Page 909 - Williams Hematology ( PDFDrive )

884 Part VI: The Erythrocyte Chapter 57: Primary and Secondary Erythrocytoses 885

clonal, with the exception of a few patients who converted to polyclonal polycythemia, but it should be recognized that during the natural his-
hematopoiesis after therapy with interferon-α. While it was previously tory of patients who develop primary or secondary polycythemia, their
50
reported that clonality assays based on X-chromosome inactivation are red cell mass is, at some point, within the normal range while it is rising
not suitable for studies of older women using the HUMARA assay, 212–214 to abnormal values. Because of the significant error rate of red cell mass
that was not confirmed by studies using quantitative transcriptional measurement, it is recommended that both red cell mass and plasma
analysis of active X-chromosomes. 215,216 volume be measured simultaneously.

OTHER POLYCYTHEMIAS THERAPY
Clinical history is of the utmost importance for the differential diagnosis
of polycythemic states. Differentiation of an acquired from congenital POLYCYTHEMIAS OTHER THAN
disorder, and distinction between sporadic versus familial occurrence POLYCYTHEMIA VERA
of polycythemia, when possible, will streamline the diagnosis. Thus, an
autosomal dominant disorder is likely a result of polycythemia from Treatment of patients with post–renal transplant erythrocytosis with
gain-of-function EPOR, EPAS1 (HIF-2α) or EGLN1 (PHD2) mutations, drugs that suppress the renal–angiotensin system has virtually elimi-
or a high-affinity hemoglobin. Recessively inherited conditions may be nated the need for therapeutic phlebotomy. The maximal reduction of
from VHL gene mutations. Although rare patients with polycythemia hemoglobin and hematocrit levels usually manifests by 6 months after
vera may have a history of other affected family members (Chap. 84), starting therapy with either the angiotensin-converting enzyme inhib-
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polycythemia vera is always an acquired condition. Many familial poly- itor, enalapril, or the angiotensin II receptor type 1 blocker, losartan.
cythemias are the result of yet-to-be-discovered genetic events. Some patients are exquisitely sensitive and may become severely anemic.
Patients with a low level of erythropoietin and autosomal domi- High-altitude erythrocytosis is also associated with pulmonary
nant inheritance should have sequence analysis of the EPOR gene. This hypertension, proteinuria, and elevated blood pressure. A prospective
will define the defect in some patients with PFCP; if the polycythemia is randomized trial of enalapril reported decreased hemoglobin concen-
acquired and present in multiple relatives, a diagnosis of familial clus- tration, proteinuria and beneficial effects on elevated blood pressure. 219
tering of polycythemia vera should be pursued. Patients with second- When erythrocytosis is secondary to a renal tumor or cyst, pheo-
217
ary erythrocytosis have a genuine increase in the number of circulating chromocytoma, myoma, or brain tumor, removal of the neoplasm usually
erythrocytes and the red cell mass. Such patients do not typically have results in disappearance of the erythrocytosis, but in the syndrome of con-
increased platelet or leukocyte counts or splenomegaly, which are often genital polycythemia with pheochromocytoma caused by EPAS1 muta-
seen in polycythemia vera. The lack of involvement of other cell lineages tions (see above paragraphs) erythrocytosis persist after tumor resection.
in hematopoietic proliferation should arouse suspicion that the patient No specific therapy is currently available for polycythemic subjects
may have erythrocytosis other than polycythemia vera. with VHL, EGLN1, or EPAS1 mutations.
However, reactive thrombocytosis, leukocytosis, and splenomeg- Lowering the hematocrit to a normal or near-normal level by
aly may occasionally also be present in secondary erythrocytosis, which phlebotomy is the usual, but empiric, treatment of secondary erythro-
then renders the distinction from polycythemia vera more difficult. In cytosis, 220,221 but should always be viewed in the context of a particular
patients in whom secondary erythrocytosis is caused by lung or car- subject. 28,178 The appropriate level is that at which the patient becomes
diac disease, clubbing is often present. In some cases, determining the asymptomatic. Although cytotoxic agents are sometimes used for this
arterial oxygen saturation will clarify the diagnosis, but modest arte- purpose, phlebotomy is preferred, if indeed needed, because of the leuke-
rial oxygen desaturation may also be present in polycythemia vera. 85,218 mogenic risk of the agents that are used in polycythemia vera. This author
Imaging of the kidneys may reveal a neoplasm or cyst in some patients. favors, in most instances, benign neglect, unless specific therapy, such as
Determining the hemoglobin oxygen dissociation curve (Chaps. 32, 34, that seen in erythropoietin-secreting tumors or post–renal transplant
50), or estimation of p50 from venous blood will detect abnormalities erythrocytosis, is available. One should phlebotomize only those patients
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related to increased oxygen affinity either because of inheritance of a who are symptomatic from the elevated red cell mass and continue to do
high-affinity hemoglobin (Chap. 49), or because of very rare 2,3-BPG so cautiously only if symptoms respond promptly to phlebotomy.
depletion, as in phosphoglyceromutase deficiency (Chap. 47). The mild
erythrocytosis associated with hereditary methemoglobinemia (Chap. COURSE AND PROGNOSIS
50) is readily diagnosed because of coexistent cyanosis.
In patients with elevated erythropoietin, or with erythropoietin CHUVASH POLYCYTHEMIA
levels inappropriately normal for the degree of hemoglobin elevation,
analysis of VHL, EGLN1, and EPAS1 genes may be in order; some of A study compared 96 patients with Chuvash polycythemia diagnosed
these patients may have a history of autosomal recessive inheritance and before 1977 to 65 spouses, and 79 unrelated community members with
have a typical history of congenital polycythemia. It may also be useful normal hemoglobin concentration, same age, sex, and village of birth;
to determine the carboxyhemoglobin level of the blood if smoker’s poly- the estimated survival to 65 years was 31 percent or less for Chuvash
cythemia is suspected. polycythemia patients versus 67 percent or greater for spouses and
community members (p ≤0.002). 99
SPURIOUS POLYCYTHEMIA
The erythrocytosis observed in patients with spurious polycythemia OTHER POLYCYTHEMIAS
(apparent polycythemia, stress polycythemia) is the consequence of a The clinical course of secondary erythrocytosis is largely a function
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decrease in plasma volume. The observed erythrocytosis does not of the underlying disorder. In patients with PFCP secondary to muta-
represent a true increase in the red cell mass. Usually, the increase in tions of the EPOR gene, coronary artery disease and strokes have been
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hematocrit is very modest. Such patients do not have an increased white reported, although not in all series. The rarity of patients having
blood count, thrombocytosis, splenomegaly, or JAK2 mutation. The mutations of the EPOR, VHL, EGLN1, and EPAS1 genes and polycythe-
arterial oxygen saturation is normal. Estimation of the red cell mass mias from globin mutations and or red cell enzyme deficiencies pre-
and plasma volume is required to establishing a diagnosis of spurious cludes any meaningful prognostic evaluation.

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