Polycythemia vera (PV) is a clonal disorder of a multipotent hematopoietic stem cell in which overproduction of morphologically normal red cells, white cells, and platelets occurs in the absence of an apparent cause. The commonest of the chronic myeloproliferative disorders, PV, is uncommon, occurring at an average frequency of 2/100,000, but with increasing age, rates as high as 18/100,000 have been observed. Females predominate, particularly below age 40 years.
The etiology of PV is unknown. Abnormalities of chromosomes 1, 8, 9, 13, and 20 have been identified in up to 30% of PV patients, but they are neither specific for the disorder nor necessary for its pathogenesis; in many instances they appear to occur as secondary events and their expression can be enhanced by exposure to chemotherapeutic agents (1). Erythropoietin-independent in vitro erythroid colony formation is a characteristic feature of PV, although not specific for it, since this behavior has also been observed in primary myelofibrosis (PMF) and essential thrombocytosis. Constitutive activation of JAK2 (2), which is the cognate tyrosine kinase for type 1 hematopoietic growth factor receptors such as the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors, has been identified to be the molecular basis for such growth factor independence in PV and its companion myeloproliferative disorders PMF and essential thrombocytosis.
The mechanism for constitutive JAK2 activation in the chronic myeloproliferative disorders is an acquired point mutation in the autoinhibitory JH2 domain of the JAK2 gene, replacing valine with phenylalanine (V617F). JAK2 is located on the short arm of chromosome 9 and loss of heterozygosity for 9p is a common cytogenetic lesion in PV, leading to homozygosity for the JAK2 V617F mutation; in some patients, there is also reduplication of chromosome 9. In PV, approximately 90% of patients express the JAK2 V617F mutation, of which approximately 35% are homozygous for it. Approximately 5% have a JAK2 exon 12 activating mutation. No clinical differences have been identified between heterozygotes and those homozygous for JAK2 V617F, nor are there any clinical differences between PV patients expressing JAK2 V617F and those who do not. Thus, although the JAK2 V617F mutation provides an explanation for the hematopoietic growth factor independence of PV hematopoietic cells in vitro, their apoptosis resistance and their uncontrolled growth in vivo, the absence of the mutation in some patients with classical PV, and its expression in PMF and essential thrombocytosis patients strongly suggest that other as yet unidentified molecular lesions are involved in the pathogenesis of these disorders.
PV is extremely variable in its presenting manifestations as well as its clinical features, which also change over the course of the disorder. Because its onset can be insidious, an abnormal blood count is often the first sign of the disease. In approximately 40% of patients, there will be ...