Polycythemia vera (PV) is a clonal disorder involving a multipotent hematopoietic progenitor cell in which phenotypically normal red cells, granulocytes, and platelets accumulate in the absence of a recognizable physiologic stimulus. The most common of the chronic myeloproliferative disorders, PV occurs in 2 per 100,000 persons, sparing no adult age group and increasing with age to rates as high as 18/100,000. Familial transmission occurs but is infrequent. A slight overall male predominance has been observed, but women predominate within the reproductive age range.
The etiology of PV is unknown. Although nonrandom chromosome abnormalities such as 20q, trisomy 8, and especially 9p, have been documented in up to 30% of untreated PV patients, unlike CML no consistent cytogenetic abnormality has been associated with the disorder. However, a mutation in the autoinhibitory, pseudokinase domain of the tyrosine kinase JAK2-which replaces valine with phenylalanine (V617F), causing constitutive activation of the kinase-appears to have a central role in the pathogenesis of PV.
JAK2 is a member of an evolutionarily well-conserved, nonreceptor tyrosine kinase family and serves as the cognate tyrosine kinase for the erythropoietin and thrombopoietin receptors. It also functions as an obligate chaperone for these receptors in the Golgi apparatus and is responsible for their cell-surface expression. The conformational change induced in the erythropoietin and thrombopoietin receptors following binding to erythropoietin or thrombopoietin leads to JAK2 autophosphorylation, receptor phosphorylation, and phosphorylation of proteins involved in cell proliferation, differentiation, and resistance to apoptosis. Transgenic animals lacking JAK2 die as embryos from severe anemia. Constitutive activation of JAK2 can explain the erythropoietin-independent erythroid colony formation, and the hypersensitivity of PV erythroid progenitor cells to erythropoietin and other hematopoietic growth factors, their resistance to apoptosis in vitro in the absence of erythropoietin, their rapid terminal differentiation, and their increase in Bcl-XL expression, all of which are characteristic in PV.
Importantly, the JAK2 gene is located on the short arm of chromosome 9, and loss of heterozygosity on chromosome 9p, due to uniparental disomy is the most common cytogenetic abnormality in PV. The segment of 9p involved contains the JAK2 locus; loss of heterozygosity in this region leads to homozygosity for the mutant JAK2 V617F. Over 90% of PV patients express this mutation, as do approximately 45% of IMF and ET patients. Homozygosity for the mutation occurs in approximately 30% of PV patients and 60% of IMF patients; homozygosity is rare in ET. Over time, a portion of PV JAK2 V617F heterozygotes become homozygotes, but usually not after 10 years of the disease. PV patients who do not express JAK2 V617F are not clinically different than those who do, nor do JAK2 V617F heterozygotes differ clinically from homozygotes. In general, patients who express JAK2 V617F are older than those who do not, but they do not have a longer duration of disease. JAK2 V617F is the basis for many of the phenotypic and biochemical characteristics of PV, such as elevation of the leukocyte alkaline phosphatase (LAP) score and increased expression of the mRNA of PVR-1, a glycosylphosphatidylinositol (GPI)-linked membrane protein; however, it cannot solely account for the entire PV phenotype. First, PV patients with the same phenotype and documented clonal disease lack this mutation. Second, IMF patients have the same mutation but a different clinical phenotype. Third, familial PV can occur without the mutation, even when other members of the same family express it. Fourth, not all the cells of the malignant clone express JAK2 V617F. Fifth, JAK2 V617F has been observed in patients with long-standing idiopathic erythrocytosis. However, while JAK2 V617F alone may not be sufficient to cause PV, it is essential for the transformation of ET to PV, though not for its transformation to IMF.
Although splenomegaly may be the initial presenting sign in PV, most often the disorder is first recognized by the incidental discovery of a high hemoglobin or hematocrit. With the exception of aquagenic pruritus, no symptoms distinguish PV from other causes of erythrocytosis. Uncontrolled erythrocytosis causes hyperviscosity, leading to neurologic symptoms such as vertigo, tinnitus, headache, visual disturbances, and transient ischemic attacks (TIAs). Systolic hypertension is also a feature of the red cell mass elevation. In some patients, venous or arterial thrombosis may be the presenting manifestation of PV. Any vessel can be affected, but cerebral, cardiac, or mesenteric vessels are most commonly involved. Intraabdominal venous thrombosis is particularly common in young women and may be catastrophic if a sudden and complete obstruction of the hepatic vein occurs. Indeed, PV should be suspected in any patient who develops hepatic vein thrombosis. Digital ischemia, easy bruising, epistaxis, acid-peptic disease, or gastrointestinal hemorrhage may occur due to vascular stasis or thrombocytosis. Erythema, burning, and pain in the extremities, a symptom complex known as erythromelalgia, is another complication of the thrombocytosis of PV. Given the large turnover of hematopoietic cells, hyperuricemia with secondary gout, uric acid stones, and symptoms due to hypermetabolism can also complicate the disorder.
The plasma erythropoietin level is a useful diagnostic test in patients with isolated erythrocytosis, because an elevated level excludes PV as the cause for the erythrocytosis.
When PV presents with erythrocytosis in combination with leukocytosis, thrombocytosis, or both, the diagnosis is apparent. However, when patients present with an elevated hemoglobin or hematocrit alone, or with thrombocytosis alone, the diagnostic evaluation is more complex because of the many diagnostic possibilities (Table 103-2). Furthermore, unless the hemoglobin level is ≥20 gm% (hematocrit ≥60%), it is not possible to distinguish PV from disorders causing plasma volume contraction. Uniquely in PV, an expanded plasma volume can mask an elevated red cell mass; thus, red cell mass and plasma volume determinations are mandatory to establish the presence of an absolute erythrocytosis and to distinguish this from relative erythrocytosis due to a reduction in plasma volume alone (also known as stress or spurious erythrocytosis orGaisb�ck's syndrome). This is true even in with the discovery of the JAK2 V617F mutation, because not very patient with PV expresses this mutation, while patients without PV do. Figure 58-18 illustrates a diagnostic algorithm for the evaluation of suspected erythrocytosis.
Once absolute erythrocytosis has been established, its cause must be determined. An elevated plasma erythropoietin level suggests either a hypoxic cause for erythrocytosis or autonomous erythropoietin production, in which case assessment of pulmonary function and an abdominal CT scan to evaluate renal and hepatic anatomy are appropriate. A normal erythropoietin level does not exclude a hypoxic cause for erythrocytosis. In PV, in contrast to hypoxic erythrocytosis, the arterial oxygen saturation is normal. However, a normal oxygen saturation does not exclude a high-affinity hemoglobin as a cause for erythrocytosis; documentation of previous hemoglobin levels and a family study are important.
Other laboratory studies that may aid in diagnosis include the red cell count, mean corpuscular volume, and red cell distribution width (RDW). Only three situations cause microcytic erythrocytosis: β-thalassemia trait, hypoxic erythrocytosis, and PV. With β-thalassemia trait the RDW is normal, whereas with hypoxic erythrocytosis and PV, the RDW is usually elevated due to iron deficiency. In many patients, the LAP level is also increased, as is the uric acid level. Elevated serum vitamin B12 or B12-binding capacity may be present. In patients with associated acid-peptic disease, occult gastrointestinal bleeding may lead to presentation with hypochromic, microcytic anemia.
A bone marrow aspirate and biopsy provide no specific diagnostic information since these may be normal or indistinguishable from ET or IMF, and unless there is a need to establish the presence of myelofibrosis or exclude some other disorder, these procedures need not be done. Although the presence of a cytogenetic abnormality such as trisomy 8 or 9 or 20q� in the setting of an expanded red cell mass supports a clonal etiology, no specific cytogenetic abnormality is associated with PV, and the absence of a cytogenetic marker does not exclude the diagnosis.
The major clinical complications of PV relate directly to the increase in blood viscosity associated with red cell mass elevation and indirectly to the increased turnover of red cells, leukocytes, and platelets with the attendant increase in uric acid and cytokine production. The latter appears to be responsible for the increase in peptic ulcer disease and for the pruritus associated with this disorder, although formal proof for this has not been obtained. A sudden massive increase in spleen size can be associated with splenic infarction or progressive cachexia. Myelofibrosis appears to be part of the natural history of the disease but is a reactive, reversible process that does not itself impede hematopoiesis and by itself has no prognostic significance. In some patients, however, the myelofibrosis is accompanied by significant extramedullary hematopoiesis, hepatosplenomegaly, and transfusion-dependent anemia. The organomegaly can cause significant mechanical discomfort, portal hypertension, and cachexia. Although the incidence of acute nonlymphocytic leukemia is increased in PV, the incidence of acute leukemia in patients not exposed to chemotherapy or radiation is low, and the development of leukemia is related to older age but not disease duration, suggesting that the treatment exposure may be a more important risk factor than the disease itself.
Erythromelalgia is a curious syndrome of unknown etiology associated with thrombocytosis, primarily involving the lower extremities and manifested usually by erythema, warmth, and pain of the affected appendage and occasionally digital infarction. It occurs with a variable frequency in myeloproliferative disorder patients and is usually responsive to salicylates. Some of the central nervous system symptoms observed in patients with PV, such as ocular migraine, may represent a variant of erythromelalgia.
If left uncontrolled, erythrocytosis can lead to thrombosis involving vital organs such as the liver, heart, brain, or lungs. Patients with massive splenomegaly are particularly prone to thrombotic events because the associated increase in plasma volume masks the true extent of the red cell mass elevation as measured by the hematocrit or hemoglobin level. A "normal" hematocrit or hemoglobin level in a PV patient with massive splenomegaly should be considered indicative of an elevated red cell mass until proven otherwise.
Polycythemia Vera: Treatment
PV is generally an indolent disorder whose clinical course is measured in decades, and its medical management should reflect its tempo. Thrombosis due to erythrocytosis is the most significant complication, and maintenance of the hemoglobin level at ≤140 g/L (14 g/dL; hematocrit <45%) in men and ≤120 g/L (12 g/dL; hematocrit <42%) in women is mandatory to avoid thrombotic complications. Phlebotomy serves initially to reduce hyperviscosity by bringing the red cell mass into the normal range. Periodic phlebotomies thereafter serve to maintain the red cell mass within the normal range and to induce a state of iron deficiency, which prevents an accelerated reexpansion of the red cell mass. In most PV patients, once an iron-deficient state is achieved, phlebotomy is usually only required at 3-month intervals. Neither phlebotomy nor iron deficiency increases the platelet count relative to the effect of the disease itself, and thrombocytosis is not correlated with thrombosis in PV, in contrast to the strong correlation between erythrocytosis and thrombosis in this disease. The use of salicylates as a tonic against thrombosis in PV patients is potentially harmful if the red cell mass is not controlled by phlebotomy. Anticoagulants are only indicated when a thrombosis has occurred and can be difficult to monitor owing to the artifactual imbalance between the test tube anticoagulant and plasma that occurs when blood from these patients is assayed for prothrombin or partial thromboplastin activity. Asymptomatic hyperuricemia (<10 mg%) requires no therapy, but allopurinol should be administered to avoid further elevation of the uric acid when chemotherapy is employed to reduce splenomegaly or leukocytosis or to treat pruritus. Generalized pruritus intractable to antihistamines or antidepressants such as doxepin can be a major problem in PV;hydroxyurea, interferon α (IFN-α),and psoralens with ultraviolet light in the A range (PUVA) therapy are other methods of palliation. Asymptomatic thrombocytosis requires no therapy unless the platelet count is sufficiently high to cause an acquired form of von Willebrand's disease due to proteolysis of high-molecular-weight vWF multimers. Symptomatic splenomegaly can be treated with IFN-α. Although the drug can be associated with significant side effects when used chronically, IFN-α reduces JAK2 V617F expression in PV patients, and its role in this disorder may be expanding. Anagrelide, a phosphodiesterase inhibitor, can reduce the platelet count and, if tolerated, is preferable to hydroxyurea because it lacks marrow toxicity. A reduction in platelet number may be necessary in the treatment of erythromelalgia or ocular migraine if salicylates are not effective or the platelet count is sufficiently high to cause an hemorrhagic diathesis. Alkylating agents and radioactive sodium phosphate (32P) are leukemogenic in PV, and their use should be avoided. If a cytotoxic agent must be used, hydroxyurea is preferred, but this drug does not prevent either thrombosis or myelofibrosis in this disorder. Chemotherapy should be used for as short a time as possible. In some patients, massive splenomegaly unresponsive to reduction by hydroxyurea or IFN-α therapy and associated with intractable weight loss will require splenectomy. In some patients with end-stage disease, pulmonary hypertension may develop due to fibrosis and extramedullary hematopoiesis. Allogeneic bone marrow transplantation may be curative in young patients.
Most patients with PV can live long lives without functional impairment when their red cell mass is effectively managed with phlebotomy. Chemotherapy is never indicated to control the red cell mass unless venous access is inadequate.
Categories: Hematologic Disorders