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CHAPTER 57 mass is the singular finding, distinguishing it from polycythemia vera
in which, classically, there is an increase in red cells, granulocytes, and
PRIMARY AND SECONDARY platelets. Although this usage has much to recommend it, no consen-
sus about terminology has been reached and the term polycythemia is
ERYTHROCYTOSES used interchangeably with erythrocytosis by many physicians. In some
instances, time-honored terms such as post–renal transplant erythro-
cytosis or Chuvash polycythemia will be used. A classification of the
polycythemias is presented in Chap. 34 in Table 34–2.
Josef T. Prchal
PRIMARY POLYCYTHEMIAS
Polycythemia vera (Chap. 84) and primary familial and congenital poly-
SUMMARY cythemia (PFCP) are primary polycythemic disorders, which have ery-
1–3
throid progenitors that are hypersensitive to erythropoietin. These are
Increased blood red cell mass can be termed either polycythemia or erythro- caused by somatic (polycythemia vera) or germline (PFCP) mutations
cytosis; no clear consensus for either term has been achieved. Primary poly- wherein erythroid progenitors are intrinsically hyperproliferative by
cythemias are caused by acquired or inherited mutations causing functional mechanisms other than the presence of increased levels of erythropoi-
changes within hematopoietic stem cells or erythroid progenitors leading etin and have, as shown by in vitro assays, an augmented response to
to an accumulation of red cells. The most common primary polycythemia, erythropoietin. Some congenital polycythemias, as best described in
polycythemia rubra vera, which is a clonal disorder, is discussed in Chap. 84; Chuvash polycythemia, have erythroid progenitors that are hypersensi-
tive to erythropoietin, but also may have normal or even increased ery-
other primary polycythemias, such as those inherited from mutations in the thropoietin levels despite the increased red cell volume. Thus, some of
4,5
erythropoietin receptor or congenital disorders of hypoxia sensing, are dis- these rare inherited polycythemias share features of both primary and
cussed herein. In contrast, secondary polycythemias are a result of either an secondary polycythemias. 6
appropriate or inappropriate increase in the red cell mass, most often as a
result of augmented levels of erythropoietin; these polycythemias can also be
either acquired or hereditary. Although the clinical presentations of primary SECONDARY POLYCYTHEMIAS/
and secondary polycythemias may be similar, distinguishing amongst them is ERYTHROCYTOSES
important for accurate diagnoses and proper management. The term secondary polycythemia, more appropriately secondary
For example, those secondary polycythemic states that represent an appro- erythrocytosis, which refers to those conditions in which only erythro-
priate physiologic compensation to tissue hypoxia, should not be treated by cytes are increased in number and volume, describes a group of dis-
phlebotomies. An occasional patient may experience hyperviscosity symptoms orders characterized by an increased red cell mass brought about by
and may benefit from isovolemic reduction of hematocrit. Inappropriate poly- enhanced stimulation of red cell production by circulating physiologic
cythemias are caused by erythropoietin-secreting tumors, self-administration mediators, most commonly erythropoietin. Secondary polycythemia
of erythropoiesis-stimulating agents, including androgens, inherited disorders may be subdivided into appropriate polycythemia, that is, responding
of hypoxia sensing, or, rarely, some endocrine disorders (described in Chap. 38). normally to tissue hypoxia such as in pulmonary disease, Eisenmenger
Correction of hypoxia, discontinuation of erythropoiesis-stimulating agents or complex, high-altitude polycythemia and hemoglobins with increased
affinity for oxygen (Chaps. 49 and 50), and inappropriate polycythemia
resection of erythropoietin-secreting tumors will typically correct the associ- in which erythropoiesis is being stimulated by the aberrant produc-
ated polycythemia. tion of erythropoietin, as in erythropoietin-secreting tumors, by high
levels of insulin growth factor 1, by cobalt toxicity, by self-administra-
tion of erythropoietin, androgens, or adrenocorticotropic hormone,
or by other stimulators of erythropoiesis (as in post–renal transplant
DEFINITION AND HISTORY erythrocytosis). 7
In his important monograph on barometric pressure published in
The term polycythemia, denoting an increased amount of blood cells, 1878, Paul Bert showed that physiologic impairment observed at high
has traditionally been applied to those conditions in which the mass altitude was caused by a reduction in the oxygen content of the air. A
8
of erythrocytes is increased. Erythrocytosis is an alternative term that few years earlier, his friend and mentor, Dennis Jourdanet, had observed
has also been applied to circumstances in which the increased red cell
an increase in the number of red corpuscles in blood of the highland-
9
ers in Mexico, and Bert recognized that such an increase would tend
to ameliorate the effect of atmospheric hypoxia. However, neither Bert
nor Jourdanet suspected a cause-and-effect relationship. It was not until
Acronyms and Abbreviations: BFU-E, burst-forming unit–erythroid; 2,3-BPG, 1890, when Viault observed a prompt increase in the number of his
10
2,3-bisphosphoglycerate; COPD, chronic obstructive pulmonary disease; EGLN1, a own red corpuscles after having traveled from Lima, Peru, at sea level,
gene encoding for PHD2; EPAS1, a gene encoding for HIF-2α; EPOR, erythropoie- to Morococha, at 4570 m (15,000 ft) above sea level, that altitude ery-
tin receptor (protein); HCP, hematopoietic cell phosphatase; HIF, hypoxia-inducible throcytosis was accepted as a compensatory adaptation to hypoxia. At
11
factor; HUMARA, human androgen-receptor gene; JAK, Janus-type tyrosine kinase; about the same time, it was observed that many patients with cyanosis
12
OSA, obstructive sleep apnea; PAI-1, plasminogen activator inhibitor; PFCP, primary were also polycythemic. Both cardiacos negros, with severe pulmo-
familial and congenital polycythemia; PHD2, proline hydroxylase 2; STAT, signal nary failure and arterial oxygen desaturation, and children with morbus
transducer and activator of transcription; VEGF, vascular endothelial growth factor; caeruleus, or right-to-left shunt through a congenital cardiac malforma-
VHL, von Hippel-Lindau syndrome. tion, were found to have increased red cell counts. Mechanical or neu-
13
rogenic hypoventilation as a cause of cyanosis and polycythemia was

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