Definition and Etiology

PV is a clonal disorder characterized by the overproduction of mature red blood cells in the bone marrow.¹ Myeloid and megakaryocytic elements are also often increased. No obvious cause exists.⁴ Genetic and environmental factors have been implicated in rare cases. Familial PV has been associated with mutation of the erythropoietin receptor.⁵ An increased number of cases has been reported in survivors of the atomic bomb explosion in Hiroshima during World War II.

Epidemiology

The disorder typically occurs in the sixth or seventh decade of life. The prevalence of the disease is approximately 5 per million population; it occurs more commonly in men and in men and women of East European Jewish ancestry.^1,4

Pathophysiology

The primary defect involves a pluripotent stem cell capable of differentiating into red blood cells, granulocytes, and platelets.⁴ Clonality has been demonstrated through glucose-6-phosphate dehydrogenase (G6PD) studies as well as restriction fragment length polymorphism of the active X chromosome.⁵ Erythroid precursors in PV are exquisitely sensitive to erythropoietin, which leads to increased red blood cell production. Precursors in PV are also more responsive to cytokines such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and steel factor. Myeloid and megakaryocytic elements are often increased in the bone marrow (Fig. 1). More than 60% of patients have endogenous megakaryocyte colony unit formation.

Figure 1 Bone marrow biopsy.

The bone marrow in polycythemia vera is hypercellular as a result of an increase in myeloid, erythroid, and megakaryocytic elements. (Hematoxylin-eosin stain, ×40.)

Increased red blood cell production in PV leads to an increased red cell mass and increased blood viscosity. This in turn can lead to arterial or venous thrombosis, bleeding, or both.¹ The hematocrit is directly proportional to the number of thrombotic events.⁴ Investigators have demonstrated a reduction in cerebral blood flow in patients with hematocrits between 53% and 62%.⁵ An increased platelet count can also contribute to bleeding and thrombosis. Although platelet aggregation abnormalities exist in most patients, these abnormalities do not appear to correlate with the risk of bleeding or thrombosis. Increased production and breakdown of blood cells can lead to hyperuricemia and hypermetabolism.

Signs and Symptoms

Patients may be asymptomatic at the time of diagnosis and have only isolated splenomegaly, erythrocytosis, or thrombocytosis.⁵ However, most patients develop symptoms as the hematocrit, platelet count, or both increase. An elevated white blood cell (WBC) count is found in 50% to 60% of patients. Symptoms of hyperviscosity associated with an elevated hematocrit include headache, blurred vision, and plethora.¹

Thrombosis in small blood vessels can lead to cyanosis, erythromelalgia (painful vessel dilation in the extremities), ulceration, or gangrene in the fingers or toes. Thrombosis in larger vessels can lead to myocardial infarction, deep venous thrombosis, transient ischemic attacks, and stroke. A cerebrovascular event precedes the diagnosis in 35% of patients with PV.⁴ Unusual sites of thromboses also tend to be seen more frequently in PV—splenic, hepatic, portal, and mesenteric.

Of patients with Budd-Chiari syndrome (hepatic–inferior vena cava obstruction), 10% have coexisting PV. Abnormalities in platelet function lead to epistaxis, bruising, and gastrointestinal and gingival bleeding in 2% to 10% of patients. Severe bleeding episodes are unusual. Hypermetabolism caused by increased blood cell turnover can lead to hyperuricemia, gout, stomach ulcers, weight loss, and kidney stones. Pruritis is especially common after a warm bath or shower. As the disease progresses, many patients develop abdominal pain secondary to hepatomegaly, splenomegaly, or both.

Diagnosis

PV should be suspected in men with a hematocrit higher than 50% and in women with a hematocrit higher than 45%.⁵ Confirmation of an elevated hematocrit involves measuring a red blood cell mass¹ using direct tagging of red blood cells with chromium 51, a test unfortunately not widely available. These studies might not be needed in men with hematocrits higher than 60% or in women with hematocrits higher than 55%.

Secondary causes of polycythemia also need to be ruled out: hypoxia caused by heart or lung disease or smoking and cysts or tumors in the liver, kidneys, or brain, all of which can secrete erythropoietin. Serum erythropoietin levels should be low to normal in patients with PV but high in patients with secondary polycythemia, although there may be some overlap. Molecular testing for the JAK2 V617 or other functionally similar mutation plays a central role in the diagnosis of PV as a way of separating neoplastic from reactive myeloid proliferations.

The initial diagnostic criteria defined by the PVSG (Polycythemia Vera Study Group) have undergone changes over the last several years. The current diagnostic criteria have been published by WHO.⁶ A diagnosis of PV is met if a patient has the first two A criteria together with any other A criterion or two B criteria. New proposed revised WHO criteria for polycythemia vera include major and minor criteria, and diagnosis will require the presence of both major criteria and 1 minor criterion or the presence of the first major criterion together with 2 minor criteria.³

Treatment

Treatment of PV focuses on decreasing the hemoglobin level, thereby reducing plasma viscosity and its attendant complications. Therapeutic options include phlebotomy, radioactive phosphorus (³²P), and myelosuppressive agents. The goal of therapy is a hematocrit of 45% on the basis of cerebral blood flow studies.⁴ Several clinical trials have tried to address the optimal treatment of PV.

Treatment for PV should be risk-adapted.⁶ Patients at high risk for thrombosis include patients older than 60 years and those with a prior history of thrombosis. Low-risk patients include those who are younger than 60 years with no history of thrombosis, a platelet count below 1500 × 10⁹/L, and the absence of cardiovascular risk factors (e.g., smoking, hypertension, congestive heart failure). In the PSVG-01 study, thrombotic events were increased in the phlebotomy arm, particularly in patients with a history of thrombosis, advanced age, or high phlebotomy requirement.⁴ Therefore, high-risk patients should be treated with phlebotomy plus hydroxyurea or interferon. Hydroxyurea is typically used as first-line therapy. However, interferon should be used in women of childbearing age and in patients who cannot tolerate hydroxyurea. Low-risk or intermediate-risk patients may be treated with phlebotomy alone.

In the PVSG-01 study, there was an increased risk of leukemia in the ³²P and chlorambucil arms (two or three times that seen in the phlebotomy arm).⁴ Because of the increased leukemogenicity associated with chlorambucil, hydroxyurea, which inhibits ribonucleotide reductase, is now the most widely used myelosuppressive agent. Side effects of hydroxyurea include myelosuppression, macrocytosis, leg ulcers, increased creatinine level, and jaundice.⁵ A recent large study has demonstrated no increased incidence of leukemia in PV patients treated with hydroxyurea.⁶ For older high-risk patients, ³²P can be used to help with issues of compliance and convenience, especially if the patient’s life expectancy is less than 10 years.

Myelosuppressive agents should also be used for symptomatic splenomegaly, pruritis intractable to antihistamines, or patients with poor venous access.⁴ Interferon-alfa may also be used in the place of hydroxyurea for myelosuppression, particularly in younger patients and n patients with intractable pruritus. Side effects of interferon include flulike syndromes, fevers, neuritis, and fatigue.⁵ Patients with PV who are undergoing surgery are at extremely high risk of developing postoperative complications if their erythrocytosis is not controlled before surgery.

Patients with PV and no drug contraindications or evidence of acquired von Willebrand syndrome should be treated with low-dose aspirin.⁶ One study has demonstrated an antithrombotic benefit for low-dose aspirin (100 mg/day) in patients already receiving treatment for PV.⁶ Patients with erythromelalgia also experience a rapid relief of their symptoms after low-dose aspirin.⁴

Outcomes

The median survival is more than 10 years with treatment. The major causes of death in untreated patients are thrombosis and hemorrhage.¹ Less than 10% of patients develop acute myelogenous leukemia.¹ Fifteen percent of patients develop postpolycythemic myelofibrosis (MF) at an average interval of 10 years from diagnosis.⁴ Once they develop MF, most patients die within 3 years.⁴ MF often transforms to acute myelogenous leukemia.

Definition and Causes

Other common names for CIMF include agnogenic myeloid metaplasia and primary myelofibrosis.^1,7 In CIMF, a clonal hematopoietic stem cell expansion in the bone marrow is accompanied by a reactive nonclonal fibroblastic proliferation and marrow fibrosis. As the bone marrow becomes fibrotic and normal hematopoiesis can no longer occur, extramedullary hematopoiesis (myeloid metaplasia) occurs in the liver and spleen.⁸ The cause is unknown.

Epidemiology

The prevalence of CIMF is 2 per 1,000,000 population.¹ The risk of developing CIMF is increased by exposure to benzene or radiation. It typically occurs in whites, and the median age at diagnosis is 67 years.⁵ Men and women are affected equally. As noted earlier, patients with PV and other myeloproliferative disorders can develop secondary MF late in the course of their disease.⁴

Pathophysiology

Clonal studies have demonstrated a stem cell origin.⁸ The clonal proliferation of hematopoietic stem cells is believed to produce growth factors (platelet-derived growth factor, transforming growth factor-β, epidermal growth factor, and basic fibroblastic growth factor) that lead to fibrosis of the bone marrow.^1,5 Initially, the bone marrow is hypercellular, but normal hematopoiesis is diminished as the bone marrow becomes fibrotic and patients become pancytopenic (Fig. 2).¹ Because of this, the extramedullary hematopoiesis occurring in the liver and spleen causes these organs to enlarge.

Figure 2 Bone marrow biopsy.

The fibrotic stage of chronic idiopathic myelofibrosis is marked by extensive replacement of the normal marrow stroma by fibrous tissue. In this example from an advanced case, several atypical megakaryocytes with hyperchromatic and hyposegmented nuclei are shown, surrounded by pink fibrous tissue. (Hematoxylin-eosin stain, ×40.)

Signs and Symptoms

Many symptoms are attributable to the pancytopenia associated with myelofibrosis. Pancytopenia occurs as a result of decreased hematopoiesis and splenic sequestration. Most patients are anemic and feel short of breath and fatigued. Thrombocytopenia and neutropenia can lead to hemorrhage and infection, respectively.

Other constitutional symptoms include anorexia, weight loss, and night sweats.¹ The WBC and platelet counts might increase initially but typically decrease as the disease progresses. The blood film displays a characteristic leukoerythroblastic picture (teardrop poikilocytosis, nucleated red blood cells, and immature myeloid elements) caused by crowding out of normal hematopoietic elements by fibrosis in the bone marrow (Fig. 3).⁵

Figure 3 Peripheral blood abnormalities in the fibrotic stage of chronic idiopathic myelofibrosis.

These can include teardrop-shaped erythrocytes (A, B), circulating nucleated erythroid precursors (C), occasional blasts (D), and abnormal giant platelets (E, F). (Wright-Giemsa stain, ×100.)

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