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

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Polycythemia of High Altitude endemic congenital polycythemia in the world. Outside of Chuvashia,
Elevation of red cell mass as a response to high altitude hypoxia rep- Chuvash polycythemia has also been found sporadically in diverse eth-
resents an appropriate adjustment to reduced blood oxygen content nic and racial groups, 50,51 and recently a high prevalence of this disorder
and delivery. The exponentially decreasing atmospheric oxygen pres- has also been reported on the Italian island of Ischia. 52
sure with altitude stimulates the body to accommodate by an increase
in respiratory rate and volume. Such adaptation is possible only in the
short-term, because the body may not always be able to adequately ETIOLOGY AND PATHOGENESIS
enhance respiration. Polycythemia is considered to be a universal, uni-
form adaptation response to hypoxia that arises in normal individuals, PRIMARY POLYCYTHEMIAS
but when it is exaggerated, in some cases it results in chronic mountain Primary Familial and Congenital Polycythemia
sickness with associated symptoms of fatigue, headache, and pulmonary In contrast to polycythemia vera, PFCP is caused by germline rather
hypertension. 42 than acquired somatic mutations. It is congenital and manifests autoso-
Altitude above sea level should be used as an independent variable mal dominant inheritance and, not infrequently, sporadic occurrence
3
for the definition of polycythemia and Centers for Disease Control from de novo germline mutations. Like polycythemia vera (Chap. 84),
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data lists the appropriate adjustment values. 44 it is primary in that the defect changes intrinsic responses of erythroid
progenitors, and erythropoietin levels are low.
Post–Renal Transplant Erythrocytosis To date, 12 mutations of the erythropoietin receptor (EPOR) asso-
This syndrome, defined as a persistent elevation of hematocrit at greater ciated with PFCP have been described (Table 57–1). Nine of the 12
than 51 percent, is a relatively common condition found in approxi- result in truncation of the EPOR cytoplasmic carboxyl terminal, and are
mately 5 to 10 percent of renal allograft recipients. 45,46 Post–renal the only mutations convincingly linked with PFCP. Such truncations
transplant erythrocytosis usually develops within 8 to 24 months after lead to a loss in the negative regulatory domain of the EPOR (Chaps.
transplantation, despite persistently good function of the allograft, and 32 and 34). Three missense EPOR mutations have also been described,
resolves spontaneously within 2 years in approximately 25 percent of but these have not been linked to PFCP or any other disease phenotype
patients. Factors that increase the likelihood of its development are (Table 57–1).
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lack of erythropoietin therapy prior to transplantation, a history of Erythropoietin-mediated activation of erythropoiesis involves sev-
smoking, diabetes mellitus, renal artery stenosis, low serum ferritin eral steps (also see Chap. 32). First, erythropoietin activates its receptor
levels, and normal or higher pretransplant erythropoietin levels. Post– by inducing conformational changes of its dimers (Chap. 17). These
renal transplant erythrocytosis is also more frequent in patients who are changes lead to initiation of an erythroid-specific cascade of events.
not undergoing graft rejection. The first signal is initiated by conformation change-induced activation
of Janus-type tyrosine kinase 2 (JAK2) and its phosphorylation and
Chuvash Polycythemia activation of a transcription factor, signal transducer and activator of
A Russian hematologist, Lydia A. Polyakova, described polycythemia transcription 5 (STAT5), which regulates erythroid-specific genes. This
in the Chuvash population (an ethnic isolate in the mid-Volga River “on” signal is negated by dephosphorylation of EPOR by hematopoietic
region of Russia of Turkish descent) in the early 1960s, and by 1974, cell phosphatase (HCP), also known as SHP1, that is, the “off” signal.
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103 cases from 81 families had been described. Since then, more cases EPOR truncations lead to a loss of the negative regulatory domain of the
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have come to light; hundreds of children and adults suffer from this EPOR, a binding site for HCP, explaining the gain-of-function proper-
condition, indicating that Chuvash polycythemia is the only known ties of these EPOR mutations (Fig. 57–1).

TABLE 57–1. Summary of Erythropoietin Receptor Gene Mutations
Type of Mutation Mutation Structural Defect Association with PFCP Ref.
Deletion (7bp) Del5985–5991 Frameshift > ter truncation Yes 163, 192
Duplication (8 bp) 5968–5975 Frameshift > ter truncation Yes 222
Nonsense G6002 Trp439 > ter truncation Yes 223
Nonsense 5986 C>T Gln435 > ter truncation Yes 224
Nonsense 5964C>G Tyr426 > ter truncation Yes 162
Nonsense 5881C>T Glu399 > ter truncation Yes 225
Nonsense 5959G>T Glu425 > ter truncation Yes 226
Insertion (G) 5974insG Frameshift > ter truncation Yes 227
Insertion (T) 5967insT Frameshift > ter truncation Yes 228
Substitution 6148C>T Pro 488 > Ser No 192, 229
Substitution 6146A>G Asn487 > Ser No 230
Substitution 2706 A>T Unknown No 226
Ter, termination codon.
Data from Kralovics R, Indrak K, Stopka T, et al. Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with
primary familial and congenital polycythemias. Blood 1997 Sep 1;90(5):2057–2061.

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