Download 10.20.09 Caulfield Polycythemia vera

Hypercoagulable States:
Polycythemia Vera
Chris Caulfield
AM Report
Oct 20, 2009
Hypercoagulable States
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Inherited:
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Acquired:
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Factor V Leiden mutation
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Prothrombin gene mutation
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Protein S deficiency
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Protein C deficiency
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Antithrombin III deficiency
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Hyperhomocysteinemia
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Malignancy
Surgery/Trauma
Pregnancy
OCPs, HRT, Tamoxifen
Immobilization
CHF
Nephrotic Syndrome
IBD
HIT
Myeloproliferative disorders:
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POLYCYTHEMIA VERA
Essential thrombocythemia
Paroxysmal nocturnal
hemoglobinuria
Hyperviscosity: Waldenstrom's
macroglobulinemia, MM,
Marked leukocytosis in acute
leukemia, Sickle cell anemia
Polycythemia Vera
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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:
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Chronic hypoxia
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Erythropoietin-secreting tumors
Epidemiology
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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)
Clinical Manifestations
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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.
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Examples include Budd-Chiari syndrome, and portal, splenic, or
mesenteric vein thrombosis, MI, and CVA.
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 >18.5 g/dL in men (HCT above 56 percent) and
Hemoglobin >16.5 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
Proposed 2007 revised WHO
criteria for Polycythemia Vera
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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:
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Renal cell carcinoma
Hepatocellular carcinoma
Hemangioblastoma
Uterine fibroids
Proposed 2007 revised WHO
criteria for Polycythemia Vera
JAK-2 Mutations
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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.
Understanding the Diagnostic
Criteria
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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
Recent Study regarding
Budd-Chiari Syndrome
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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%).
Treatment
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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.
Treatment
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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
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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
Prognosis and Survival
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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
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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
References
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Berlin, NI. (1975). Diagnosis and classification of
polycythemias. Semin Hematology, 12, 339.
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Murad, SD et al. (2009). Annals of Internal
Medicine, 151, 167-175.
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Smith, CA et al. (2008) Human Pathology, 39,
795-810.
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