Polycythemia Vera

BASICS

DESCRIPTION

Polycythemia vera (PV) is a chronic myeloproliferative clonal stem cell disorder marked by increased production of red blood cells (erythrocytosis) with excessive erythroid, myeloid, and megakaryocytic elements in the bone marrow.
Morbidity and mortality are primarily related to complications from blood hyperviscosity or thrombosis development as well as malignant transformation.
Myelofibrosis can develop in the bone marrow, leading to progressive hepatosplenomegaly.
Synonym(s): primary polycythemia; Vaquez disease; Waldenstrom disease; primary PV; PV rubra; polycythemia, splenomegalic; Vaquez-Osler disease

EPIDEMIOLOGY

Incidence

Predominant age: 50 to 75 years, 5% are <40 years
Predominant sex: male > female (slightly)
Incidence in the United States in 2012: 2.8/100,000 population of men and 1.3/100,000 population of women

Prevalence
In the United States in 2010, estimates ranged from 45 to 57 cases per 100,000 patients.

ETIOLOGY AND PATHOPHYSIOLOGY

JAK2 V617F mutation associated with clonal proliferative disorder
Genetics
JAK2 V617F (tyrosine kinase) mutation: >97% of patients with PV have an activating mutation; this is helpful in differentiating from secondary erythrocytosis. Homozygote carriers will have higher incidence of symptoms such as pruritus but will not have higher incidence of disease than heterozygotes.

RISK FACTORS

PV is more prevalent among Jews of Eastern European descent than other Europeans or Asians.
Familial history is rare.

COMMONLY ASSOCIATED CONDITIONS

Budd-Chiari syndrome
Mesenteric artery thrombosis
Myocardial infarction
Cerebrovascular accident or transient ischemic attack
Venous thromboembolism and pulmonary embolism

DIAGNOSIS

HISTORY

Patients may be asymptomatic or present with nonspecific complaints, including fatigue, malaise, and/or subjective weakness.
Erythromelalgia (burning pain of feet/hands, occasionally with erythema, pallor, cyanosis, or paresthesias)
Arterial and venous occlusive events
Headaches
Blurred vision or blind spots
Pruritus, especially after the shower
Spontaneous bruising/bleeding
Peptic ulcer disease (due to alterations in gastric mucosal blood flow)
Bone pain (ribs and sternum)
Tinnitus

PHYSICAL EXAM

Hypertension
Facial plethora
Splenomegaly
Hepatomegaly
Bone tenderness (especially ribs and sternum)
Skin excoriations from significant pruritus
Gouty tophi or arthritis

DIFFERENTIAL DIAGNOSIS

Secondary polycythemias
Hemoglobinopathy
Ectopic erythropoietin production
Spurious polycythemia

DIAGNOSTIC TESTS & INTERPRETATION

CBC; if suspicion is high, then obtain erythropoietin level and gene testing for JAK2 V617F.
Initial Tests (lab, imaging)

2008 World Health Organization diagnostic criteria requires two major criteria and one minor or the first major criterion with two minor criteria (1).
- Major criteria:
  - Hemoglobin (Hgb) >18.5 g/dL (men); Hgb >16.5 g/dL (women); or Hgb >17 g/dL (men) or Hgb >15 g/dL (women) if associated with a sustained increase of ≥2 g/dL from baseline that cannot be attributed to correction of iron deficiency.
  - Presence of JAK2 V617F or similar mutation
- Minor criteria:
  - Bone marrow trilineage myeloproliferation
  - Subnormal serum erythropoietin level
  - Endogenous erythroid colony (EEC) growth
Diagnosis can be made reliably based on clinical symptoms, presence of JAK2 V617 mutation, and low EPO (2).
Other lab findings that are common but not specific
- Hyperuricemia
- Hypercholesterolemia
- Elevated serum vitamin B12 levels
CT or US to assess for splenomegaly, although not necessary for diagnosis
Causes of secondary erythrocytosis:
- Sleep apnea
- Emphysema
- Cigarette smoking
- Renal artery stenosis
- Carbon monoxide poisoning

Diagnostic Procedures/Other

Bone marrow aspiration shows increased cellularity.
Cytogenetic testing (JAK2 V617F)

Test Interpretation

If JAK2 V617F mutation testing is negative and the erythropoietin level is normal or high, then PV is excluded; investigate causes of secondary erythrocytosis.
Other causes of erythrocytosis such as ectopic erythropoietin production from a renal tumor, hypoxia from chronic lung, or cyanotic heart disease can be excluded with low or undetectable serum erythropoietin level and normal oxygen saturation.

TREATMENT

GENERAL MEASURES

Risk factors: age, disease duration, disease phenotype, complications, disease activity
Phlebotomy and low-dose aspirin is first-line therapy for low-risk patients.
Phlebotomy reduces the blood hyperviscosity, improve platelet functions, restore systemic pressures, and decrease risk of thrombosis.
Phlebotomy:
- Reduce hematocrit to <45%; will significantly lower rate of cardiovascular death and major thrombosis (3)[A].
- Performed as often as every 2 to 3 days until normal hematocrit reached; phlebotomies of 250 to 500 mL. Reduce to 250 to 350 mL in elderly patients or patients with cerebrovascular disease.
- May require concurrent myelosuppressive agent if at high risk for thrombosis
Complications of phlebotomy: chronic iron deficiency (symptomatology: pica, angular stomatitis, and glossitis), possible muscle weakness, and dysphagia
Other therapies:
- Maintain hydration.
- Pruritus therapy: H1 and H2 blockers, ataractics
- Uric acid reduction therapy

MEDICATION

First Line

Primary therapies:
- Low-dose aspirin 81 mg PO has been associated with a statistically nonsignificant reduction in the risk of fatal thrombotic events without increasing bleeding complications when used in conjunction with phlebotomy (4)[A].
- Hydroxyurea is recommended for patients at high risk for thrombosis (age >60 years or history of thrombotic event) and with splenomegaly and hepatomegaly. Common starting dose 500 to 1,500 mg PO daily, titrating to control hematocrit and platelet count. Be aware that hydroxyurea can lead to higher risk of leukemic transformation (5)[A].
- Radioactive phosphorous (32P) may control Hgb level and platelet count by destroying overactive marrow cells. May take up to 3 months before affecting cells. Consider for patients intolerant or nonadherent to hydroxyurea or short expected survival due to mutagenic potential.
- Tyrosine kinase inhibitor imatinib 400 to 800 mg daily was shown to have moderate cytoreductive effects in PV (6)[B].
- Pegylated interferon-α-2a is effective in controlling erythrocytosis, although dosing is generally limited secondary to intolerable side effects (7)[B].
- Refer to hematologist/oncologist for further dosing and instructions.
Symptomatic/adjunctive:
- Allopurinol 300 mg/day PO for uric acid reduction
- Cyproheptadine 4 to 16 mg PO daily as needed for pruritus
- H2-receptor blockers or antacids for GI hyperacidity; cimetidine is also used for pruritus.
- SSRIs (paroxetine or fluoxetine) have shown some efficacy in controlling pruritus.
- Ultraviolet light may help with pruritus.

Second Line
Myelosuppression: chlorambucil or busulfan; busulfan at 2 to 4 mg daily may be effective option for elderly patients with advanced PV refractory or intolerant to hydroxyurea, but significant rate of transformation was observed.

ISSUES FOR REFERRAL

Referral to a hematologist to assist in diagnosis and management

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring
Monitor hematocrit often and phlebotomize as needed to maintain target goal.

DIET

Avoid high-sodium diet, can cause fluid retention.
Avoid iron supplement, a permissive chronic state of iron deficiency can help decrease blood production.

PATIENT EDUCATION

Perform leg and ankle exercises to prevent clots.
Continuous education regarding possible complications and seeking treatment early for any change or increase in symptoms

PROGNOSIS

PV cannot be cured but can be controlled with treatment.
Survival is >15 years with treatment.
Patients are at risk for developing postpolycythemic myelofibrosis (PPMF) and an increased risk of malignant transformation.

COMPLICATIONS

Splenomegaly or hepatomegaly
Budd-Chiari syndrome
Vascular thrombosis (major cause of death)
Transformation to acute leukemia
Transformation to myelofibrosis
Hemorrhage
Peptic ulcer
Uric acid stones
Secondary gout
Increased risk for complications and mortality from surgical procedures. Assess risk/benefits and ensure optimal control of disorder before any elective surgery.

REFERENCES

11 Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009;115(17):3842 " 3847.22 Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88(6):507 " 516.33 Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22 " 33.44 Squizzato A, Romualdi E, Passamonti F, et al. Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev. 2013;(4):CD006503.55 Mascarenhas J, Mughal TI, Verstovsek S. Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Curr Med Chem. 2012;19(26):4399 " 4413.66 Merx K, Fabarius A, Erben P, et al. Effects of imatinib mesylate in patients with polycythemia vera: results of a phase II study. Ann Hematol. 2013;92(7):907 " 915.77 Quint ‘s-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27(32):5418 " 5424.

ADDITIONAL READING

Passamonti F. How I treat polycythemia vera. Blood. 2012;120(2):275 " 284.
Tefferi A, Fonseca R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus. Blood. 2002;99(7):2627.

CODES

ICD10

D45 Polycythemia vera
D75.1 Secondary polycythemia

ICD9

238.4 Polycythemia vera
289.0 Polycythemia, secondary

SNOMED

109992005 Polycythemia vera (disorder)
127062003 Erythrocytosis (disorder)

CLINICAL PEARLS

JAK2 mutations are an important component of myeloproliferative disorders.
Common complications include thrombosis, malignant transformation, and myelofibrosis.
Phlebotomy is first-line treatment, and consultation with an experienced hematologist is recommended.

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