The Thalassemias

Introduction

•      Heritable, hypochromic anemias-varying degrees of severity

•      Genetic defects result in decreased or absent production of mRNA and globin chain synthesis

•      At least 100 distinct mutations

•      High incidence in Asia, Africa, Mideast, and Mediterrenean countries

Hemoglobin Review

•      Each complex consists of :

–   Four polypeptide chains, non-covalently bound

 

–   Four heme complexes with iron bound

 

–   Four O2 binding sites

 

 

Globin Chains

•      Alpha Globin

–    141 amino acids

–    Coded for on Chromosome 16

–    Found in normal adult hemoglobin, A1 and A2

•      Beta Globin

–    146 amino acids

–    Coded for on Chromosome 11, found in Hgb A1

•      Delta Globin

–    Found in Hemoglobin A2--small amounts in all adults

•      Gamma Globin

–    Found in Fetal Hemoglobin

•      Zeta Globin

–    Found in embryonic hemoglobin

Hemoglobin Types

       Hemoglobin Type

•      Hgb A1—92%---------

•      Hgb A2—2.5%--------

•      Hgb F  — <1%---------

•      Hgb H ------------------

•      Bart’s Hgb--------------

•      Hgb S--------------------

•      Hgb C-------------------

Globin Chains

         a2b2

         a2d2

         a2g2

         b4

         g4

         a2b26 ^gluàval

         a2b26 ^gluàlys

Genetics

•      Alpha globins are coded on chromosome 16

–    Two genes on each chromosome

–    Four genes in each diploid cell

–    Gene deletions result in Alpha-Thalassemias

•      Also on chromosome 16 are Zeta globin genes—Gower’s hemoglobin (embryonic)

•      Beta globins are coded on chromosome 11

–    One gene on each chromosome

–    Two genes in each diploid cell

–    Point mutations result in Beta-Thalassemias

•      Also on chromosome 11 are Delta (Hgb A2) and Gamma (Hgb F) and Epsilon (Embryonic)

 

 

Alpha Thalassemias

•      Result from gene deletions

•      One deletion—Silent carrier; no clinical significance

•      Two deletions—a Thal trait;  mild hypochromic microcytic anemia

•      Three deletions—Hgb H; variable severity, but less severe than Beta Thal Major

•      Four deletions—Bart’s Hgb; Hydrops Fetalis;  In Utero or early neonatal death

Alpha Thalassemias

•      Usually no treatment indicated

•      4 deletions incompatible with life

•      3 or fewer deletions have only mild anemia

Beta Thalassemias

•      Result from Point Mutations on genes

•      Severity depends on where the hit(s) lie

–  b⁰-no b-globin synthesis;

–  b⁺ reduced synthesis

•      Disease results in an overproduction of a-globin chains, which precipitate in the cells and cause splenic sequestration of RBCs

•      Erythropoiesis increases, sometimes becomes extramedullary

b-Thal--Clinical

•   b-Thalassemia Minor

–   Minor point mutation

–   Minimal anemia; no treatment indicated

•   b-Thalassemia Intermedia

–   Homozygous minor point mutation or more severe heterozygote

–   Can be a spectrum; most often do not require chronic transfusions

•   b-Thalassemia Major-Cooley’s Anemia

–   Severe gene mutations

–   Need careful observation and intensive treatment

Beta Thalassemia Major

•      Reduced or nonexistent production of b-globin

–    Poor oxygen-carrying capacity of RBCs

•    Failure to thrive, poor brain development

–    Increased alpha globin production and precipitation

•    RBC precursors are destroyed within the marrow

•      Increased splenic destruction of dysfunctional RBCs

–    Anemia, jaundice, splenomegaly

•      Hyperplastic Bone Marrow

–    Ineffective erythropoiesis—RBC precursors destroyed

•    Poor bone growth, frontal bossing, bone pain

–    Increase in extramedullary erythropoiesis

•      Iron overload—increased absorption and transfusions

–    Endocrine disorders, Cardiomyopathy, Liver failure

b-Thalassemia Major—Lab findings

 

•      Hypochromic, microcytic anemia

–   Target Cells, nucleated RBCs, anisocytosis

•      Reticulocytosis

•       Hemoglobin electrophoresis shows

–   Increased Hgb A2—delta globin production

–   Increased Hgb F—gamma globin production

•      Hyperbilirubinemia

•      LFT abnormalities (late finding)

•      TFT abnormalities, hyperglycemia (late endocrine findings)

b-Thalassemia Major--Treatment

•      Chronic Transfusion Therapy

–    Maximizes growth and development

–    Suppresses the patient’s own ineffective erythropoiesis and excessive dietary iron absorption

–    PRBC transfusions often monthly to maintain Hgb 10-12

•      Chelation Therapy

–    Binds free iron and reduces hemosiderin deposits

–    8-hour subcutaneous infusion of deferoxamine, 5 nights/week

–    Start after 1year of chronic transfusions or ferritin>1000 ng/dl

•      Splenectomy--indications

–    Trasfusion requirements increase 50% in 6mo

–    PRBCs per year >250cc/kg

–    Severe leukopenia or thrombocytopenia

b-Thalassemia Major Complications and Emergencies

•      Sepsis—Encapsulated organisms

–   Strep Pneumo

•      Cardiomyopathy—presentation in CHF

–   Use diuretics, digoxin, and deferoxamine

•      Endocrinopathies—presentation in DKA

–   Take care during hydration so as not to precipitate CHF from fluid overload

Anticipatory Guidance and Follow Up

•      Immunizations—Hepatitis B, Pneumovax

•      Follow for signs of diabetes, hypothyroid, gonadotropin deficiency

•      Follow for signs of cardiomyopathy or CHF

•      Follow for signs of hepatic dysfunction

•      Osteoporosis prevention

–   Diet, exercise

–   Hormone supplementation

–   Osteoclast-inhibiting medications

•      Follow ferritin levels

On The Horizon

•      Oral Chelation Agents

•      Pharmacologically upregulating gamma globin synthesis, increasing Hgb F

–   Carries O2 better than Hgb A2

–   Will help bind a globins and decrease precipitate

•      Bone Marrow transplant

•      Gene Therapy

–   Inserting healthy b genes into stem cells and transplanting