Hypercoagulable States: Polycythemia Vera

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Hypercoagulable StatesPolycythemia Vera

• Chris Caulfield
• AM Report
• Oct 20, 2009

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Hypercoagulable States

• Inherited
• Factor V Leiden mutation
• Prothrombin gene mutation
• Protein S deficiency
• Protein C deficiency
• Antithrombin III deficiency
• Hyperhomocysteinemia

• Acquired
• Malignancy
• Surgery/Trauma
• Pregnancy
• OCPs, HRT, Tamoxifen
• Immobilization
• CHF
• Nephrotic Syndrome
• IBD
• HIT
• Myeloproliferative disorders
• POLYCYTHEMIA VERA
• Essential thrombocythemia
• Paroxysmal nocturnal hemoglobinuria
• Hyperviscosity Waldenstrom's macroglobulinemia,
  MM, Marked leukocytosis in acute leukemia, Sickle
  cell anemia

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Polycythemia Vera

• One of the chronic myeloproliferative disorders
  characterized by clonal proliferation of myeloid
  cells in which the bone marrow produces too many
  red blood cells (can cause overproduction of
  white blood cells and platelets.)
• Distinguished clinically by the presence of an
  elevated red blood cell mass, but must exclude
• Chronic hypoxia
• Erythropoietin-secreting tumors

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Epidemiology

• Occurs in all populations and all ages, including
  early adulthood and occasionally in children and
  adolescents
• At Mayo, the incidence during the period from
  1935 through 1989 was estimated to be 1.9/100,000
  per year
• Incidence is slightly higher in men than women
  (2.8 versus 1.3 cases/100,000 per year), and is
  highest for men aged 70 to 79 years (24
  cases/100,000 persons per year)

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Clinical Manifestations

• Nonspecific complaints headache, weakness,
  dizziness, and excessive sweating.
• Pruritus has been present in 30-40 of patients
  in previous studies, may be due may be due to
  abnormal histamine release/prostaglandin
  production
• Erythromelalgia burning pain in the feet or
  hands accompanied by erythema, pallor, or
  cyanosis, in the presence of palpable pulses.
• Transient visual disturbances (amaurosis fugax)
• Thrombosis Venous and arterial thromboses are
  common in PV. Hypercoagulable state most likely
  due to abnormalities in blood viscosity.
• Examples include Budd-Chiari syndrome, and
  portal, splenic, or mesenteric vein thrombosis,
  MI, and CVA.

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Proposed 2007 revised WHO criteria for
Polycythemia Vera

• Diagnosis requires
• Both major criteria and one minor criteria, or
  the first major criterion and 2 minor criteria
• Major criteria
• 1. Hemoglobin gt18.5 g/dL in men (HCT above 56
  percent) and Hemoglobin gt16.5 g/dL in women (HCT
  above 50 percent) or other evidence of increased
  red cell volume
• 2. Presence of JAK-2 mutation
• Minor criteria
• 1. Bone marrow biopsy showing hypercellularity
  for age with trilineage growth (panmyelosis) with
  prominent erythroid, granulocytic, and
  megakaryocytic proliferation
• 2. Serum EPO level below the reference range
• 3. Endogenous erythroid colony formation in
  vitro

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Proposed 2007 revised WHO criteria for
Polycythemia Vera

• Must rule out disorders causing secondary
  erythrocytosis, which include hypoxia, familial
  polycythemic disorders, and inappropriately high
  levels of EPO production as seen with a tumor
  such as
• Renal cell carcinoma
• Hepatocellular carcinoma
• Hemangioblastoma
• Uterine fibroids

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Proposed 2007 revised WHO criteria for
Polycythemia Vera
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JAK-2 Mutations

• This mutation is found in the majority of
  polycythemia vera patients (74).
• However, also seen in over a third of essential
  thrombocythemia (36) and chronic idiopathic
  myelofibrosis patients (44), and in a low
  proportion of other myeloproliferative or
  myelodysplastic diseases.  

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Understanding the Diagnostic Criteria

• Still no definitive and agreed upon method for
  diagnosis of PV, but identifying the JAK-2
  mutation may be helpful in providing additional
  information
• Patients with severe complications related to
  PV (eg, Budd-Chiari syndrome) but without
  classical features of the disease may not fulfill
  the classic PV Study Group criteria

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Recent Study regardingBudd-Chiari Syndrome

• JAK-2 mutation had been found in 40-59 of
  patients with BCS in prior studies
• Recent Annals of IM article from 8/09 found JAK-2
  mutations in only 29 of tested patients with BCS
• Found that 84 of patient with BCS had an
  underlying thrombophilia and 46 had 2 or more
  thrombotic risk factors
• Most patients received treatment with
  anticoagulation (86) TIPS procedure (34).

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Treatment

• Based primarily upon the observations of the PV
  Study Group, the mainstay of therapy in PV
  remains phlebotomy to keep the hematocrit below
  45 percent in men and 42 percent in women
• Since phlebotomy is effective in controlling
  polycythemia by producing a state of relative or
  absolute iron deficiency, iron supplementation
  should not be given.

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Treatment

• For special groups
• Can supplement phlebotomy with hydroxyurea in
  patients who are at high-risk for thrombosis.
• Should give Aspirin 75 to 100 mg/day to all
  patients, may need to consider additional forms
  of anticoagulation depending on extent of
  thrombosis.
• Use of radioactive 32P can be used in patients
  whose life expectancy is less than 10 years.
• Interferon use in patients with refractory
  pruritus, high-risk women of childbearing
  potential, and patients refractory to all other
  medications (eg, hydroxyurea).

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Prognosis and Survival

• The median survival of untreated symptomatic
  patients with PV was initially estimated at 6 to
  18 months from the time of diagnosis, whereas
  current survival of treated patients might be ten
  years or more

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Prognosis and Survival

• Based on PV Study Group, the most common causes
  of death due to PV include
• Thrombosis (29 percent)
• Hematologic malignancies (ie, AML or MDS, 23
  percent)
• Non-hematologic malignancies (16 percent)
• Hemorrhage (7 percent)
• Myeloid metaplasia with myelofibrosis (3 percent)

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Take Home Points

• PV is a myeloproliferative disorder characterized
  by overproduction of RBCs (can also cause
  overproduction of WBCs and platelets)
• Clinical manifestations of PV can be nonspecific,
  but thrombosis can be the most severe and causes
  the most deaths
• Diagnostic criteria still remains unsettled, but
  the JAK-2 mutation can be found in the majority
  of polycythemia vera patients (74).
• Phlebotomy is the mainstay of therapy, should
  consider low dose Aspirin in all patients

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References

• Berlin, NI. (1975). Diagnosis and classification
  of polycythemias. Semin Hematology, 12, 339.
• Murad, SD et al. (2009). Annals of Internal
  Medicine, 151, 167-175.
• Smith, CA et al. (2008) Human Pathology, 39,
  795-810.
• Uptodate Online