Morning Report 7/7/2010 Pahresah Roomiany

 Factor V Leiden  Prothrombin gene mutation  Protein C/S deficiency  Antithrombin deficiency  Malignancy  Antiphospholipid Ab syndrome  Myeloproliferative disorders  Paroxysmal nocturnal hemoglobinuria  Nephrotic syndrome  Multiple myeloma  HIV/AIDS

2008 WHO diagnostic criteria 6 Polycythemia vera Essential thrombocythemia Primary myelofibrosis Major criteria1 Hgb >18.5 g dl -1 (men) >16.5 g dl -1 (women) or Hgb>17 g dl -1 (men), or>15 g dl -1 (women) if associated with a sustained increase of 2 g dl -1 from baseline that cannot be attributed to correction of iron deficiency or Elevated red cell mass >25% above mean normal predicted value 1Platelet count l -1 1 Megakaryocyte proliferation and atypia accompanied by either reticulin and/or collagen fibrosis, or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e. pre-fibrotic PMF). 2 Presence of JAK2V617F or similar mutation 2 Megakaryocyte proliferation with large and mature morphology. No or little granulocyte or erythroid Proliferation. 2 Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm 3 Not meeting WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm 3 Demonstration of JAK2V617F or other clonal marker or no evidence of reactive marrow fibrosis 4 Demonstration of JAK2V617F or other clonal marker or no evidence of reactive thrombocytosis Minor criteria1BM trilineage myeloproliferation 1Leukoerythroblastosis 2Subnormal serum Epo level 2Increased serum LDH 3EEC growth 3Anemia 4Palpable splenomegaly

Types of polycythemia  Relative: due to decreased plasma volume  Secondary: # of erythrocytes increased.  Physiologically appropriate:  High altitude  COPD  R to L shunts  Carboxyhemoglobinemia  Cobalt ingestion  Physiologically inappropriate:  Renal vascular disease  Hepatic tumors  Renal cysts, transplant, RCC  Pheochromocytoma  Polycythemia vera: myeloproliferative disease

 Increased production of RBCs and often wbc and platelets due to neoplastic disorder of hematopoetic stem cells.  Peak incidence in 6 th /7 th decades  Often found on routine blood counts  Slight male predominance

 “vasomotor” symptoms  Hyperviscosity: HA, dizziness, tinnitus, blurred vision  Thrombosis: transient visual disturbance (amaurosis, ocular migraine), Budd-chiari, erythromelalgia  Bleeding: easy bruising, epistaxis, GI bleed  Pruritus 2/2 to histamine release from basophils  PUD, gout (increased cell turnover)

Proposed criteria for PV Major criteria Hemoglobin >18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume* Presence of JAK2 617V>F or other functionally similar mutation such as JAK2 exon 12 mutation Minor criteria Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation Serum erythropoietin level below the reference range for normal Endogenous erythroid colony formation in vitro Suspect in patients with elevated RBC mass or elevated H/h with an arterial O2>92%, splenomegaly, thrombocytosis +/- leukocytosis, thrombotic complications, erythromelalgia or pruritus.

 Phlebotomy: goal Hct <45% in men, <42% in women.  Microcytic anemia can cause increase in whole blood viscosity  Low dose ASA: decrease risk of cardiac event  Hydroxyurea: for high risk patients  Allopurinol for gout, H2 blocker/antihistamine for pruritus  JAK-2 inhibitors are showing positive treatment response in clinical trials 5

 Arterial, venous thrombosis  Evolution to AML due to cytotoxic agents (1- 2%, a 100-fold increase in incidence in adult pop by age)  Remission with standard chemotherapy is low  15-20% develop myeloid metaplasia  Replacement of marrow by fibrotic tissue  Movement of hematopoiesis into spleen and liver with worsening pancytopenia  Gout  Budd-chiari Syndrome

 Hepatic venous outflow obstruction  Most cases of BCS in west are associated with MPD  Tx with TIPS, balloon angioplasty 2  High incidence of rethrombosis and graft failure in PV 3 Fluoroscopic image of transjugular intrahepatic portosystemic shunt (TIPS) in progress. A catheter has been passed into the hepatic vein and a guidewire was passed into a portal vein branch. A stent has yet to be placed over the wire.

1. Spivak, J. (2010). Narrative Review: thrombocytosis, polycythemia vera and JAK2 mutations: the phenotypic mimicry of chronic myeloproliferation. Ann Intern Med. 152: Cruz, E. et.al. (2005).High incidence of recurrence and hematologic events following liver transplantation for budd-chiari syndrome. Clin transplant. 16: Buzas, C. (2009). Budd-chiari syndrome secondary to polycythemia vera. J Gastrointestin Liver Dis. 18: Rossi, D. (2007). Usefulness of JAK2V617F mutation in distinguishing idiopathic erythrocytosis from polycythemia vera. Leuk Res. 31: Finazzi, G. Barbui, T. (2008). Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia. 22: Tefferi, A and Vardiman JW. (2008) Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 7. Kasper et.al. (16 th Ed) Harrisons Principles of Internal Medicine.