The Chronic Myeloproliferative Disorders (MPD) A JENABIAN MD

MPD - concepts Neoplastic (clonal) disorders of hemopoietic stem cells Over-production of all cell lines, with usually one line in particular Fibrosis is a secondary event Acute Myeloid Leukemia may occur

1. Myeloproliferative disorders are clonal and the fibrosis is ‘reactive’

MPD - inclusions and nomenclature 1. Polycythemia (Rubra) Vera (PRV, PV) 2. Myelofibrosis (with Myeloid Metaplasia), Agnogenic Myeloid Metaplasia (MF,MMM, AMM) 3. Essential (Primary) Thrombocythemia

Essential Thrombocythemia

Normal Regulation of Platelet Numbers by Thrombopoietin - TPO Constitutive production of thrombopoietin by liver Bound by platelets Excess stimulates megakaryopoiesis

Essential Thrombocythemia (ET) Neoplastic stem cell disorder causing dysregulated production of large numbers of abnormal platelets Some cases non-clonal (esp young women) Abnormal platelets aggregate in vivo, causing thrombosis Abnormal platelets also cause bleeding

ET-Typical Blood Count WBC x 10 9 /L10.0[4-11] Hb g/L156[ ] MCV fl85[80-100] Platelets x 10 9 /L1560[ ] Neuts x 10 9 /L7.0[2-7.5] Lymphs x 10 9 /L2.0[1.5-4] Monos x 10 9 /L0.8[ ] Eos x 10 9 /L0.1[0-0.7] Basos x 10 9 /L0.1[0-0.1] Film Comment:many large and abnormal platelets present

ET – clinical features None Peripheral Vascular Occlusion Transient Ischemic Attack (TIA) Stroke Bleeding (esp surgical)

ET - diagnosis Distinguish from reactive thrombocytosis, and Chronic Myeloid Leukemia Clinical setting, blood film, bone marrow, and cytogenetics help 50% JAK-2 mutation

ET- treatment None in low-risk cases Anti-platelet agents (aspirin) Platelet reduction treatment

Polycythemia (Rubra) Vera (PRV) A neoplastic stem cell disorder possessing a JAK-2 mutation, which leads to excessive production of all myeloid cell lines, but predominantly red cells. The increase in whole blood viscosity causes vascular occlusion and ischemia, compounded by the increase in platelets.

Loss of heterozygosity of chromosome 9 – occurs commonly in P vera normalLOH

Campbell P and Green A. N Engl J Med 2006;355: Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation EPO-dependent signalEPO-independent signal

PRV - typical blood count WBC x 10 9 /L18.0[4-11] Hb g/L200[ ] HCt0.62[ ] MCV fl75[80-100] Platelets x 10 9 /L850[ ] Neuts x 10 9 /L14.6[2-7.5] Lymphs x 10 9 /L2.0[1.5-4] Monos x 10 9 /L0.8[ ] Eos x 10 9 /L0.1[0-0.7] Basos x 10 9 /L0.5[0-0.1] Film:microcytosis: large and abnormal platelets present

PRV - clinical features Headaches Itch Vascular occlusion –Venous thrombosis –TIA, stroke, MI Splenomegaly

PRV - diagnosis red cell mass if necessary exclude secondary causes of true polycythemia (measure erythropoietin) look for features of primary polycythemia JAK-2 mutation analysis if available

PRV - treatment phlebotomy to hematocrit less than 0.45 low-dose aspirin hydroxyurea if necessary do not treat with iron

Mr LW: response to weekly venesection of 500 cc Hb Hct Days Hemoglobin Hematocrit

(Primary) Myelofibrosis (MF) neoplastic (clonal) hemopoietic stem cell disorder distinguish from secondary marrow fibrosis bone marrow failure myeloid metaplasia (extra- medullary hemopoiesis)

MF - typical blood count WBC x 10 9 /L2.4[4-11] Hb g/L88[ ] MCV fl85[80-100] Platelets x 10 9 /L60[ ] Neuts x 10 9 /L1.0[2-7.5] Lymphs x 10 9 /L1.0[1.5-4] Monos x 10 9 /L0.2[ ] Eos x 10 9 /L0.1[0-0.7] Basos x 10 9 /L0.1[0-0.1] Film Comment: a few nucleated red cells and myelocytes (leukoerythroblastic). Tear-drop poikilocytes

Tear Drop Cells (or Tear Drop Poikilocytes)

MF - clinical Marrow failure splenomegaly

MF - diagnosis typical blood picture splenomegaly dry aspirate fibrosis on trephine biopsy absence of other cause

MF - treatment supportive care splenectomy if necessary consider allo-BMT