Hypercoagulable States: Polycythemia Vera Chris Caulfield AM Report Oct 20, 2009

Hypercoagulable States Inherited: Inherited: Factor V Leiden mutation Prothrombin gene mutation Protein S deficiency Protein C deficiency Antithrombin III deficiency Hyperhomocysteinemia Acquired: 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

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.) 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

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)

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.

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 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

Proposed 2007 revised WHO criteria for Polycythemia Vera

This mutation is found in the majority of polycythemia vera patients (74%). 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. 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. JAK-2 Mutations

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 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 JAK-2 mutation had been found in 40-59% of patients with BCS in prior studies 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 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 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%). Most patients received treatment with anticoagulation (86%) & TIPS procedure (34%).

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.

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).

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

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

Take Home Points PV is a myeloproliferative disorder characterized by overproduction of RBCs (can also cause overproduction of WBCs and platelets) 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 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%). 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 Berlin, NI. (1975). Diagnosis and classification of polycythemias. Semin Hematology, 12, 339. Murad, SD et al. (2009). Annals of Internal Medicine, 151, Smith, CA et al. (2008) Human Pathology, 39, Uptodate Online