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Polycythemia (Rubra) Vera       SX |  DX  |  RX        See also  Polycythemia / Erythrocytosis  

A clonal cell hematologic malignant disorder with excessive erythroid, myeloid and megakaryocytic elements in the bone marrow. It is one of a group of myeloproliferative disorders.

Predominant age: Middle to late years, mean is 60 years (range 15-90).  Predominant sex: Male > Female (slightly)

SIGNS AND SYMPTOMS: Early stages may produce no symptoms      

• Symptoms
  flushing, headache, dizziness, tinnitus, visual disturbances, pruritus, dyspnea, lassitude, or weakness.
  Headache- 48%, Weakness- 47%, Pruritis- 43% [A common complaint is intense itching after exposure to water (most typically in a bath or shower)--the so-called "aquagenic pruritus." This may be the initial presentation of PV, and is reported in up to 60% of PV patients under the age of 40], Dizziness- 43%, Diaphoresis- 33%, Visual disturbances- 31%, Weight loss- 29%, Paresthesias- 29%, Dyspnea- 26%, Joint symptoms- 26%, Epigastric discomfort- 24%
• Physical Findings
  Splenomegaly-70%; Hepatomegaly-  40%, Skin plethora/erythema-67%, Conjunctival plethora-59%,
  Engorged vessels in the optic fluid- 46%,  Systolic BP>140 mm Hg-  72%, Diastolic BP>90 mm Hg-  32%

CAUSES: unknown

DIFFERENTIAL DIAGNOSIS

1. Secondary polycythemias
2. Hemoglobinopathy
3. Spurious polycythemia

LABORATORY
Polycythemia with elevated Hgb, Hct, platelet counts, WBC, uric acid; decreased erythropoietin, bone marrow erythroid hyperplasia, increased leukocyte alkaline phosphatase, increased vit.B12 level, decreased folic acid level, elevated alk.phosphatase & conjungated bilirubin, hypercalcemia.
Bone marrow aspiration (red cell hyperplasia, absent iron stores) and biopsy (fibrosis during spent phase of the disease)

Drugs that may alter lab results: Diuretics may cause a spurious polycythemia.
Disorders that may alter lab results: Excessive use of alcohol or tobacco

Diagnosis of Polycthemia Vera (Study Group Diagnostic Criteria and Their Significance)
DX: M1 + M2 +M3, or M1 + M2 + any 2 from m1-4 category.

• M1. Red Cell Mass: Male >36 ml/mg,  Female >32 ml/kg
          Identifies actual polycythemia vs. spurious polycythemia.
• M2. Arterial O2 saturation>92%
         Rules out most common etiology of secondary polycythemia.
• M3. Splenomegaly

Evidence of a myeloproliferative state.

• m1. Thrombocytosis >400,000 /µL
• m2. Leukocytosis >12,000 /µL
• m3. Leukocyte alkaline phosphatase activity >100 (no fever or infection)
• m4. Serum B12 (>900 pg/ml) or unsaturated B12 binding capacity (>2200 pg/ml)

The diagnosis of PV requires the presence of all three major criteria (M) or the first two major criteria and two minor criteria (m). The first major criterion provides confirmation that the patient has actual polycythemia, as indicated by an elevated red cell mass. The second major criterion rules out the most common etiology of secondary polycythemia, severe arterial hypoxemia, by demonstrating a normal or only moderately reduced arterial oxygen saturation. The third criterion, evidence of a myeloproliferative syndrome, is provide either by the third major criterion, splenomegaly, or by two of the four minor criteria.

TREATMENT
Individualized management necessary. Dependent on many factors - age, disease duration, disease phenotype, complications, disease activity.

Currently, phlebotomy is mainstay of therapy.
Beyond that, differences exist among authorities about use and effectiveness of myelosuppressives.

Phlebotomy: To reduce hematocrit to approximately 45%. Performed as often as every 2 or 3 days until normal hematocrit reached. Phlebotomies of 250-500 m/L. Reduce to 250-350 m/L in elderly patients or patients with cardiovascular disease. Phlebotomy repeated as necessary for maintenance. If patient cannot tolerate phlebotomy - chemotherapy (hydroxyurea is the least mutagenic agent) or radiation therapy.
Phlebotomy offers prompt and effective reduction of the red cell mass and blood volume to normal values. Many patients can be maintained in an essentially normal state by phlebotomy together with a few simple adjuvants, when necessary, to control hyperuricemia or pruritus.

Concomitant therapy possibilities, e.g., some form of myelosuppression, radioactive phosphorus (in elderly patients)

Other therapy

• Maintain hydration
• Pruritus therapy:cyproheptadine, (4 mg three or four times per day) 
• Manage thrombotic or hemorrhagic complications the same as with nonpolycythemic patient
• Uric acid reduction therapy

Adjunctive  Therapy:

• Allopurinol 300 mg/day for uric acid reduction
• Cyproheptadine for pruritus, 4-16 mg as needed
• Radioactive phosphorous ³²P in selected cases:
  In patients with PV, 32 P induces satisfactory clinical and hematologic remissions that may last years [40] [184] . The fall in the red cell count usually does not begin until 30 to 60 days from the time 32 P is given. Therefore, initial phlebotomy may be indicated for symptomatic control. As with any myelosuppressive agent, care must be taken to avoid producing anemia, leukopenia, or thrombocytopenia.  A usual dose is 3 to 5 millicuries (mCi) of 32 P, intravenously, or 2.3 mCi/M2.  32 P is effective and easily tolerated therapy. Survival after treatment is reported to be 10 to 14.5 years. The principal drawback to 32 P therapy is the increased incidence of acute leukemia.
• Busulfan or alkylating agents (e.g., hydroxyurea):
  Busulphan and chlorambucil are two alkylating agents that were widely used in PV, but the increased frequency of leukemia observed with alkylating agents led to a discontinuation of their routine use.
  The nonalkylating myelosuppressive agent hydroxyurea is the chemotherapeutic agent most widely used in PV at present. Its efficacy in controlling erythrocyte, leukocyte, and platelet counts in PV has been clearly demonstrated . Thrombotic complications are less common than are observed in patients treated with phlebotomy only. Hydroxyurea permits rapid reduction of leukocyte and platelet counts; supplemental phlebotomy may occasionally be necessary to reduce the red cell mass. As a rule, neutropenia or thrombocytopenia will correct rapidly following cessation or reduction of hydroxyurea dose; for the same reason, however, missing a few days of therapy may be associated with recurrence of leukocytosis or thrombocytosis.
• The use of low-dose aspirin is controversial in view of bleeding risk, but small doses may be given if required.
  There is no definite answer to the question of whether antiplatelet therapy is beneficial in conjunction with phlebotomy.
• Interferon is an emerging treatment: Recombinant human interferon alpha is an agent that has also demonstrated efficacy in PV. One of these studies compared phlebotomy to interferon therapy and reported that interferon was more efficacious.
• Anagrelide is a platelet-aggregating agent that is useful in the control of thrombocytosis refractory to hydroxyurea or interferon in myeloproliferative disorders such as PV.
• Splenectomy is useful only as a palliative measure in the late stages of the disease, when the spleen becomes massive and causes early satiety and weight loss, severe anemia, or thrombocytopenia.

Summary and Recommendations for Treatment       

Although treatment with phlebotomy, 32 P, or a variety of chemotherapeutic agents is effective and prolongs survival, no modality is clearly the best for everyone. The following recommendations represent a reasonable approach. More detailed recommendations have been published by the Polycythemia Vera Study Group

1. Most newly diagnosed patients should undergo phlebotomy to obtain symptomatic control of polycythemia. The rate and volume of phlebotomy is dictated by the patient's clinical status, as outlined in the section on phlebotomy above. The hematocrit should be reduced to the upper normal range (approximately 0.45).
   
2. The long-term therapy chosen to control PV varies according to the patient's clinical status. Young patients (under 50) with no history of thrombosis and without severe thrombocytosis (greater than 1000 × 103 /muL) can probably be managed best with phlebotomy alone, with a target hematocrit of 0.45. The addition of aspirin, 325 mg per day or less, may be beneficial, although this is not proven at present. Patients with a history of thrombosis, over the age of 70, or with severe thrombocytosis, should be treated with myelosuppressive agents. Patients between the ages of 50 and 70 with no history of thrombosis or severe thrombocytosis can be managed with myelosuppressive agents or phlebotomy, although the latter modality may increase their risk for thrombotic events.
   
3. The current myelosuppressive agent of choice is hydroxyurea. Although the additional risk of leukemia with longterm hydroxyurea therapy appears to be small, it may not be zero [198] . ³²P may be useful in selected patients, in whom the potential leukemic risks are outweighed by ease of administration and limitations imposed by other clinical conditions. The role of interferon in routine therapy of PV is not established at present and merits further investigation.

• Uric acid stones ,  Secondary gout
• Vascular thromboses (major cause of death)
• Transformation to leukemia
• Hemorrhage
• Peptic ulcer
• Increased risk for complications and mortality from surgery procedures.
• Assess risk-benefits and assure optimal control of disorder before any elective surgery.

EXPECTED COURSE/PROGNOSIS

Median survival without treatment - 6 to 18 months following diagnosis

Survival up to 10 years with treatment

Some patients live, symptom-free, for 20 or more years

ASSOCIATED CONDITIONS: Budd-Chiari syndrome ,  Mesenteric artery thrombosis

Ref:
Dambro: Griffith's 5-Minute Clinical Consult, 1999 ed.-  Stanley G Smith MA, MB, FCFPC
Lee: Wintrobe's Clinical Hematology, 10th ed., Copyright © 1999
Diagnosing polycythemia vera: a paradigm shift. Mayo Clin Proc 1999;74:159-162
DxPlain - Mass. Gen. Hospital: http://dxplain.mgh.harvard.edu/dxp/dxp.pl      (5-1999)
Williams WJ, Beutler E, Erslev AJ, et al, eds: Hematology. 4th Ed. New York, McGraw-Hill, 1990
Conley CL: Polycythemia vera, diagnosis and treatment. Hosp Practice 1987; 22:107
Berk PD, et al. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986;23:132.
Fruchtman SM, Wasserman LR. Therapeutic recomendations for polycythemia vera. In: Wasserman LR, Berk PD, Berlin NI, eds. Polycythemia Vera and the Myeloproliferative Syndromes. ed. Philadelphia: WB Saunders, 1995:337-350.