patients inheriting a high-affinity hemoglobin that is also unstable 311 G>T/wild-type German (?) 102
(Chaps. 34 and 49).
In patients with appropriate erythrocytosis, the underlying defect 376 G>T/wild-type Ukrainian 105 ?VHL
is usually demonstrable. Arterial hypoxia can be demonstrated in most syndrome
cases. Some obese patients who, like Mr. Wardle’s proverbial boy, Joe, 598 C>T/wild-type English, 102
in The Pickwick Papers by Charles Dickens, are always half asleep, will German
be very much awake when exposed to arterial puncture and ventilatory 523 A>G/ Portuguese 101 A-T patient
testing, and their apprehensive hyperventilation will result in the dis- wild-type
appearance of all abnormalities in arterial oxygen tension. As soon as 370 A>G/562 C>G Native PMID:
they return to bed, however, they will go to sleep again and display the American 23772956
characteristic somnolent cyanosis.
In inappropriate erythrocytosis, the laboratory findings will be 376 G>A/376 G>A Bangladeshi PMID: Fatal pul-
those of the underlying defect. 24729484 monary
hypertension
413 C>T/413 C>T Punjabi PMID:
DIFFERENTIAL DIAGNOSIS 23538339

Also refer to Chaps. 34 and 59, Table 57–3, and Fig. 57–6. A-T, ataxia-telangiectasia; VHL, von Hippel-Lindau.
Distinguishing between polycythemia vera and other polycythemic
disorders used to be challenging, but discovery of the JAK2 V617F and
JAK2 exon 12 mutations has made it, in most instances, straightfor- vera and erythroid progenitor burst-forming unit–erythroid (BFU-E)
ward. Some of the clinical and laboratory features that can be helpful growth without added erythropoietin, referred to as “endogenous
186
for differential diagnosis are summarized in Chap. 34, Table 34–2, and erythroid colonies.” Detection of endogenous erythroid colonies in cul-
in Fig. 57–6. tures of marrow or blood used to be the most specific test for polycythe-
mia vera. 50,187,188 In one study, all patients with polycythemia vera, but
RED CELL MASS DETERMINATION none with secondary or other causes of polycythemia, had endogenous
189
erythroid colonies. Rare endogenous erythroid colonies may at times
Determination of red cell mass is invaluable for differentiation of appar- be observed in PFCP, Chuvash polycythemia, and in a single studied
ent (spurious) polycythemia from true polycythemic states. Unfor- subject with the HIF-2α mutation, but unlike the endogenous ery-
190
tunately, determination of the red cell mass is expensive and, when throid colonies of polycythemia vera, these are abrogated by pretreat-
185
performed by the inexperienced, often inaccurate. It is not useful in ment with erythropoietin and EPOR-blocking antibodies. 191,192
distinguishing polycythemia vera from secondary erythrocytoses, the In experienced hands, endogenous erythroid colonies is a specific
differentiation that is usually needed, because it is increased in both and sensitive means for detecting polycythemia vera and may be useful
disorders. Ideally, the red cell mass and plasma volume should be mea- in diagnosing patients with unusual presentations of polycythemia vera,
sured separately. Unfortunately, the I-labeled albumin necessary to such as Budd-Chiari syndrome 193–196 or isolated thrombocytosis. How-
131
197
measure the plasma volume is often unavailable. Fortunately, in most ever, this test has not been standardized, is expensive and laborious, and
cases, the diagnosis of polycythemia vera and other true polycythemic technical variations make interlaboratory results difficult to compare.
states can be established with confidence without measuring the red cell
mass. ERYTHROPOIETIN LEVELS
All patients with PFCP encountered have erythropoietin below nor-
54
ERYTHROID COLONY CULTURES mal levels or below levels of detection. Thus, a low erythropoietin level
In vitro assays of erythroid progenitor cells permit the study of their is not pathognomonic of polycythemia vera, as patients with PFCP have
responsiveness to erythropoietin. This can be applied to polycythemia as low or even lower erythropoietin levels. 18

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