Polycythemia Vera (PV)

DEFINITION, ETIOLOGY, PATHOGENESIS Top

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by marked increase in red blood cell (RBC) counts, frequently accompanied by increased production of white blood cells (WBCs) and platelets. The disease is caused by a malignant proliferation of a mutant clone derived from a multipotential hematopoietic stem cell of the bone marrow. The incidence is 2 to 3/100,000 population per year.

CLINICAL FEATURES AND NATURAL HISTORY Top

Signs and symptoms depend on the number of blood cells, degree of increase in the circulating blood volume, and presence of thrombotic and hemorrhagic complications. In many patients PV is an incidental diagnosis made as a result of a routine complete blood count (CBC).

1. Symptoms include manifestations of hyperviscosity (headache, vertigo, tinnitus, visual disturbances), erythromelalgia, aquagenic pruritus (pruritus worsening after water exposure; present in ~40% of patients), arterial or venous thrombosis (stroke, myocardial infarction, superficial or deep vein thrombosis, pulmonary embolism; the overall risk is ~20% over a 10-year period), hypertension, or gout. Nonspecific symptoms also occur including weakness, weight loss, abdominal distention, or pain due to splenomegaly. Bleeding may occur, due to acquired von Willebrand disease (particularly when the platelet count is >1500×109/L), acquired platelet function defect, or by coincident drug use, such as antiplatelet agents.

2. Signs: Splenomegaly; plethora of the face, hands, feet, and ears; lip cyanosis; hepatomegaly; hyperemia and erythema of oral mucosa and conjunctivae; venous stasis seen on fundoscopy.

3. Natural history: The disease may remain asymptomatic for many years. Symptoms are associated with increasing RBC counts and circulating blood volumes, thrombocytosis, and extramedullary hematopoiesis leading to hepatosplenomegaly. Progression to myelofibrosis is manifested by severe anemia, thrombocytopenia, and emerging extramedullary hematopoiesis in the liver and spleen. In ~10% of patients transformation to either acute myelogenous leukemia or more frequently to myelodysplastic syndrome occurs. The most common cause of death in patients with PV is thrombosis.

DIAGNOSIS

Diagnostic Tests

1. CBC: Increased RBC, hemoglobin (Hb), and hematocrit (Ht) levels; thrombocytosis (>400×109/L in ~60% of patients), frequently abnormal size, shape, and function of platelets; leukocytosis (>10×109/L in ~40% of patients) consisting mainly of neutrophils.

2. Bone marrow aspiration: Hypercellular marrow with hyperplastic erythropoietic, granulopoietic, and megakaryopoietic lineages; megakaryocytes are frequently of abnormal shape and variable size. The results of biopsy additionally reveal minor features of fibrosis that are more pronounced in a more advanced disease.

3. Molecular studies: Mutations of JAK2 gene including V617F (96% of cases) or mutations in exon 12 (3%). The absence of JAK2 mutations almost excludes the diagnosis of a primary polycythemia.

4. Other studies may be performed to establish the etiology of secondary erythrocytosis (see Differential Diagnosis, below).

Diagnostic Criteria

The diagnosis of PV requires meeting either all 3 major criteria or the first 2 major criteria and the minor criterion:

1) Major criteria:

a) Hb >16.5 g/dL (or Ht >49%) in men or Hb >16.0 g/dL (or Ht >48%) in women; or increased red cell mass.

b) Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic mature megakaryocytes (differences in size).

c) Presence of JAK2 V617F or JAK2 exon 12 mutation.

2) Minor criterion: Subnormal serum erythropoietin level.

Differential Diagnosis

Differential diagnosis of erythrocytosis: Table 1.

1. Familial erythrocytosis (rare): Hypersensitivity of erythropoietic progenitors to normal serum levels of erythropoietin.

2. Secondary erythrocytosis due to the following:

1) Hypoxia and erythropoietin hypersecretion caused by pulmonary or cardiovascular diseases (particularly heart defects with right-to-left shunts), obstructive sleep apnea, high altitude, tobacco smoking (owing to the presence of carboxyhemoglobin), high-affinity hemoglobins (causing relative hypoxia due to the inability to normally release oxygen in the periphery).

2) Erythropoietin hypersecretion not related to tissue hypoxia: Polycystic kidneys; Cushing syndrome; primary hyperaldosteronism; use of anabolic steroids; long-term glucocorticoid therapy; use of exogenous erythropoiesis-stimulating agents; erythropoietin-secreting tumors such as hepatocellular carcinoma, renal cancer, hemangioblastoma, uterine myoma, and pheochromocytoma.

3) Unknown etiology: After kidney transplant.

3. Relative erythrocytosis: Hemoconcentration due to fluid loss (vomiting, diarrhea, increased diuresis including diuretic treatment), decreased fluid intake, obesity, excessive alcohol consumption, or protein loss (enteropathy, extensive burns).

TREATMENTTop

The choice of treatment depends on the presence of risk factors for thrombotic complications (age >60 years and prior thrombosis). Phlebotomy is the primary therapy used in patients with marked erythrocytosis with the goal of Ht <45%.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (imprecision, total of 23 events in two groups). Marchioli R, Finazzi G, Specchia G, et al; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013 Jan 3;368(1):22-33. doi: 10.1056/NEJMoa1208500. Epub 2012 Dec 8. PubMed PMID: 23216616. We recommend antiplatelet therapy (acetylsalicylic acid [ASA]) for all patients, unless oral anticoagulants are indicated. All patients should have cardiovascular risk factors addressed and modified.

1. Phlebotomy: Usually 200 to 500 mL every 2 to 3 days until Ht <45% is achieved (in elderly patients with cardiovascular diseases, phlebotomies should be less frequent and of lower volumes, ie, 100-150 mL). A 500 mL phlebotomy eliminates 200 mg of iron. After iron stores become depleted (based on serum ferritin), iron replacement therapy should be avoided and the frequency of phlebotomy can be reduced.

2. Cytotoxic therapy is indicated in the following patients:

1) At high risk of thrombotic complications (age >60 years or history of arterial or venous thrombosis).

2) Intolerant of or dependent on frequent phlebotomies.

3) With progressive symptomatic splenomegaly.

4) With severe symptoms of PV.

5) With persistent platelet counts >1500×109/L.

First-line agents: Hydroxyurea (INN hydroxycarbamide) (starting dose, 15-20 mg/kg/d; maintenance dose, 500-1500 mg/d) or interferon alpha (typically pegylated). In the event of intolerance of or resistance to one of these agents, the patient may be switched to the other.

Hydroxyurea resistance/intolerance: Patients meeting the European Leukemia Network criteria for hydroxyurea resistance or intolerance may be considered for treatment with the JAK inhibitor ruxolitinib.

3. Antiplatelet therapy is recommended in all patients with no contraindicationsEvidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to uncertainty about exclusion of AvWS and potential heterogeneity in this respect with lack of power to detect differences in subgroups. Squizzato A, Romualdi E, Passamonti F, Middeldorp S. Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev. 2013 Apr 30;4:CD006503. doi: 10.1002/14651858.CD006503.pub3. Review. PubMed PMID: 23633335.; use ASA 50 to 100 mg/d. Antiplatelet therapy should be used with caution in patients with a bleeding diathesis, including the form of acquired von Willebrand disease that can be seen in patients with marked thrombocytosis. In the case of contraindications to ASA, such as allergy, consider oral ticlopidine 250 mg bid or clopidogrel 75 mg once daily.

4. Treatment of hyperuricemia: Daily consumption of ~2 L of fluids; allopurinol (see Gout) or other uric acid reduction strategies.

5. Symptomatic treatment:

1) Pruritus: Avoidance of aggravating factors; use cyproheptadine or cimetidine. If these are unsuccessful, administer paroxetine, interferon alpha, or photochemotherapy using psoralen and ultraviolet A light (PUVA).

2) Erythromelalgia can be treated with ASA used bid.

6. Modification of cardiovascular risk factors: Prevention or treatment of hypertension, diabetes, obesity, and hypercholesterolemia; smoking cessation.

7. Treatment of hemorrhagic complications: A short course of tranexamic acid, usually 10 to 15 mg/kg orally or IV every 8 hours, discontinuation of antiplatelet therapy. In acquired von Willebrand disease, desmopressin 0.3 microg/kg and vWF concentrates may be used (see Inherited Coagulation Disorders).

MONITORINGTop

After achieving normal Hb levels, schedule follow-up visits as necessary for ongoing phlebotomy (if required), to monitor for recurrent cytosis, and to address complications such as progressive splenomegaly or progression.

PROGNOSISTop

In patients with PV aged >65 years life expectancy is similar to that of the age-matched general population, while in younger patients life expectancy is shorter, mainly due to the development of secondary myelofibrosis, transformation to acute leukemia, or thrombosis (the 10-year risk being, respectively, ~10%, 3%, and >20%).

TablesTop