Chapter 42: Polycythemia Vera

INTRODUCTION

• Polycythemia vera (PV) is a clonal disorder arising from somatic mutations of a hematopoietic stem, or closely related multipotential cell, in which blood cell production, notably in the erythroid lineage, but also in the granulocytic, monocytic, and platelet lineages, is increased and is independent of cytokine regulation. This results in exaggerated proliferation and accumulation of erythrocytic, and often granulocytic and megakaryocytic, precursors in the marrow and their mature cells in the blood. PV is one of the myeloproliferative neoplasms (MPNs), along with essential thrombocythemia (ET), primary myelofibrosis (MF), and chronic myelogenous leukemia (CML).

• Three MPNs (PV, ET [Chap. 43], and MF [Chap. 48]) may share a common molecular abnormality/marker, the JAK2 kinase V617F mutation. In contrast, CML is caused by a different molecular alteration, the BCR/ABL oncogene, due to a reciprocal translocation between chromosome 9 and chromosome 22, t(9;22)(q34;q11), and the production of the BCR-ABL protein product (Chap. 47).

ETIOLOGY AND PATHOGENESIS

• PV arises from a neoplastic transformation of a single hematopoietic stem or multipotential cell, which then produces a clone that suppresses normal polyclonal stem cells.

• The JAK2 kinase V617F mutation directly activates the erythropoietin (EPO) receptor signaling but also thrombopoietin (TPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors. However, since the only one of these receptors present on the cell of origin of PV is the TPO receptor, that molecule appears to be critical for the pathogenesis of the MPNs.

• In vitro erythroid colonies develop in the absence of added EPO, and this EPO independence is characteristic of primitive erythroid cell PV.

• Karyotypic abnormalities are not specific; they develop later in the disease and may portend transformation into myelofibrosis, a hyperproliferative phase of PV or acute leukemia.

• Familial incidence of PV and/or other MPNs is found in about 5% to 7% of patients.

• Incidence ranges from 1 to 2.5 per 100,000 as reported in different countries.

CLINICAL FEATURES

• PV usually has an insidious onset, most commonly during the sixth decade of life, although it may occur at any age, including childhood.

• Presenting symptoms and signs may include headache, plethora, aquagenic pruritus (itching after hot bath or shower), thrombosis, erythromelalgia, and gout. Many patients are diagnosed because of elevated hemoglobin and/or platelets on routine medical examination. Other cases may be uncovered during investigation for idiopathic thrombosis, aquagenic pruritus, erythromelalgia, or iron deficiency. Symptoms are reported by at least 30% of patients at the time of diagnosis.

• Neurologic complaints include vertigo, diplopia, scotomata, migraines, and transient ischemic events.

• Associated disorders include peptic ulcer disease and gout.

• Thrombotic events are the principal cause of PV morbidity and mortality. They may occur prior to diagnosis of the disease in about one-third of patients and may be fatal. These events include ischemic stroke, myocardial infarction, venous thromboembolism, splanchnic vein thrombosis (Budd-Chiari syndrome, mesenteric and/or portal vein thrombosis), and cerebral sinus venous thrombosis.

• Bleeding ...