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Molecular pathogenesis of congenital erythrocytoses and polycythemia vera

Molecular pathogenesis of congenital erythrocytoses and polycythemia vera
Author:
Josef T Prchal, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Jan 2024.
This topic last updated: Sep 23, 2022.

INTRODUCTION — Erythrocytosis and polycythemia are interchangeable terms for an elevated level of hemoglobin (Hb) or hematocrit (Hct). No clear consensus for either term has been achieved, but in this topic we use the term polycythemia only with reference to polycythemia vera (PV), while we use erythrocytosis to describe various polyclonal disorders that cause elevated Hb/Hct.

Erythrocytosis can result from increased red blood cell (RBC) mass (absolute erythrocytosis) and/or decreased intravascular volume (relative erythrocytosis). Absolute erythrocytosis can be caused by an erythroid progenitor-intrinsic disorder (primary erythrocytosis) or in response to elevated levels of the key regulatory hormone, erythropoietin (EPO), and other causes (secondary erythrocytosis) (table 1).

Most cases of primary erythrocytosis are due to PV, a myeloproliferative neoplasm caused by an acquired (ie, not inherited) somatic mutation of JAK2 in bone marrow stem cells. Rare inherited (germline) conditions can cause erythrocytosis due to inherited gene variants that cause augmented hypoxia sensing, increased affinity of Hb for oxygen (O2), and other causes.

This topic discusses molecular mechanisms associated with inherited (congenital) erythrocytoses and PV.

The clinical approach to a patient with erythrocytosis or suspected PV is discussed separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia" and "Clinical manifestations and diagnosis of polycythemia vera" and "Methemoglobinemia".)

TERMINOLOGY

●Erythrocytosis – Erythrocytosis, also called polycythemia, describes an elevated hemoglobin (Hb) or hematocrit (Hct).

•Adults

-Increased Hb – >17.5 g/dL in adult males or >15.3 g/dL in non-pregnant females [1]

-Increased Hct – >50 percent in males or >45 percent in females

•Children – For children, normal values for red blood cell (RBC) parameters vary with age (table 2)

In addition to age and sex (table 3 and table 2), altitude of residence is an independent variable for defining erythrocytosis. Adjustments for a given population, sex, age, and the altitude of residence have been published [2]. Even moderate altitude should be considered when interpreting erythrocytosis, as normal values for Hb/Hct are significantly higher in Denver or Salt Lake City compared with New York or Los Angeles [3]. Analysis of 71,798 Swiss males aged 18 to 22 years showed significant Hb differences with the altitude of residence between 200 and 2000 meters [4].

●Absolute versus relative erythrocytosis – Erythrocytosis can be caused by increased RBC mass (absolute erythrocytosis) or by volume contraction, without an increase in RBC mass (relative erythrocytosis). Numerous conditions can cause erythrocytosis (table 1).

Evaluation of the cause of erythrocytosis/polycythemia is discussed separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

●Primary erythrocytosis – RBC-intrinsic erythrocytosis caused by an acquired (ie, not inherited) mutation in hematopoietic cells or by an inherited (ie, germline) gene variant that renders proliferation of erythroid progenitors independent of or hypersensitive to serum levels of erythropoietin (EPO).

●Secondary erythrocytosis – Erythrocytosis caused by excessive EPO or other non-RBC-intrinsic conditions. This can be an appropriate physiologic response (eg, increased EPO from tissue hypoxia caused by lung disease, high carboxy-hemoglobin in cigarette smokers, methemoglobinemia, or inheritance of high oxygen affinity Hbs) or an inappropriate (ie, not physiologic) response, such as an EPO-secreting tumor or "blood doping."

●Mixed (ie, primary and secondary) disorders – Some disorders share features of both primary and secondary erythrocytosis (eg, Chuvash erythrocytosis).

REGULATION OF ERYTHROPOIESIS — Erythropoiesis is the process of production and renewal of the red blood cell (RBC) mass. A brief review of basic aspects of erythropoiesis is presented below to allow for a better understanding of the potential mechanisms by which erythrocytosis can occur. A more detailed discussion of the regulation of erythropoiesis is presented separately. (See "Regulation of erythropoiesis".)

Erythropoietin (EPO) — EPO is the principal hormone that regulates erythropoiesis in adults. EPO is primarily produced by cells in the kidney, while a small amount is produced in the liver. EPO is required at various stages of erythroid maturation [5]. In adult erythropoiesis, EPO is most important for terminal maturation of erythroid cells, acting especially at the level of the early and late committed erythroid progenitor cells (figure 1). By contrast, pluripotent hematopoietic stem cells (HSCs) and early progenitor cells require stem cell factor, thrombopoietin, granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or interleukin (IL)-3 for growth, in addition to EPO.

Erythropoietin receptor (EPO-R) — EPO effects are mediated by EPO-R, an EPO-specific receptor that is expressed as a cell surface homodimer on erythroid progenitor cells [6]. The interaction of EPO with EPO-R leads to conformational changes of the EPO-R homodimer and activation of intracellular signals:

●Stimulation of proliferation

●Induction of erythroid-specific protein expression and their activation, and also cellular differentiation

●Inhibition of apoptosis

The cytoplasmic portion of the EPO-R, distal to the transmembrane domain, is a positive regulatory domain that interacts with Janus 2 tyrosine kinase (JAK2) [7]. Soon after interacting with EPO-R, JAK2 phosphorylates itself and the STAT5 transcription factor, which initiates a cascade of erythroid-specific signaling and inhibition of apoptosis [8].

The C-terminal cytoplasmic domain of EPO-R functions as a negative regulatory domain [7]. Hematopoietic cell phosphatase (HCP; also called SH protein tyrosine phosphatases [SHP-1, SH-PTP1]) interacts with this portion of EPO-R and downregulates signal transduction [9]. Mutants lacking this portion of EPO-R are hypersensitive to EPO and display prolonged EPO-induced autophosphorylation of JAK2 and increased erythroid progenitor proliferation [9].

Gain-of-function mutations of EPOR have been found in patients with primary familial and congenital erythrocytosis/polycythemia, as described below. (See 'Primary familial and congenital erythrocytosis/polycythemia' below.)

Oxygen sensor — The major stimulus for EPO production is decreased oxygen (O2) delivery caused by anemia (reduced RBC mass) or decreased O2 saturation of hemoglobin (hypoxemia) [10-13]. Factors that regulate EPO transcription are referred to as a cellular oxygen sensor (figure 2) [14]. This process is discussed in greater detail separately. (See "Regulation of erythropoiesis", section on 'Hypoxia-inducible factor and the response to hypoxia'.)

●Hypoxia inducible factors (HIFs) – Hypoxic stimulation of the O2 sensor signaling pathway increases production of HIF-1 and HIF-2; HIF-2 is the principal regulator of EPO gene transcription [15]. Protein levels of HIF-1 and HIF-2 alpha subunits are stabilized by hypoxia, while they decay rapidly in normoxia [16].

HIF-1 and HIF-2 are essential for life; they play important roles in cellular adaptation to hypoxia by controlling transcription of EPO and other genes required for erythropoiesis. HIFs regulate levels of vascular endothelial growth factor (VEGF) and its receptor, energy metabolism (eg, the glucose transporter and glycolytic enzymes), iron metabolism (ie, hepcidin and transferrin receptor), and cellular development. HIFs also play a major role in cancer and facilitate energy metabolism of cancer cells (ie, the Warburg effect) [17].

●Control of HIF protein levels – HIF alpha subunit isoforms (HIF-1 alpha, HIF-2 alpha, HIF-3 alpha) are rapidly destroyed in the presence of O2 by a mechanism that involves prolyl hydroxylation by the iron-dependent enzyme, PHD2 (encoded by EGLN). Prolyl hydroxylated HIF alpha subunits bind to the VHL tumor suppressor protein, which leads to ubiquitylation and rapid proteasomal degradation of HIF alpha by an E3 ligase complex.

Mutations of genes involved in the oxygen sensor pathway (figure 2) have been associated with various congenital erythrocytoses. (See 'EGLN1 mutations' below and 'EPAS1 mutations' below.)

●Other regulators of erythropoiesis – Insulin-like growth factor-I (IGF-I) and angiotensin II contribute to erythropoiesis, but they have not been shown to cause congenital erythrocytosis.

•IGF-I – IGF-I has EPO-like activity that targets circulating early erythroid progenitors [18,19]. IGF-I may play a role in patients with end-stage kidney disease and with post-renal transplant erythrocytosis. (See "Kidney transplantation in adults: Posttransplant erythrocytosis".)

•Angiotensin II – Inhibitors of angiotensin converting enzyme (ACE), such as enalapril or losartan, lower hematocrit in patients with post-transplant erythrocytosis and may act through JAK2. Post-transplant erythrocytosis is discussed separately. (See "Kidney transplantation in adults: Posttransplant erythrocytosis".)

•The iron regulatory protein (IRP-1) – Hypoxic regulation of iron availability and erythropoiesis are closely related. Iron deficiency inhibits PHD2 and augments levels of HIFs, while it has an opposite effect on erythropoiesis (ie, it represses HIF-2 alpha by the direct interaction of iron and HIF-2 alpha). The iron regulatory protein (IRP-1) binds to the iron-responsive element in the untranslated region of 5' HIF-2 alpha and represses its translation. Northern European families have been described with pathologic variants of IRP1 in association with erythrocytosis, and deletion of Irp1 in mice caused erythrocytosis [20].

CONGENITAL ERYTHROCYTOSES

Augmented hypoxia-sensing — Hypoxia-sensing is central to the regulation of erythrocytosis and other physiologic functions [12,21]. Mutations of genes in hypoxia-sensing pathways were identified because of their association with erythrocytosis:

●VHL – Chuvash erythrocytosis and other VHL gene mutations

●EGLN1 – Loss-of-function mutations of EGLN1 (encoding proline hydroxylase 2 [PHD2])

●EPAS1 – Gain-of-function mutations of EPAS1 (encoding hypoxia inducible factor [HIF]-2 alpha)

●IRP1 – Loss-of-function mutations of iron regulatory protein (IRP-1)

Chuvash erythrocytosis — This entity, also called Chuvash polycythemia, is a rare congenital polycythemia caused by a mutation of the von Hippel-Lindau gene (VHL). This condition has features of both primary and secondary erythrocytosis.

●Clinical – Chuvash erythrocytosis is a congenital erythrocytosis associated with thrombotic or hemorrhagic vascular complications and pulmonary hypertension, which is associated with early mortality (eg, <40 years) [22,23]. Levels of serum erythropoietin (EPO) are elevated or inappropriately normal for the level of hematocrit (Hct), while serum hepcidin levels are reduced [22,24,25].

Phlebotomy is not warranted for Chuvash erythrocytosis. Phlebotomy may increase the rate of thrombotic complications because iron deficiency inhibits PHD2 and augments levels of HIFs, which augment expression of prothrombotic factors [24,26-28]. In one report, the JAK2 inhibitor ruxolitinib decreased phlebotomy requirements in patients with Chuvash erythrocytosis [29].

●Epidemiology – Chuvash erythrocytosis arises sporadically, but it is endemic in the Chuvash population of the mid-Volga region of European Russia and on the Italian island, Ischia [30-36].

●Pathophysiology – Chuvash erythrocytosis is caused by the VHL R200W mutation. The role of VHL in regulating erythropoiesis is discussed above. (See 'Oxygen sensor' above.)

The VHL R200W mutation is present in both alleles of affected patients and in one allele of carriers. Most other VHL mutations are associated with characteristic VHL-related tumors (eg, pheochromocytoma, renal cell carcinoma, and hemangioblastomas), rather than congenital polycythemia; however, some cases of acquired polycythemia may be related to excessive EPO produced by such tumors [37,38].

Other homozygous and compound heterozygous germline mutations of VHL are associated with erythrocytosis, but not with VHL tumor syndrome, including Croatian erythrocytosis (VHL H191D), VHL exon 2 mutation (VHL P138L), alternative splicing with exon 2 skipping, other compound heterozygous germline mutations (eg, VHL T124A and VHL L188V), and homozygous c.222C→A, p.V74V) [39-43].

EGLN1 mutations — Autosomal dominant erythrocytosis is associated with loss-of-function mutations of EGLN1, which encodes PHD2 (prolyl hydroxylase domain protein 2), an enzyme involved in the degradation of HIF alpha under normoxic conditions [44]. (See 'Oxygen sensor' above.)

A study of 67 patients with spontaneous or familial erythrocytosis identified mutations in the catalytic domain of PHD2 [45]. All gene variants were germline, heterozygous, missense loss-of-function mutations and coded for a predicted full-length mutant PHD2 protein; a non-erythroid phenotype has not been identified with these mutations [12]. Inhibitors of PHD2 may be of clinical interest for therapy of anemia associated with chronic kidney disease. However, compared with EPO, a PHD2 inhibitor was associated with higher rates of thrombosis in a phase 3 trial and it was not approved by the US Food and Drug Administration [46].

Gain-of-function mutations of EGLN1 (Asp4Glu; Cys127Ser) may contribute to protection of Tibetans from the development of erythrocytosis at high altitude [47].

EPAS1 mutations — Autosomal dominant familial erythrocytosis has been associated with a gain-of-function germline mutation in EPAS1, which encodes HIF-2 alpha and renders HIF-2 alpha less susceptible to hydroxylation by PHD2 [48-51]. (See 'Oxygen sensor' above.)

Affected individuals usually present with congenital erythrocytosis and elevated or inappropriately normal EPO levels for the given level of Hct. Some patients with congenital erythrocytosis associated with mutations of EPAS1 develop recurrent pheochromocytomas, paragangliomas, and/or somatostatinomas [52,53]. The tumors are heterozygous for gain-of-function mutations of EPAS1, and EPO transcripts are present in the tumor. The mutations are in the vicinity of the primary hydroxylation site of the HIF-2 alpha protein, leading to increased HIF-2 alpha activity, prolonged protein half-life, and upregulation of the hypoxia-responsive genes, EPO, VEGFA, GLUT1, and END1 in the tumors [54,55]. The association may result from embryonic mosaicism, because the mutations are generally not found in non-tumor tissues.

Increased oxygen affinity — Increased affinity of hemoglobin (Hb) for O2 (figure 3) causes tissue hypoxia and results in congenital erythrocytosis.

Hb mutants — Congenital erythrocytosis due to high O2 affinity Hb mutants is uncommon, but mutations of alpha, beta, and gamma globin genes have been described that lead to autosomal dominant erythrocytosis. (See "Hemoglobin variants that alter hemoglobin-oxygen affinity".)

●Oxygen binding by Hb – The Hb tetramer oscillates between the R (relaxed; fully oxygenated hemoglobin) and T (tense; fully deoxygenated hemoglobin) states and requires interactions between globin subunits. The high affinity conformation is due to stabilizing the R state or destabilizing the low affinity T state. Increased O2 affinity has been associated with single point substitutions, double point substitutions, deletions, insertions, reading frame shift mutations, and fusion genes [5].

Examples include:

•Alteration in areas of the molecule directly involved in the R→T transition, such as in Hb Chesapeake and Hb Montefiore

•A change of the alpha1:beta1 interface, such as in Hb Crete

•A mutation reducing the affinity of Hb for 2,3-BPG, such as is seen in Hb Rahere and Hb Providence

•Elongation of chains by termination codon or frame-shift mutations

A complete list of high affinity hemoglobins can be found on the Globin Gene Server (globin.bx.psu.edu).

●Clinical presentation – Affected individuals are generally asymptomatic, since erythrocytosis compensates to maintain adequate tissue O2 delivery. The age at diagnosis varies with the affected subunit. Germline mutations of alpha globin genes are associated with life-long erythrocytosis, while those of beta globin genes are silent at birth, but erythrocytosis develops after the fetal to adult Hb switch at approximately six months of age. Rare gamma globin mutations are associated with transient neonatal erythrocytosis that disappears by approximately six months of age, when most fetal Hb is replaced by adult Hb.

●Diagnosis – Among patients with erythrocytosis, a high O2 affinity Hb should be considered in those who have an inappropriately normal or an elevated serum EPO concentration, a normal arterial partial pressure of O2 (pO2), and normal O2 saturation, especially in those with autosomal dominant pattern of inheritance; these mutations can also arise de novo in a subject whose parents are not affected.

The hemoglobin-O2 dissociation curve is the benchmark for diagnosis of a high O2 affinity Hb (figure 3). The p50 (ie, 50 percent saturation of Hb) can be estimated from venous blood by measuring the saturation of Hb, pH, and pO2. Importantly, an accurate p50 value cannot be "calculated" from the arterial pO2, although this is often attempted erroneously. Although not widely available, the hemox-analyzer apparatus is required when accurate p50 and Hill coefficients are needed [56].

Note that Hb electrophoresis misses some of these mutants and should not be the initial screening test. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Gel-based electrophoresis'.)

●Management – Erythrocytosis is an appropriate physiologic response to a high O2 affinity Hb. Patients with a high affinity Hb should not be phlebotomized, as it further decreases tissue O2 delivery.

Further details of diagnosis and management of patients with high O2 affinity Hb are presented separately. (See "Hemoglobin variants that alter hemoglobin-oxygen affinity".)

Congenital methemoglobinemia — Methemoglobin is oxidized Hb that contains iron in the ferric state. Auto-oxidation of Hb to methemoglobin occurs spontaneously at a slow rate in normal individuals, which converts a small percent of available Hb to methemoglobin. This process and its clinical effects are discussed in greater detail separately. (See "Methemoglobinemia".)

●Formation of methemoglobin – During the formation of oxyhemoglobin from deoxyhemoglobin and molecular O2, one electron is partially transferred from heme iron to the bound oxygen, forming a ferric-superoxide anion complex (Fe3+/O2-) [57]. During deoxygenation, most oxygen leaves as O2, but a small amount of it leaves as a superoxide (O2-) radical. In the latter circumstance, the partially transferred electron is not returned to the iron moiety, leaving the iron in the ferric state and forming methemoglobin:

 HbFe2+/O2   —>   HbFe3+   +   O2-

Ferric hemes of methemoglobin are unable to bind O2. In addition, the O2 affinity of any accompanying ferrous hemes in the hemoglobin tetramer is increased. As a result, the O2 dissociation curve is "left-shifted" (figure 3) and O2 delivery to the tissues is impaired; this leads to a compensatory erythrocytosis in some affected individuals [57,58].

The only physiologically important pathway for reducing methemoglobin back to Hb is the NADH-dependent reaction catalyzed by cytochrome b5 reductase (b5R; also called methemoglobin reductase).

●Molecular basis – The major cause of hereditary methemoglobinemia is a deficiency of cytochrome b5 reductase. Less common causes are hemoglobin M disease, in which there is a mutated globin that facilitates the oxidation of iron in the ferric state, and extremely rare cytochrome b5 deficiency.

●Diagnosis – The laboratory diagnosis of methemoglobinemia is based upon analysis of its absorption spectrum, which has peak absorbance at 631 nm.

●Clinical presentation – Most individuals with recessively inherited congenital methemoglobinemia from type I cytochrome b5 reductase (enzyme deficiency restricted to erythrocytes) or dominantly inherited hemoglobin M disease are asymptomatic, although some complain of headache and easy fatigue, despite methemoglobin levels as high as 40 percent of total Hb. The main clinical finding is "cyanosis" or slate-blue color of the skin and mucous membranes, which is due to the different absorbance spectrum of methemoglobin compared with oxyhemoglobin. (See "Methemoglobinemia", section on 'Clinical presentation (congenital)'.)

In addition to methemoglobinemia and cyanosis, patients with the less common type II cytochrome b5 reductase also have a deficiency of enzyme activity in non-erythroid cells, which is associated with severe developmental defects and premature death.

2,3-bisphosphoglycerate deficiency — Familial deficiency of 2,3-BPG (previously known as 2,3-DPG) is a rare cause of congenital secondary erythrocytosis caused by a deficiency of the red blood cell (RBC) enzyme, bisphosphoglyceromutase (BPGM) [59-61]. The resultant increase in Hb-O2 affinity decreases the amount of O2 released peripherally, leading to compensatory erythrocytosis.

Only one family with 2,3-BPG deficiency has been studied comprehensively [59-61]. The proband had undetectable BPGM activity and very low 2,3-BPG levels; his children were not polycythemic, a finding compatible with an autosomal recessive disease. The proband and three sisters had compound heterozygosity for mutations in BPGM [61]. However, the children had partially reduced enzyme activity and mildly decreased 2,3-BPG levels. Other heterozygous progeny of this enzyme-deficient patient and heterozygous subjects from unrelated families had moderate erythrocytosis, casting doubt on the autosomal recessive mode of its inheritance [60].

Finding a decreased p50 is a prerequisite for consideration of 2,3-BPG deficiency as a cause of congenital erythrocytosis (figure 3). In comparison to the high O2 affinity Hbs, the level of 2,3-BPG is very low in familial 2,3-BPG deficiency. Similar to high O2 affinity Hb mutants, the p50 should be the first screening test that can be estimated from venous blood when the hemox-analyzer apparatus (described above) is not available.

Other disorders — Other disorders can also cause congenital erythrocytosis.

Primary familial and congenital erythrocytosis/polycythemia — Primary familial and congenital erythrocytosis/polycythemia (PFCP), also called benign erythrocytosis and autosomal dominant erythrocytosis, is an uncommon cause of erythrocytosis that is caused by mutations of EPOR (which encodes the EPO receptor).

●Clinical/laboratory characteristics – PFCP is characterized by:

•Elevated RBC mass

•Low serum EPO

•Normal Hb-O2 dissociation curve

•Absence of progression to acute leukemia

•Hypersensitivity of erythroid progenitors to EPO

●Genetics – Gene variants of EPOR associated with PFCP are typically inherited as an autosomal dominant trait, or it may be due to sporadic (de novo) mutations [62-66].

Analysis of 53 unrelated subjects with congenital erythrocytosis identified EPOR mutations in 9 percent [64,67]. Most EPOR mutations encode a truncated receptor that lacks the C-terminal negative regulatory domain [63,64,68,69]. The absence of a binding site for the negative regulator, hematopoietic phosphatase (HCP), triggers proliferation-inducing/apoptosis-inhibiting pathways that contribute to the erythrocytosis. An exception is the EPOR missense mutant, EPOR p.Gln434Pro; its C-terminal tail was shown to increase EPO-R dimerization and stability, resulting in augmented JAK2 constitutive signaling and hypersensitivity to EPO [70]. (See 'Regulation of erythropoiesis' above.)

EPO mutations — Congenital erythrocytosis has rarely been associated with mutations of EPO.

A five-generation family with autosomal dominant erythrocytosis had moderately increased EPO levels, no splenomegaly, and normal leukocyte and platelet numbers; normal Hb O2 dissociation curve; and no mutations of HIF2A, HIF1A, EPOR, PHD2, EGLN1 and VHL [71]. A novel single nucleotide polymorphism was found at -136 nucleotides upstream of the EPO translation initiation site; this variant was identified in all seven affected family members and in none of eight unaffected relatives [72].

In a multigenerational Norwegian family with erythrocytosis, the phenotype segregated with the EPO locus, according to a genome-wide association study (GWAS) [73]. Exome sequencing revealed a single nucleotide deletion of exon 2. In an unrelated family, a different mutation was found in the same exon [73].

POLYCYTHEMIA VERA — Polycythemia vera (PV) is the most common cause of primary erythrocytosis. It is a myeloproliferative neoplasm (MPN) that is clinically manifest as erythrocytosis, variable increases of platelets and leukocytes, possible splenomegaly, and increased risk for thromboses. PV is a clonal disorder, and the vast majority of cases are caused by a specific acquired mutation, JAK2 V617F. Clinical manifestations, diagnosis, management, and prognosis of PV are presented separately. (See "Clinical manifestations and diagnosis of polycythemia vera" and "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)

Clonality of PV — PV is a clonal disorder that arises from a single hematopoietic pluripotent stem cell; as a result, virtually all circulating myeloid cells are clonal in origin [74,75]. The mutation is present in erythroid and myeloid cells, megakaryocytes, and a variable proportion of B lymphocytes; by contrast, most, but not all, T cells and natural killer cells remain polyclonal [76].

A hallmark of the disease is the ability of PV bone marrow cells to form in vitro erythroid colonies in the absence of exogenous erythropoietin (EPO), a phenomenon that is not observed with progenitor cells from normal subjects [77]. Prior to the identification of the causal mutation, this phenomenon was used as a diagnostic assay to distinguish PV from other causes of erythrocytosis [69,78-80]. This property was also useful for characterizing primary familial and congenital polycythemia (PFCP) as a separate disease [63,65,81].

JAK2 mutations — Mutated JAK2 is a hallmark of PV and is a major diagnostic criterion [82]. However, JAK2 V617F is not pathognomonic for PV; it is found in approximately half of patients with other MPNs (ie, essential thrombocythemia or primary myelofibrosis) and is seen rarely in other malignancies. The diagnosis of PV and clinical features of MPNs are discussed separately. (See "Overview of the myeloproliferative neoplasms".)

JAK/STAT signaling plays a pivotal role in erythroid proliferation and cell survival in response to EPO/EPO-R signaling [83-86]. The JAK2 V617F mutation dysregulates JAK2 tyrosine kinase activity by disrupting its inhibitory domain, thereby enabling constitutive phosphorylation of STATs, despite typically low EPO [83-85,87]. This mutation was shown to recapitulate many properties of native PV erythroid progenitor cells, including EPO-independence and hypersensitivity of PV erythroid colonies.

A small subset (eg, <3 percent) of patients with PV are JAK V617F-negative. Most have a mutation within a 20-nucleotide region of exon 12 of JAK2 [88,89]. Very rarely, mutations are found in genes that facilitate JAK2 or STAT5 signal transduction (eg, LNK, TET2, CBL) [90,91], while other patients have mutations of epigenetic regulators (eg, DNA and histone modifiers, such as EZH2, TET2, ASXL1) [91,92], or spliceosome machinery (eg, SF3B1, SRSF2, U2AF1) that may contribute to development of PV [91,93,94].

Familial PV — Approximately 5 percent of patients with PV have relatives with PV or other MPNs that appear to be inherited as an autosomal dominant trait with incomplete penetrance [95-98]. However, clinical PV or other MPNs in these families are acquired as a new mutation, occasionally at a younger age than seen in sporadic PV [97]; some of these affected relatives acquire non-JAK2 MPN-defining mutations such as CALR or MPL [95-98]. This suggests familial PV may result from a combination of an inherited (germline) predisposition to mutation followed by a "second hit" somatic mutation that leads to acquired clonal hematopoiesis.

SUMMARY

●Definitions

•Erythrocytosis – Erythrocytosis (also called polycythemia) refers to elevated hemoglobin (Hb) or hematocrit (Hct). Normal values for Hb and Hct vary with sex (table 3), age (table 2), and altitude of residence. (See 'Terminology' above.)

•Absolute versus relative erythrocytosis – Erythrocytosis can be caused by increased red blood cell (RBC) mass (absolute erythrocytosis) and/or decreased plasma volume (relative erythrocytosis).

There are numerous possible reasons for erythrocytosis (table 1); evaluation for the cause of erythrocytosis/polycythemia is discussed separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

•Primary erythrocytosis – Polycythemia caused by an RBC-intrinsic process, due to an acquired mutation in hematopoietic cells or by an inherited (ie, germline) gene variant that renders proliferation of erythroid progenitors independent of/hypersensitive to erythropoietin (EPO).

•Secondary erythrocytosis – Erythrocytosis caused by circulating factors that stimulate erythropoiesis (eg, EPO, cobalt) as an appropriate physiologic response to hypoxia, or in congenital disorders of hypoxia sensing, and other mechanisms.  

•Congenital erythrocytosis – Inherited condition of increased RBC mass due to a mutation that affects the interaction of Hb with oxygen (O2) (figure 3) or components of the hypoxia-sensing pathway (figure 2).

●Regulation of erythropoiesis – EPO is the key regulator of proliferation and maturation of committed erythroid progenitors and maturing erythrocytes in bone marrow. In adults, EPO is primarily produced by the kidney in response to tissue hypoxia. Hypoxia inducible factor (HIF)-2 and HIF-1 regulate EPO transcription in a pathway that includes interactions with VHL and PHD2-dependent degradation. (See 'Regulation of erythropoiesis' above.)

●Congenital erythrocytosis – Inherited disorders of erythrocytosis include:

•Enhanced O2 sensing – Mutations that cause increased EPO expression:

-VHL – Chuvash erythrocytosis and other VHL gene mutations (see 'Chuvash erythrocytosis' above)

-EGLN1 – Loss-of-function mutations of EGLN1 (PHD2) (see 'EGLN1 mutations' above)

-EPAS1 – Gain-of-function mutations of EPAS1 (HIF-2 alpha) (see 'EPAS1 mutations' above)

•Increased Hb-O2 affinity (figure 3):

-High O2 affinity Hb mutations – Various mutations (see 'Hb mutants' above)

-Congenital methemoglobinemia – Abnormal cytochrome b5 reductase and others (see 'Congenital methemoglobinemia' above)

•Other disorders:

-Primary familial and congenital erythrocytosis/polycythemia (PFCP) – Mutations of EPO-receptor (EPOR) and other genes (see 'Primary familial and congenital erythrocytosis/polycythemia' above)

-EPO mutations – Rare mutations (see 'EPO mutations' above)

●Polycythemia vera (PV) – PV is a myeloproliferative neoplasm (MPN) manifested as erythrocytosis, variable leukocytosis and platelets, bone marrow hypercellularity, and propensity for thromboses. PV and other Philadelphia chromosome (Ph)-negative MPNs are discussed separately. (See "Overview of the myeloproliferative neoplasms".)

•Clonality – PV is a clonal disorder of hematopoietic progenitors. (See 'Clonality of PV' above.)

•JAK2 mutations – Nearly all cases are caused by an acquired mutation (JAK2 V617F) in a bone marrow progenitor cell. (See 'JAK2 mutations' above.)

•Familial PV – Rare cases of PV are seen in familial clusters; some are due to an inherited JAK2 gene variant. (See 'Familial PV' above.)

ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

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  26. Gordeuk VR, Key NS, Prchal JT. Re-evaluation of hematocrit as a determinant of thrombotic risk in erythrocytosis. Haematologica 2019; 104:653.
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  44. Percy MJ, Zhao Q, Flores A, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A 2006; 103:654.
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  49. Percy MJ, Beer PA, Campbell G, et al. Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood 2008; 111:5400.
  50. Gale DP, Harten SK, Reid CD, et al. Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation. Blood 2008; 112:919.
  51. Perrotta S, Stiehl DP, Punzo F, et al. Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range. Haematologica 2013; 98:1624.
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  63. Gregg XT, Prchal JT. Erythropoietin receptor mutations and human disease. Semin Hematol 1997; 34:70.
  64. 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; 90:2057.
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  88. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356:459.
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  91. Wang L, Swierczek SI, Drummond J, et al. Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes. Leukemia 2014; 28:935.
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  93. Makishima H, Visconte V, Sakaguchi H, et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012; 119:3203.
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  97. Kralovics R, Stockton DW, Prchal JT. Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood 2003; 102:3793.
  98. Tashi T, Swierczek S, Prchal JT. Familial MPN Predisposition. Curr Hematol Malig Rep 2017; 12:442.
Topic 7106 Version 31.0

References

1 : Williams Manual of Hematology, 10th edition, Lichtman MA, Kaushansky K, Prchal JT, et al (Eds), McGraw Hill, 2022.

2 : The increase in hemoglobin concentration with altitude varies among human populations.

3 : The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?

4 : Hemoglobin concentration of young men at residential altitudes between 200 and 2000 m mirrors Switzerland's topography.

5 : Erythropoietin (Ep) dose-response curves for three classes of erythroid progenitors in normal human marrow and in patients with polycythemia vera.

6 : Human erythropoietin receptor: cloning, expression, and biologic characterization.

7 : The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains.

8 : JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin.

9 : Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals.

10 : Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.

11 : HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

12 : Oxygen sensing, homeostasis, and disease.

13 : Erythrocytosis: the HIF pathway in control.

14 : Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis.

15 : Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.

16 : Purification and characterization of hypoxia-inducible factor 1.

17 : Hypoxia. 5. Hypoxia and hematopoiesis.

18 : Human colony-forming units-erythroid do not require accessory cells, but do require direct interaction with insulin-like growth factor I and/or insulin for erythroid development.

19 : Production of erythropoietic bursts by progenitor cells from adult human peripheral blood in an improved serum-free medium: role of insulinlike growth factor 1.

20 : HIF-2 inhibitor, erythrocytosis, and pulmonary hypertension.

21 : Oxygen homeostasis.

22 : Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.

23 : Complications in children and adolescents with Chuvash polycythemia.

24 : Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.

25 : Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression.

26 : Re-evaluation of hematocrit as a determinant of thrombotic risk in erythrocytosis.

27 : Thrombotic risk in congenital erythrocytosis due to up-regulated hypoxia sensing is not associated with elevated hematocrit.

28 : Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia.

29 : Clinical Improvement with JAK2 Inhibition in Chuvash Polycythemia.

30 : [Familial erythrocytosis among the residents of the Chuvash ASSR].

31 : Congenital polycythemia in Chuvashia.

32 : Mutations in the VHL gene in sporadic apparently congenital polycythemia.

33 : Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster.

34 : Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.

35 : Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry.

36 : Congenital polycythemias/erythrocytoses.

37 : Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia.

38 : Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia.

39 : The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W).

40 : Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.

41 : Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.

42 : Novel compound VHL heterozygosity (VHL T124A/L188V) associated with congenital polycythaemia.

43 : Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria.

44 : A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis.

45 : Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene.

46 : Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene.

47 : A genetic mechanism for Tibetan high-altitude adaptation.

48 : A gain-of-function mutation in the HIF2A gene in familial erythrocytosis.

49 : Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis.

50 : Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation.

51 : Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range.

52 : Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia.

53 : Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas.

54 : New syndrome of paraganglioma and somatostatinoma associated with polycythemia.

55 : A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma.

56 : Familial polycythemia caused by a novel mutation in the beta globin gene: essential role of P50 in evaluation of familial polycythemia.

57 : Familial polycythemia caused by a novel mutation in the beta globin gene: essential role of P50 in evaluation of familial polycythemia.

58 : Familial polycythemia caused by a novel mutation in the beta globin gene: essential role of P50 in evaluation of familial polycythemia.

59 : The first case of a complete deficiency of diphosphoglycerate mutase in human erythrocytes.

60 : [Diphosphoglyceromutase deficiency: new cases associated with erythrocytosis].

61 : Compound heterozygosity in a complete erythrocyte bisphosphoglycerate mutase deficiency.

62 : Familial and congenital polycythemia in three unrelated families.

63 : Erythropoietin receptor mutations and human disease.

64 : Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias.

65 : Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin.

66 : Advances in understanding the pathogenesis of primary familial and congenital polycythaemia.

67 : Genetic heterogeneity of primary familial and congenital polycythemia.

68 : Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene.

69 : Classification and molecular biology of polycythemias (erythrocytoses) and thrombocytosis.

70 : New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis.

71 : Finding the novel molecular defect in a family with high erythropoietin autosomal dominant polycythemia

72 : A Novel EPO Gene Mutation In a Family With Autosomal Dominant Polycythemia

73 : A Gain-of-Function Mutation in EPO in Familial Erythrocytosis.

74 : Polycythemia vera: stem-cell and probable clonal origin of the disease.

75 : Presence of polyclonal hematopoiesis in females with Ph-negative myeloproliferative neoplasms.

76 : Polycythemia vera and other primary polycythemias.

77 : Letter: Bone-marrow responses in polycythemia vera.

78 : In vitro erythropoiesis in polycythemia vera and other myeloproliferative disorders.

79 : Diagnostic applications of haemopoietic progenitor culture techniques in polycythaemias and thrombocythaemias.

80 : In vitro culture growth of erythroid progenitors and serum erythropoietin assay in the differential diagnosis of polycythaemia.

81 : Autosomal dominant polycythemia.

82 : Autosomal dominant polycythemia.

83 : Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

84 : Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

85 : A gain-of-function mutation of JAK2 in myeloproliferative disorders.

86 : Identification of an acquired JAK2 mutation in polycythemia vera.

87 : A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.

88 : JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.

89 : Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders.

90 : New mutations and pathogenesis of myeloproliferative neoplasms.

91 : Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes.

92 : Epigenetics and mutations in chronic myeloproliferative neoplasms.

93 : Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis.

94 : Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome.

95 : Familial polycythemia vera.

96 : Increased prevalence of polycythemia vera in parents of patients on polycythemia vera study group protocols.

97 : Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease.

98 : Familial MPN Predisposition.

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