1. Diagnosis. PV must be distinguished from relative or spurious polycythemia (normal red blood cell [RBC] mass, decreased plasma volume) and from secondary erythrocytosis (increased RBC mass due to hypoxia, carboxyhemoglobinemia, inappropriate erythropoietin syndromes with tumors or renal disease, etc.). PV is suspected in patients with hemoglobin levels greater than 18.5 g/dL in men or 16.5 g/dL in women or hemoglobin levels greater than 17 g/dL in men or 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from an individual’s baseline value. Diagnostic evaluation begins with peripheral JAK2 V617F mutation screen and measurement of serum erythropoietin
levels. This is because JAK2 is present in 97% of patients with PV and is not associated with other causes of increased hemoglobin/hematocrit levels; similarly, a subnormal serum erythropoietin level is expected and encountered in more than 90% of patients with PV but not in secondary or apparent polycythemia. However, neither the absence of JAK2 nor the presence of a normal erythropoietin level rules out the diagnosis of PV.

The presence of a JAK2 V617F in suspected PV is highly supportive of the diagnosis, regardless of the serum erythropoietin level. In the absence of a JAK2 V617F mutation, the serum erythropoietin level is useful to guide further evaluation. If the serum erythropoietin level is subnormal, a JAK2 exon 12 mutation screen should be performed. In the setting of a negative JAK2 mutation and a normal erythropoietin level, the diagnosis of PV is unlikely and evaluation should focus on secondary causes of erythrocytosis.

The diagnosis of PV requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria:

2. Aims of therapy. PV is generally an indolent disorder with the decision to treat based on risk stratification. Low-risk patients (i.e., those with no history of thrombosis, age less than 60 years, or platelets below 1 × 10⁶/μL) are usually treated with phlebotomy and/or aspirin (ASA). The goal of phlebotomy is to keep the hematocrit level below 45% in men and below 42% in women. Initially, phlebotomy is used to reduce hyperviscosity by decreasing the red cell mass, and subsequent phlebotomies help maintain the red cell mass in a normal range. For patients with highrisk features (i.e., history of thrombosis, or an age greater than 60 years), treatment consists of phlebotomy, ASA, and/or cytoreductive therapy with hydroxyurea. Control of hypertension and diabetes and avoidance of smoking are also important.

4. Evolution and outcome. The median survival in patients with PV exceeds 15 years and the 10-year risk of developing either myelofibrosis (MF; < 4% and 10%, respectively) or acute myeloid leukemia (AML; < 2% and 6%, respectively) is relatively low. To date, drug therapy has not been shown to favorably affect these figures. Therefore, at present, drugs should not be used with the intent to either prolong survival or prevent disease transformation into AML or MF.

1. Diagnosis. Diagnosis of ET requires a persistent elevation of the platelet count above 450 × 10³/μL plus the absence of known causes of reactive or secondary thrombocytosis (e.g., iron deficiency, malignancy, chronic inflammatory disease). After excluding obvious causes of reactive thrombocytosis (iron deficiency, trauma, infection, etc.), peripheral blood testing for the JAK2 V617F mutation is helpful. The presence of JAK2 V617F confirms
clonal thrombocytosis but careful review of the peripheral blood smear and bone marrow histology with cytogenetics must also be performed to confirm the diagnosis of ET. Chronic myeloid leukemia (CML) can often present with thrombocytosis, therefore the presence of BCR-ABL must be excluded. As stated previously, the absence of JAK2 does not rule out the possibility of ET given that a large proportion of patients do not carry the mutation. Only 4% of patients with ET without a JAK2 V617F mutation will have a mutation in the MPL gene; however, if present, it does suggest clonal thrombocytosis. Moderate leukocytosis is common. Palpable splenomegaly is present in less than 50% of patients. Platelet function studies may show either spontaneous aggregation or impaired response to agonists. Microvascular occlusion may cause digital gangrene, transient ischemic attacks, visual complaints, and paresthesias. Large-artery thrombotic episodes are also common. Deep venous thrombosis is uncommon. The risk of hemorrhagic problems is significant, particularly with a platelet count greater than 1500 × 10³/μL. The diagnosis of ET requires meeting four criteria, as follows:

2. Treatment regimens. Given its typically indolent course, the primary goal of treatment in patients with ET is the prevention of complications from thrombocytosis, such as microvascular disturbances or hemorrhagic events caused by acquired von Willebrand disease. ASA therapy is often used to reduce microvascular symptoms for patients with all risk categories. Hydroxyurea, to reduce platelet counts, in combination with low-dose ASA, has been shown to decrease the risk of arterial thrombosis in patients with high-risk ET, such as those older than 60 years with platelets greater than 1000 × 10³/μL or a history of hypertension, diabetes requiring treatment, or ischemia, thrombosis, embolism, or hemorrhage related to ET. For patients with ET whose platelet counts are refractory to therapy with ASA or other salicylates, therapy with interferon-α (including in pegylated preparations), anagrelide, or hydroxyurea can be used. Anagrelide was developed to prevent platelet aggregation
but was subsequently found to reduce platelet counts in ET and PMF when used at low dose.

3. Evolution and outcome. The course of ET is often indolent, particularly in young patients. The median survival exceeds 15 years, and some patients appear to have normal life expectancy. Transformation to PMF, MDS, or acute leukemia occurs in 5% to 10%. Thrombosis is the major cause of ET-related death.

1. Diagnosis. This is a clonal disorder of the hematopoietic stem cell, marked by an intense reactive (nonclonal) fibrosis of the marrow; splenomegaly (frequently massive), reflecting ectopic hematopoiesis in the spleen and portal hypertension; and the presence of immature granulocytes and nucleated RBCs in the peripheral blood (leukoerythroblastic blood picture) plus teardrop RBCs and giant platelets. Mild to moderate elevations of WBC and platelet counts are common initially; cytopenias dominate later on.

JAK2 V617F mutation is present in approximately 50% of patients with PMF. An abnormal karyotype is also demonstrable in approximately 50% and connotes shortened survival
time. Other adverse prognostic factors include advanced age, anemia, WBC count of less than 4000/μL or greater than 30,000/μL, thrombocytopenia, blasts in peripheral blood, and hypercatabolic symptoms (weight loss, night sweats, fever). Diseases causing secondary marrow fibrosis, such as metastatic carcinoma, hairy-cell leukemia, and granulomatous infections, must be excluded. Similar to ET, the presence of a JAK2 V617F or an MPL mutation can be helpful to rule out reactive marrow fibrosis. However, the absence of both of these molecular markers does not exclude the presence of an MPN. Therefore, causes of reactive marrow fibrosis must be excluded in cases where no clonal marker is found. Again, bone marrow histology in combination with other clinical and laboratory features helps to establish the diagnosis of PMF. BCR-ABL should be performed to rule out the presence of CML and criteria for another myeloid neoplasm should not be met. The minor criteria, which help to establish a diagnosis of PMF, include leukoerythroblastosis, increased serum lactate dehydrogenase, anemia, and palpable splenomegaly. Major causes of death in PMF include marrow failure, infection, portal hypertension, and leukemic transformation. Cases of MDS with marrow fibrosis are easily confused with PMF. Postpolycythemic myelofibrosis is clinically indistinguishable but carries a poor prognosis, evolving to acute leukemia in 25% to 50% of patients (compared to 5% to 20% for de novo PMF). Acute megakaryoblastic leukemia (M7) may also present with a myelofibrotic picture and be confused with PMF.

The diagnosis of PMF requires meeting all three major criteria and two minor criteria:

2. Treatment regimens. PMF has a much more aggressive course than ET and PV, and treatments include androgen preparations (e.g., fluoxymesterone or danazol), corticosteroids, erythropoietin, and lenalidomide. Splenectomy should be considered for patients with portal hypertension, to improve anemia (due to sequestration) or for symptomatic relief of abdominal pain or problems with alimentation. Radiation therapy may be beneficial for palliative relief; however, a significant increase in the risk of neutropenia and infection is seen.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only curable treatment option for patients with PMF. This option should be considered in young patients with intermediate-/high-risk PMF. For patients older than 60 years of age, a reasonable option would be a reduced-intensity conditioning regimen. Studies assessing the efficacy of JAK kinase inhibitors are ongoing and, in the setting of clinical benefit, may eventually change the course of the disease. Intervention is indicated in the following situations.