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Primary and secondary erythrocytosis
The term “polycythemia,” particularly as it pertains to newborns and children, should be more accurately termed erythrocytosis because it generally refers to conditions in which only erythrocytes are increased in number. It is usually a response to tissue hypoxia from any disorder causing inadequate oxygen, the presence of high-oxygen-affinity hemoglobins or increased production of erythropoietin (EPO) or other circulating erythropoietic stimulating factors, or mutations making erythroid progenitors intrinsically hyperproliferative. Erythrocytosis can be primary or secondary. In primary erythrocytosis the erythroid progenitors are either independent or hypersensitive to EPO and, thus, have very low EPO levels. Secondary erythrocytoses, on the other hand, have normal responsive erythroid progenitors but excessive production of EPO. Elevated hematocrit can also be associated with normal red cell mass and decreased plasma volume, so-called spurious, stress, or relative polycythemia.
Erythrocytosis or polycythemia
Increased red cell mass, mostly accompanied by elevated hemoglobin concentration and hematocrit, is variably denoted as polycythemia or erythrocytosis. However, there is no consensus on the use of either term. The term “polycythemia,” particularly as it pertains to newborns and children, should be more accurately termed erythrocytosis because it generally refers to conditions in which only erythrocytes are increased in number. Some founders of modern hematology have reasoned that the proper meaning of polycythemia is too many cells in blood , while others have reasoned that polycythemia implies that several lineages are increased along with erythrocytosis, that is, increased neutrophils, and/or platelet counts. With this definition, the only form of polycythemia is polycythemia vera (PV) . As the acceptance of this definition is now increasing, this chapter will reserve term the “polycythemia” only for PV , while other conditions with elevated red cell mass will be referred to as “erythrocytosis.” The term “erythrocytosis” applies to an increase in circulating red cell mass to above the normal upper limits of 30 mL/kg body weight (excluding hemoconcentration due to dehydration). However, the measurement of red cell mass and plasma volumes that uses radioactive isotopes is no longer available in the United States, and estimates of the red cell mass can be made using measured hemoglobin and hematocrit. A hemoglobin level greater than the 99th percentile of the method-specific reference range for age and sex, and adjusted for normal range at the altitude of residence should be applied. It should be noted that a patient may have decreased plasma volume and elevated hemoglobin and hematocrit, so-called spurious erythrocytosis, while high altitude dwellers such as Tibetans and Sherpas may have a normal hemoglobin levels but increased both red cell mass and plasma volumes, and, thus, have true erythrocytosis.
Erythrocytosis can be primary or secondary. Both can be congenital or acquired. Primary erythrocytosis, both congenital and acquired, has lower than normal serum EPO levels because the underlying genetic defect in the hematopoietic progenitors makes them hypersensitive to, or even independent of EPO. Congenital primary erythrocytosis, such as primary familial and congenital erythrocytosis/polycythemia (PFCP), has mutations in the EPO receptors (EPORs) and is associated with polyclonal hematopoiesis, while acquired primary erythrocytosis such as PV has clonal hematopoiesis due to mutations in hematopoietic progenitors, mainly JAK2 mutation that confers EPO independence. Secondary erythrocytosis, on the other hand, has normally responsive erythroid progenitors but excessive production of erythropoietic stimulating factors such as EPO. From a functional perspective, the increased red cell mass in secondary erythrocytosis can be physiologically appropriate or inappropriate. Appropriate responses are due to tissue hypoxia that increases red cell mass to assure adequate tissue oxygen delivery that can be either from congenital causes (high-oxygen-affinity hemoglobins) or acquired causes (Eisenmenger complex, exposure to low oxygen environment such as high altitude, or lung disease). Inappropriate responses can also be congenital (mutations of normal hypoxia sensing pathways) or acquired (EPO producing tumors, postrenal transplant erythrocytosis, and EPO doping).
See Table 10.1 for various causes and classification of erythrocytosis.
Table 10.1
Classification of erythrocytosis.
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Abbreviations: BPG , Bisphosphoglycerate; EPOR , primary familial congenital erythrocytosis; TEMPI , Telangiectasias, Erythrocytosis, Monoclonal gammopathy, Perinephric fluid, Intrapulmonary shunt; VHL , von Hippel–Lindau.
Primary erythrocytosis
Polycythemia vera
PV is an acquired primary erythrocytosis—a clonal disorder arising from a pluripotent hematopoietic stem cell manifesting by the excess production of erythrocytes with low EPO levels and variable overproduction of leukocytes and platelets. It is one of the Philadelphia chromosome-negative myeloproliferative neoplasms and can be differentiated from other myeloproliferative disorders by the predominance of erythrocyte production. This is a well-characterized disease in middle- to older age adults, but it is extremely rare in childhood and adolescence, and, thus, published literature on clinical presentation, treatment, and long-term prognosis in children is very limited. However, overall clinical course, disease biology, and management do not differ significantly from the adults and much of the information available is extrapolated from the adult literature.
Pathophysiology
The biology of PV is characterized by clonality and EPO independence. In PV a single clonal population of erythrocytes, granulocytes, and platelets arises when a hematopoietic stem cell that preferentially differentiates to myelopoiesis gains a proliferative advantage over other nonmutated stem cells.
Genome-wide scanning that compared clonal PV and nonclonal cells from the same individuals revealed a loss of heterozygosity in chromosome 9p, found in approximately 50% of patients with PV. This is not a classical chromosomal deletion, but, rather, duplication of a portion of the chromosome and loss of the corresponding parental region, a process referred to as uniparental disomy. The 9p region contains a gene encoding for JAK2 tyrosine kinase, which transmits an activating signal in the EPOR-signaling pathway. A point mutation involving valine-to-phenylalanine substitution at codon 617 in the pseudokinase JAK2 domain on exon 14, known as JAK2 V617F , leads to constitutive gain-of-function of the kinase, which at least partly explains EPO hypersensitivity/independence. Over 98% of adult patients with PV carry the JAK2 V617F mutation, as well as approximately 50% of adults with essential thrombocythemia and idiopathic myelofibrosis. However, in children, the frequency of the JAK2 V617F mutation is reported much lower, in the range of 25–40% by several studies, although the number of studied patients was small due to the rarity of the disease in the children. It is very likely that many of these children did not actually have PV and had some other, possibly inherited, polycythemic disorder.
In about 2% of JAK2 V617F -negative PV patients, other JAK2 mutations have been found in exon 12 and these mutations are heterogeneous, consisting of insertions, deletions, or stop codons. These patients may have marked erythrocytosis without affecting other cell lines. However, the risk of thrombosis and transformation to myelofibrosis are similar to JAK2 V617F -positive adult PV patients.
There is compelling evidence against JAK2 V617F and JAK2 exon 12 mutations being a disease-initiating mutation, but rather that these mutations play a major role in the behavior of the PV clone. Leukemic transformation from PV that is seen in adults, however, can sometimes arise from JAK2 V617F -negative PV progenitor cells.
Clinical features
PV in children is extremely rare. The incidence in adults is approximately 10–20 per 100,000, of which 1% present before the age of 25 and 0.1% present before the age of 20. Patients usually present with elevated hemoglobin and hematocrit found on routine testing. Some patients may initially present with isolated elevated platelet count, often diagnosed as essential thrombocythemia, but later develop erythrocytosis, thus, transforming to PV. Some patients are asymptomatic, while others may have various nonspecific symptoms recognized retrospectively to be consistent with PV. Overall, children tend to be less symptomatic than adults.
In adults, about one-third of patients present with thrombosis or hemorrhage. Thrombosis is about equally distributed between arterial and venous thrombosis. Less frequent, but more specific for PV, is Budd–Chiari syndrome (hepatic vein thrombosis). In younger adults, about 20–30% may present with Budd–Chiari syndrome or mesenteric thrombosis. The presence of leukocytosis at presentation has been shown to be an independent risk factor for thrombosis. A few studies have shown that the rate of thrombosis is much lower in children with PV, at about 5%, and the thrombosis invariably occurs in the setting of leukocytosis associated with infections. It has been suggested that children may have much better vascular integrity than adults, which may negate some prothrombotic factors associated with PV. Transformation to more advanced myelofibrosis and secondary acute leukemia has been reported to be extremely rare in the pediatric population.
Less than 5% of patients will have erythromelalgia, that is, erythema and warmth of the distal extremities, especially the hands and feet, with a painful burning sensation that can progress to digital ischemia. Erythromelalgia is associated with augmented platelet aggregation and frequently responds within hours to low- or regular-dose aspirin therapy. Less commonly, PV may present with elevated uric acid, with or without associated gout, due to increased cell turnover. Hemorrhagic presentations are usually mild, with gum bleeding and easy bruising, although serious gastrointestinal hemorrhage can occur, typically when the platelet count is >1 million which can be associated with acquired von Willebrand disease. About 40% of adult patients present with pruritus, which typically gets worse after a warm bath or shower, known as aquagenic pruritus. This has been attributed to increased numbers of mast cells and elevated histamine levels, and these patients may have plethora and ruddiness of the face.
Diagnosis
The WHO criteria which were updated in 2016, listed in Table 10.2 , are used for diagnosis. While the presence of EPO-independent erythroid colonies is specific for PV, this test is difficult and not widely available and is now removed from the criteria. The hemoglobin level for the criteria has been lowered to 16.5 g/dL for men (from 18.5 g/dL) and 16.0 g/dL for women (from 18 g/dL). This was done to increase the sensitivity to detect “masked” PV where many had PV but did not fulfill the older WHO criteria.
Table 10.2
Revised 2016 WHO criteria.
| Diagnosis requires the presence of all three major criteria or the presence of the first two major criteria together with one minor criterion a |
| Major criteria |
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Minor criteria
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a Bone marrow biopsy (criterion 2) may be not be required if there is sustained erythrocytosis, JAK2 mutation positive and subnormal serum erythropoietin level.
Treatment
Unlike for adult patients, there are no consensus on treatment guidelines for pediatric patients. Therefore the treatment approach in pediatric population is extrapolated from the guidelines for adults. Thromboembolism is the major cause of morbidity in PV and the goal of the treatment is primarily directed at reducing vascular events by restraining clonal proliferation with cytoreductive therapy. In adults, treatment is initiated for those with “high-risk” disease, that is, those who have a prior history of thrombosis, those who are >60 years old and with multiple cardiovascular risk. However, in children the rate of thrombosis is significantly lower than adults, and typically children do not have significant cardiovascular risks; therefore some experts have suggested adopting a conservative initial approach.
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Phlebotomy is performed by many to maintain hematocrits <45%. As more blood is removed and the patient becomes iron deficient, the hematocrit becomes easier to control and the phlebotomy schedule should be adjusted accordingly. However, in some patients, iron deficiency can become symptomatic and can cause neurocognitive impairment and decreased exercise tolerance. Although phlebotomy is effective for controlling erythrocytosis, it does not affect variable leukocytosis, thrombocytosis, risk of thromboembolic events, or overall natural course of the disease. In fact, there have been reports that the risk of thrombosis is slightly higher during the immediate postphlebotomy period.
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Low-dose aspirin is employed to reduce the risk of thromboembolic events and results in a minor, but statistically significant, decreased risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, and major venous thrombosis without a significant increase in rates of hemorrhage.
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Chemotherapeutic cytoreductive therapy : Cytoreductive therapy can be achieved either with hydroxyurea or interferon-alpha (IFN-α). Indications are:
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Prior history of thrombosis or transient ischemic attacks.
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A platelet count >1.5 million/mm 3 . Platelet counts at this level are a risk factor for bleeding.
The following cytoreductive therapy is used:
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Hydroxyurea . Initial dose of 20–30 mg/kg daily. This dose is adjusted depending on the hematological response or signs of toxicity. Hydroxyurea reduces the risk of thrombosis compared to phlebotomy or phlebotomy and aspirin. The safety and efficacy are unclear in pediatric patients. Leukemogenic risk of hydroxyurea has long been debated, but unlike alkylating agents and radioactive phosphorus that lead to an increase in fatal PV leukemic transformation, such an association with hydroxyurea has not been proven.
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IFN-α achieves a complete hematological response in a high percentage of cases, and some patients achieve durable reduction in their JAK2 V617F mutant allele. However, many patients do not tolerate IFN-α well because of a high rate of side effects and inconvenience of frequent intravenous administration. Newer pegylated formulations are much better tolerated, with less side effects and better efficacy, and some consider pegylated-IFNα as the first-line therapy in children, mainly due to its ability to achieve molecular response. However, safety and efficacy are unclear in patients younger than 18 years old.
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JAK2 inhibitor —ruxolitinib is FDA approved for PV if they are intolerant or resistant to first-line hydroxyurea. It is effective in controlling the hematocrit level and achieving spleen volume reduction if the patient has concomitant splenomegaly. It can also be very effective for symptoms of aquagenic pruritus. However, there are no conclusive evidence on the prevention of thromboses or slowing disease transformation to myelofibrosis or acute leukemia in adults.
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Anagrelide is useful to decrease platelet counts in patients presenting with thrombocytosis. The induction dose of anagrelide in children is 0.5 mg twice daily, followed by a maintenance dose of 0.5–1.0 mg twice a day, adjusted to the lowest effective dosage required to maintain platelet counts below 600,000/mm 3 and ideally to maintain it in the normal range.
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