Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 2) doc

Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 2) Etiology 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-X L 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. Clinical Features 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. . Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 2) Etiology The etiology of PV is unknown. Although nonrandom chromosome abnormalities. 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. erythropoietin- independent erythroid colony formation, and the hypersensitivity of PV erythroid progenitor cells to erythropoietin and other hematopoietic growth factors, their resistance to