MLAB 1415- Hematology Keri Brophy-Martinez MYELOPROLIFERATIVE DISORDERS (MPDs)

CHRONIC MYELOPROLIFERATIVE DISORDERS (MPDs) Defect found in pluripotential hematopoietic stem cell due to a genetic mutation Production of a pathogenic clone Bone marrow and peripheral blood show increases in RBCs, WBCs and/or platelets Clonal expansion Characterized by a hypercellular bone marrow with increased quantities of one or more cellular lineages in the peripheral blood.

MPDs Most common diseases included in the WHO classification of MPDs: Chronic myelogenous leukemia (CML) Ph positive Polycythemia rubra vera (PRV or PV) Essential thrombocythemia (ET) Primary myelofibrosis (PMF) MPDs present in a clinically stable phase that may transform to an aggressive cellular growth phase

General Features of MPDs Occurs in persons over the age of 50 Peak incidence over age 60 Onset is gradual

Clinical Features of MPDs Hemorrhage Thrombosis Infection Pallor Weakness Hepatosplenomegaly, splenomegaly Night sweats Weight loss

Chronic Myelocytic Leukemia -CML-

CML Also known as Chronic Granulocytic Leukemia (CGL) A clonal myeloproliferative disorder Observe marked leukocytosis and excessive production of granulocytes at all stages of maturation Etiology unknown (95% of cases) Seen more commonly in males Associated with acquired chromosomal abnormality called Philadelphia Chromosome 90-95% of patients with CML carry Philadelphia Chromosome Translocation of chromosomes 9 and 22 t(9:22)

Philadelphia Chromosome Main portion of the long arm of chromosome 22 is deleted and translocated to distal end of long arm of chromosome 9, and a small part of chromosome 9 reciprocally translocates to the broken end of chromosome 22

Three Phases of CML Unresponsive to treatment Chronic Controllable with chemotherapy Lasts 2-5 years Accelerated Lasts 6-18 months 10-19% blasts in PB and BM Low Platelet counts Increasing WBC counts Blast crisis Involves the PB, BM, extramedullary tissue Unresponsive to treatment Prognosis less than 6 months > 20% blasts in bm

Blasts in accelerated phase CML with left shift Blasts in blast crisis

Laboratory Findings in CML Extreme leukocytosis (WBC > 100,000 x 109/L) Marked left shift Predominance of segs and myelocytes Thrombocytosis (can exceed 1000 x 109/L) Variant platelet shapes Function can be abnormal Normochromic-normocytic anemia (Hgb 9-13 g/dL) NRBC’s rare Bone marrow M:E ratio is 10:1(Hypercellular) Low LAP score (leukemoid reaction has high LAP) Uric acid elevated- due to cell turnover

Chronic myelogenous leukemia (CML) Treatment Chemotherapy to reduce the myeloid mass Bone marrow/stem cell transplant Imatinib mesylate to inhibit tyrosine kinase

Polycythemia Erythrocytosis with increased hgb concentration and red cell mass (hct) Classified into two types Absolute- Result from increased red cell mass Polycythemia vera (PV) Secondary polycythemia Relative- Due to a decrease in plasma volume

Polycythemia Vera (PV) Stem cell disorder characterized by an increase in red blood cell mass and total blood volume. Mutation in JAK2 gene- activated erythrocyte production EPO levels are decreased to normal Cell death is inhibited There can also be an increase in myeloid and megakaryocytic elements in the bone marrow. Peak incidence in white males, around age 60

Clinical Features: Polycythemia vera Patients have a ruddy cyanotic complexion due to congestion of blood vessels. “Plethora” Itching(pruritus) Headache Weakness Fever and night sweats Splenomegaly Brain circulatory disorders Myocardial infarction

Lab Features of PV Absolute erythrocytosis of 6-10 x 10 12/L Hemoglobin Concentrations Male: >18.5 g/dL Female: >16.5 g/dL Hct Concentrations Male: 52% Female: 48% Increased WBC, plts Bone marrow Hypercellular

Polycythemia vera Treatment Prognosis Therapeutic phlebotomy for rapid reduction of RBC mass. Radioactive phosphorous for myelosuppression. Prognosis Survival time from diagnosis is 8-15 years 10-15% of patients convert to acute nonlymphocytic leukemia.

Secondary polycythemias EPO levels increased Causes of increased secretion of erythropoietin Increase in erythropoietin in response to tissue hypoxia High altitude Chronic pulmonary disease Obesity/sleep apnea Smoking Familial hemoglobin variants High oxygen affinity hemoglobinopathies Inappropriate increase in erythropoietin Renal cysts or renal transplants due to tissue hypoxia of the juxtaglomerular apparatus that generates EPO Neoplasms Endocrine disorders

Relative polycythemia Red cell mass normal Decreased plasma volume Normal EPO Mild polycythemia

Essential thrombocythemia Defect in megakaryocytic line Results in increase in megakaryocytes in the BM Increase in platelets in PB Platelet abnormalities in diameter, shape, granularity, function Synonyms include primary thrombocythemia, idiopathic thrombocytosis, primary thrombocytosis

ET Platelet count is > 600 x 109/L Giant Bizarre platelets Platelet aggregates

Primary myelofibrosis Characteristics Marrow fibrosis 90% of attempts result in dry tap. Fibroblasts and increased collagen production lock in the marrow contents. Extramedullary hematopoiesis occurs in spleen and liver Splenomegaly, hepatomegaly Left shift, thrombocytosis with bizarre platelets, teardrops, elliptocytes, ovalocytes

Primary myelofibrosis Treatment Transfusion for anemia Iron, folate and B12 Steroids Splenectomy BM transplant Prognosis Median survival time is about 5 years from time of diagnosis.

References McKenzie, Shirlyn B., and J. Lynne. Williams. "Chapter 21." Introduction. Clinical Laboratory Hematology. Boston: Pearson, 2010. Print