Thalassemia

Objectives

Explain the pathophysiology that causes thalassemia & hemoglobinopathies. Explain how thalassemias are categorized. Correlate the results of laboratory testing w/ specific thalassemias & hemoglobinopathies.
Dithionite

tube test Hemoglobin electrophoresis Alkali denaturation test for fetal hemoglobin

Objectives

Discuss specifics of specimen collection, handling, storage, and preparation. Explain the physiologic theory relevant to the test/procedure. Explain the principle of the test/procedure Identify the disease manifestation/clinical correlation. Differentiate or resolve technical, instrument, or physiologic causes of problems or unexpected test results.

Characteristics: Thalassemia

Hereditary disorders Results into moderate to severe anemia Basic defect: reduced production of selected globin chains

Epidemiology: Mediterranean, Africa, Western SEA, India, Burma Distribution parallels that of P. falciparum

Types of Thalassemia

T:Mediteranean, African Normal / Minor / 0 / + Intermedia 0/+ Major 0 / 0 + / + Age of onset: 6-12 mo

T: SEA Normal Silent carrier Minor

/ -/ -/- --/ Hb H dse --/- Barts hydrops fetalis--/-(incompatible w/ life)

Special Cases Thalassemia

Hb Lepore: fusion seen in some types of thalassemia Hb Constant Spring

chain with 31 additional amino acids --/cs

Hereditary persistence of fetal hemoglobin (HPFH)

Clinical Picture

Thalassemia minor:
Asymptomatic

or minimal pallor and mild

splenomegaly

Thalassemia major:
Severe HSM LAD Growth

pallor / Jaundice (muddy face)

retardation Mongoloid face

Laboratory Investigations

Peripheral blood exam:

Microcytic hypochromic anemia S. iron and S. Ferritin

- Reticulocytic ct - B1

Hb electrophoresis:

Hgb Barts; Hgb H HbF; HbA2 Erythroid hyperplasia Resistant X-Ray skull: wide diploic space and Hair on end appearance Long bones: widen medullary cavities; Trabeculations

B.M exam:

Alkaline denaturation test: Radiological Investigations: (Beta Thal)

Differential Diagnosis
Other microcytic hypochromic anemias (ATIS) Other hemolytic anemias: Facial appearance; Hb electrophoresis

Course and Treatment Thalassemia

Time of presentation

Related to degree of severity Usually in first few years of life

Course and Treatment Thalassemia

Untreated severe T:
--/--: Prenatal or perinatal death --/- & --/cs: Normal life span w/ chronic hemolytic anemia

Untreated T:
Major: Death in first or second decade of life Intermedia: Usually normal life span Minor/Minima: Normal life span

Treatment

Blood transfusion: when

Hb 6 gm% Keep Hb 10 (hypertransfusion) Keep Hb 12 (supertransfusion)

Iron chelating agent (Desferroxamine) Folic acid Antibiotics for Intercurrent infections Spleenectomy

Hypersplenism Pressure manifestations

BMT

Complications:
Heart Failure Liver Failure Intercurrent Infections

Thalassemia

N to inc RPI Normal RDW PBS: Target cells Mentzer index <13 MI= MCV / RBC Youdens index: RDW & Mentzer I Sensitivity = 82% Specificity = 80% Confirm w/ Hgb elect

Alpha Thalassemia

Alpha Thalassemia

Each RBC precursor has 2 alpha globin genes on each chr 16, a total of 4 alpha globin genes Types of alpha thalassemia result from deletion of 1 or more of these genes

AT 1 (Hetero-) SEA AT Trait Gene deletions

AT 2 (Hetero-) African/ Medit Silent Carrier

AT 2 (Homo-) African/ Medit AT Trait

Clinical (s/s)

Minimal / no anemia
Microcytosis w/ dec MCV 4 to 10% in NB

Silent / no anemia No RBC abnormality in adults

1 to 3% in NB

Minimal / no anemia
Microtytosis w/ dec MCV 4 to 10% in NB

Hgb Barts

Hgb H

(+) in NB & adult Normal Hgb (+) in NB & adult electrophoresis in adults

Hemoglobin H Disease
. Survive to adulthood 10 to 25% Hgb H in NB & adults Tetramer unstable & precipitate as Heinz bodies or lead to increased poikilocytosis

Hemoglobin H Disease

Marriage: AT 1 minor X AT 2 minor

Unusual, because of marked disparity in geographic & racial distribution, Except for a small number of persons in SEA who have AT 2

W/ Hgb Constant Spring, in SEA population along w/ AT 1 Hgb-CS: Presence of a non-functional alpha globin gene on 1 chr 16

Heterozygous- no detectable abnormality Homozygous- w/ an abnormal gene on each chr 16- mild hemolytic anemia (normocytic)

Hemoglobin H Disease

Marriage: Heterozygous AT 1 + homo- or hetero- zygous for Hgb CS Hgb H dse

Alpha Thalassemia Major

AT 1 (Hetero-) + AT 1 (Hetero-) = AT major (Homozygous) Most common cause for hydrops fetalis in persons of SEA ancestry Anemic in utero; severe hydrops fetalis stillbirth, or death soon after birth from pulmonary hypoplasia or cardiac failure 80% Hgb Bart's & 20% Hgb Portland (sometimes Gower 1)

Alpha Thalassemia Major

Marked anisopoikilocytosis, w/ presence of immature RBC's (Polychromasia, NRBC's & erythroblasts)

Beta thalassemia

Beta T GENERAL FEATURES:

PBS:
HYPOCHROMIC

BM
Erythroid

RBCs TARGET CELLS Basophilic STIPPLING NRBC

Hyperplasia Skeletal Deformities

Extramedullary Hematopoiesis HSM

N- INC. SERUM Fe INC. Hb F & A2

BETA (MEDITERRANEAN/ COOLEYS)

MINOR (HETEROZYGOUS)

MAJOR (HOMOZYGOUS)

ASYMPTOMATIC (DDx vs IDA) DEC. Hb RBC> 5 (MILD ANEMIA) INC. A2 & F INC. S. Fe/ N TIBC MOD SEVERE ANEMIA NO NEED FOR TRANSFUSION

FATAL BEFORE 10 Y/O MASSIVE SPLEENOMEG/ HEMOLYSIS INC. HbF & A2 VARIANTS: BETAo; BETA+; DELTA BETA

INTERMEDIA

Thalassemia

Puffy cheeks & frontal bossing

Pencil shaped RBCs

Target cells

Microcytic hypochromic RBCs

Hair on end appearance of the skull on X-raydue to extramedullary hematopoiesis

Beta T Major: Complications:

Hemolytic A, Ineffective Erythropoiesis Growth Retardation Systemic Iron Overload (Chronic BT) Death (2nd-3rd Decade)

WWW Sites of Interest

Joint Center for Sickle Cell and Thalassemic Disorders: http://wwwrics.bwh.harvard.edu/sickle/ (Overview of sickle cell disease, thalassemia and iron kinetics) The Sickle Cell Information Center, Emory University: http://www.emory.edu:80/PEDS/SICKLE/ (Includes PowerPoint presentations on sickle cell disease)