Polycythemia Vera

Chapter: Polycythemia Vera
McMaster Section Editor(s): Mark Crowther
Section Editor(s) in Interna Szczeklika: Andrzej Hellmann, Bogdan Ochrem
McMaster Author(s): Mark Crowther
Author(s) in Interna Szczeklika: Irena Frydecka
Additional Information

DEFINITION, ETIOLOGY, PATHOGENESIS Top

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by a marked increase in red blood cell (RBC) counts, frequently accompanied by an 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 cases/100,000 population per year.

CLINICAL FEATURES AND NATURAL HISTORY Top

Signs and symptoms depend on the stage of the disease, 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 a hot bath; present in ~40% of patients, may be pathognomonic), symptoms of peptic ulcer disease, 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, gout. Nonspecific symptoms (in advanced disease): weakness, weight loss, abdominal distention, or pain due to splenomegaly. Bleeding may occur; in some patients it is due to an acquired von Willebrand disease seen particularly when the platelet count is >1,500,000/microL, while in others it is due to an acquired platelet function defect and may be exacerbated by coincident medication 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; characteristic venous stasis seen in fundoscopy. Erythromelalgia is characteristic for thrombocytosis, whether reactive or occurring in the setting of myeloproliferative neoplasm.

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 (>400,000/microL in ~60% of patients), frequently abnormal size, shape, and function of platelets; leukocytosis (>10,000/microL in ~40% of patients) consisting mainly of neutrophils, and sometimes also basophils.

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 or related 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 both major criteria and 1 minor criterion or the first major criterion and 2 minor criteria:

1. Major criteria:

1) Hb >18.5 g/dL in men and >16.5 g/dL in women or other evidence of increased RBC mass (Hb or Ht >99th percentile of the reference range for age, sex, or altitude of residence; or Hb >17 g/dL in men and >15 g/dL in women associated with a documented and sustained increase in the Hb level ≥2 g/dL from baseline that cannot be attributed to correction of iron deficiency; or RBC mass >25% above the mean normal predicted).

2) Presence of JAK2 V617F or other functionally similar mutation.

2. Minor criteria:

1) Bone marrow biopsy revealing hypercellular marrow with hyperplastic erythropoietic, granulopoietic, and megakaryopoietic lineages.

2) Appropriately suppressed serum erythropoietin levels.

3) Endogenous (with no addition of erythropoietin) in vitro growth of erythroid colonies from erythropoietic precursors.

Differential Diagnosis

Differential diagnosis of PV and secondary and relative erythrocytosis: Table 7.8-6.

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 syndrome, altitude, tobacco smoking (owing to the presence of carboxyhemoglobin), high-affinity hemoglobin syndromes (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 transplantation.

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% rather than <50%.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.

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 (≥1 risk factors).

2) Intolerant of or dependent on frequent phlebotomies.

3) With progressive symptomatic splenomegaly.

4) With severe symptoms of PV.

5) With persistent platelet counts >1,500,000/microL.

6) With progressive leukocytosis >20,000 to 25,000 cells/microL.

First-line agents: Hydroxyurea (INN hydroxycarbamide) (starting dose, 15-20 mg/kg/d; maintenance dose, 500-1500 mg/d) or interferon alpha. In the event of intolerance of or resistance to one of these agents, the patient may be switched to the other (or, in countries where available, the patient may be treated with pipobroman [not available in North America]). In patients aged >70 years or with a life expectancy <10 years, treatment with busulfan or radioactive sodium phosphate (32P) may be used; however, in most patients hydroxyurea is preferred to these agents. In addition to lowering leukocyte and platelet counts, cytotoxic therapy may reduce or eliminate the need for phlebotomy.

3. Antiplatelet therapy is recommended in all patients with no contraindications;Evidence 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 (dosage: see Pruritus), interferon alpha 3 million U/d subcutaneously 3 times per week, or photochemotherapy using psoralen and ultraviolet A light (PUVA).

2) Erythromelalgia.

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 hemoglobin levels, schedule follow-up visits as necessary for ongoing phlebotomy (if required) and to monitor for recurrent cytosis and for complications such as progressive splenomegaly.

PROGNOSISTop

In patients with PV aged >65 years, the life expectancy is similar to that of the age-matched general population, while in younger patients, the 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

Table 7.8-6. Differential diagnosis of polycythemia vera, secondary erythrocytosis, and relative erythrocytosis

Feature

Polycythemia vera

Secondary erythrocytosis

Relative erythrocytosis

RBC mass

N

WBC count

N or ↑

N

N

Platelet count

N or ↑

N

N

Bone marrow

Trilineage hyperplasia

Erythropoietic lineage hyperplasia

N

Splenomegaly

+++

Pruritus

+/-

SaO2

N

N or ↓

N

Serum vitamin B12 levels

N or ↑

N

N

Granulocyte alkaline phosphatase

N

N

Serum erythropoietin levels

↓ or N

N

Endogenous growth of erythroid colonies

+

↑, increased; ↓, decreased; N, normal; RBC, red blood cell; SaO2, direct measurement of hemoglobin oxygen saturation in arterial blood; WBC, white blood cell.

 

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