II. Background

  1. Thalassemia is derived from Greek word "thalassa" for sea

III. Epidemiology

  1. Thalassemia accounts for one third of all globin abnormalities
  2. Gender: Males and females affected equally
  3. Prevalence of Thalassemia
    1. Among at risk ethnicities: 5-30%
    2. North and South America: 6 per 100,000 conceptions
    3. World wide
      1. Alpha Thalassemia: 5% worldwide Prevalence
      2. Beta Thalassemia: 1.5% worldwide Prevalence
  4. Ethnicity
    1. Alpha Thalassemia
      1. African descent (2% Incidence)
      2. Asian patients (Incidence common)
      3. Middle Eastern descent
    2. Beta Thalassemia
      1. Southern Italy and Mediterranean islands (0.1% Incidence)
      2. Central Africa
      3. Southeast Asia

IV. Pathophysiology

  1. Thalassemia is a cluster of Autosomal Recessive hematologic disorders affecting Hemoglobin
  2. Globin chain (alpha or beta) abnormalities resulting in Anemia with decreased Hemoglobin A
    1. Unbalanced red cells that are susceptible to Hemolysis
    2. Ineffective Erythropoiesis
  3. Images
    1. hemoglobin.jpg

V. Types: Based on Hemoglobin Defect

VI. Types: Based on Transfusion Dependence

  1. Transfusion-Dependent Thalassemia (TDT)
    1. Beta Thalassemia Major (Cooley's Anemia)
    2. Hemoglobin Constant Spring (Non-Deletional HbH Disease)
    3. Survived Alpha Thalassemia Major (Hemoglobin Bart, Non-Immune Hydrops Fetalis)
  2. Non-Transfusion Dependent Thalassemia (NTDT)
    1. Asymptomatic Thalassemia (silent carrier or trait)
    2. Intermittent transfusions may be required
      1. Alpha Thalassemia Intermedia (Deletional HbH Disease)
      2. Beta Thalassemia Intermedia

VII. Symptoms: Presentations

  1. Typically asymptomatic for carrier and trait states
  2. Moderate to severe Microcytic Anemia
    1. Fatigue
    2. Dyspnea
    3. Light headedness or Near Syncope
    4. Growth Delay in children
  3. Hemolytic Anemia
    1. Hyperbilirubinemia with Jaundice
    2. Cholelithiasis
  4. Chronic Anemia in Children may result in Erythropoietin induced changes
    1. Extramedullary hematopoiesis
      1. Hepatosplenomegaly
    2. Bone Marrow expansion results in bony deformities of facial and extremity long bones
      1. Frontal Bossing
      2. Maxillary Hypertrophy
      3. Malar prominence
      4. Bone masses

VIII. Labs: Red Cell Indices and Iron Sudies

  1. Complete Blood Count
    1. Hemoglobin or Hematocrit consistent with Anemia
    2. Mean Corpuscular Volume (MCV)
      1. Hematocrit >30% and MCV low but >80 fl: Iron Deficiency Anemia more likely
      2. Hematocrit >30% and MCV <75 fl: Thalassemia more likely
        1. However MCV cut-off suggestive of Thalassemia varies by age
        2. MCV <70 fl up to 6 years
        3. MCV <75 fl in age 7-12
        4. MCV <80 fl in adults
    3. Red Cell Distribution Width (RDW)
      1. Microcytosis with Normal RDW
        1. Thalassemia is most likely
      2. Microcytosis with Increased RDW
        1. Sideroblastic Anemia
        2. Iron Deficiency Anemia (typically RDW >15%)
        3. Thalassemia (RDW can be high, esp. in Beta Thalassemia)
    4. Mean Corpuscular Volume to Red Blood Cell Count ratio (applies to evaluation in children)
      1. See Mentzer Index
      2. Ratio <13: Thalassemia
      3. Ratio >13: Iron Deficiency Anemia, Hemoglobinopathy
  2. Normal Iron study indices (no Iron Deficiency Anemia)
    1. Serum Ferritin normal or elevated (often >100 ng/ml)
      1. Serum Ferritin >12 ng/ml favors Thalassemia (outside of inflammatory states)
      2. Serum Ferritin <12 ng/ml favors Iron Deficiency Anemia
    2. Other iron studies typically not needed unless inflammation is present
      1. Total Iron Binding Capacity normal
      2. Serum Iron normal
  3. Variable Reticulocyte Index
    1. May see Reticulocytosis or Reticulocytopenia

IX. Labs: Peripheral Smear

  1. Hypochromic, microcytic red cells
    1. Iron Deficiency Anemia
    2. Severe Alpha Thalassemia
    3. Beta Thalassemia
  2. Poikilocytosis (irregularly shaped red cells)
    1. Typical for Thalassemia (esp. Beta Thalassemia)
    2. May be seen in severe Iron Deficiency Anemia
  3. Hemolytic Anemia signs (Target Cells, Red Blood Cell Inclusion bodies)
    1. Typical for Thalassemia (esp. Beta Thalassemia)

X. Labs: Hemoglobin Electrophoresis (Hgb Electrophoresis)

  1. Hemoglobin Electrophoresis is required for Thalassemia diagnosis
  2. Iron Deficiency
    1. Normal Hemoglobin Electrophoresis
    2. HbA2 may be low
  3. Alpha Thalassemia
    1. Adult carrier or Alpha Thalassemia Trait
      1. HbA Normal at >95%
      2. HbA2 Normal at 2 to 3.5%
      3. HbF Normal at <1%
      4. HbH Absent (normal)
    2. Alpha Thalassemia Intermedia (HbH Disease)
      1. HbA below normal
      2. HbA2 <4%, but typically below normal
      3. HbF Abnormal at 5 to 25%
      4. HbH Abnormal at 0.8 to 40% (key finding)
    3. Newborns
      1. HbH or Hb Bart may be present
  4. Beta Thalassemia
    1. Beta Thalassemia Trait
      1. HbA Normal at >90%
      2. HbA2 Increased at 3.5 to 9%
      3. HbF may be increased to up to 5%
      4. HbH Absent (normal)
    2. Beta Thalassemia Major
      1. HbA decreased or absent
      2. HbA2 increased at >4%
      3. HbF increased to 10 to 50% (may be as high as 100%)

XI. Labs: Other

  1. Genetic Testing
    1. Confirms Thalassemia
    2. Identifies specific mutations (and predicts associated severity)
  2. Genotype and HLA Typing
    1. Obtained in all patients (esp. age <12 years old, see management below)
    2. Used in those being considered for Hematopoietic Stem Cell Transplant or gene therapy

XII. Differential Diagnosis

XIII. Imaging

  1. MRI
    1. Identifies degree of Iron Overload
    2. Obtain T2 weighted Cardiac MRI or R2 weighted Liver MRI

XIV. Evaluation: Thalassemia Screening Indications

  1. Pregnancy and Preconception Counseling
    1. Obtain Complete Blood Count in all pregnant patients (and Hgb Electrophoresis if MCV low)
    2. Also consider Hgb Electrophoresis in high risk ethnicity (see above), Thalassemia in first degree relatives
  2. Prenatal Diagnosis (in fetus of parents with Thalassemia)
    1. Chorionic Villus Sampling (10 to 12 weeks gestation)
    2. Amniocentesis (>15 weeks gestation)
  3. Newborn Screening
    1. Thalassemia is not on the U.S. core universal Newborn Screening panel, but many states screen for Thalassemia

XV. Management: General

  1. See Alpha Thalassemia
  2. See Beta Thalassemia
  3. Thalassemia International Federation uses transfusion dependence more than subtypes to direct management
    1. Transfusion-Dependent Thalassemia (TDT)
    2. Non-Transfusion Dependent Thalassemia (NTDT)

XVI. Management: Blood Transfusion

  1. Transfusion Dependent Indications
    1. Hemoglobin <7 g/dl (70 g/L) OR
    2. Anemia Complications (at least one)
      1. Growth Delay or Delayed Puberty
      2. Anemia related functional limitations (Fatigue impacting school or work, low Exercise tolerance or quality of life)
      3. Erythropoietin-Induced Changes
        1. Extramedullary hematopoiesis (Hepatosplenomegaly)
        2. Bone Marrow expansion (e.g. Frontal Bossing, Maxillary Hypertrophy, Malar prominence)
  2. Target Hemoglobin in Transfusion Dependent Thalassemia
    1. Pretransfusion Hemoglobin 9 to 10.5 g/dl (90 to 105 g/L)
    2. Posttransfusion Hemoglobin up to 11 to 12 g/dl (110 to 120 g/L)
  3. Protocol in Transfusion Dependent Thalassemia
    1. Transfusions may be needed as early as 6 months of age
    2. Transfusion scheduled every 2 to 5 weeks
    3. Risk of Transfusion Reaction, alloimmunization, bloodborne infection, Iron Overload
    4. Iron chelation often used in combination in those over age 2 years, after first 10-12 transfusions (or otherwise indicated)
    5. Folic Acid supplementation is used in Transfusion Dependent Thalassemia
  4. Intermittent transfusion indications in Non-Transfusion Dependent Thalassemia
    1. Symptomatic Anemia
    2. Pregnancy
    3. Preoperative state
    4. Serious infections

XVII. Management: Iron Chelation

  1. Thalassemia increases the risk of Iron Overload (frequent transfusion, Hemolytic Anemia, increased GI iron absorption)
    1. Iron Overload complications (liver, heart) are reduced with early initiation of chelation therapy
  2. Indications (age >2 years old, at least one criteria)
    1. Number of transfusions >10 to 12
    2. High Serum Ferritin
      1. Transfusion-Dependent Thalassemia (TDT): Serum Ferritin > 1000 ng/ml (or mcg/L)
      2. Non-Transfusion Dependent Thalassemia (NTDT): Serum Ferritin >800 ng/ml (or mcg/L)
    3. MRI demonstrating Iron Overload
      1. LiverIron (R2 Weighted MRI) >3 mg/g
      2. Cardiac Iron (T2 Weighted MRI) <20 ms
  3. Iron chelators
    1. Deferoxamine (Desferal) SQ/IV
    2. Deferasirox (Exjade) Orally

XVIII. Management: Other Measures

  1. Hydroxyurea
    1. Stimulates Hemoglobin F synthesis
    2. May reduce transfusion frequency in Beta Thalassemia Intermedia and Beta Thalassemia Major
  2. Luspatercept (Reblozyl)
    1. Activin Receptor Ligand Trap
    2. Increases Erythropoiesis and decreases transfusion frequency in Beta Thalassemia
  3. Hematopoietic Stem Cell Transplant (Bone Marrow Transplantation)
    1. Curative of transfusion dependent Beta Thalassemia when performed in childhood in low risk patients
    2. Preferred patient is <12 years old with HLA matched sibling donor
  4. Gene Therapy (experimental as of 2022)
    1. Consider in patients over age 12 years
    2. Targets increasing normal beta globin synthesis or reactivating Hemoglobin F synthesis

XIX. Complications: Anemia Related

  1. Infants and children
    1. Growth Delay
    2. Delayed Puberty
    3. Erythropoietin-Induced Bone Marrow expansion (e.g. Frontal Bossing, Maxillary Hypertrophy, Malar prominence)
  2. Anemia related functional limitations
    1. Fatigue impacting school or work
    2. Low Exercise tolerance
    3. Decreased quality of life
  3. Hypersplenism
    1. Causes
      1. Splenic hyperfunction to remove defective Red Blood Cells
      2. Erythropoietin-Induced extramedullary hematopoiesis
    2. Splenectomy
      1. Improves baseline Hemoglobin (by 1 to 2 g/dl) and reduces transfusion frequency
      2. Risk of Asplenia (infection, Venous Thromboembolism, Pulmonary Hypertension)
      3. Indications (age >5 years)
        1. Iron Overload refractory to iron chelation
        2. Hypersplenism with Clinically Significant cytopenias
        3. Symptomatic Splenomegaly
  4. Venous Thrombosis (especially after splenectomy)
    1. Most common with Beta Thalassemia Major and Intermedia
    2. Consider Perioperative Anticoagulation
    3. Thromboprophylaxis is recommended in pregnancy
    4. Avoid exacerbating Hypercoagulable state (e.g. avoid oral contarceptives in women)
  5. Osteoporosis and Osteopenia
    1. Seen in up to 50% of Beta Thalassemia Major, even with transfusions and iron chelation
    2. Encourage Osteoporosis Prevention (e.g. Physical Activity, Calcium Supplementation, Vitamin D Supplementation
    3. Consider hormonal therapy, Bisphosphonates and zinc supplementation

XX. Complications: Iron Overload Related (Transfusion Dependent Thalassemia)

  1. Endocrine Disorders (decreased with chelation therapy)
    1. Diabetes Mellitus (Iron Overload related)
    2. Hypogonadotropic Hypogonadism
    3. Hypothyroidism
    4. Hypoparathyroidism
    5. Growth Hormone Deficiency (8 to 14% of Transfusion Dependent Thalassemia)
    6. Amenorrhea (primary or secondary)
  2. Cardiac Disorders (decreased with iron chelation)
    1. Associated with cardiac Iron Overload (seen in 25% of Beta Thalassemia worldwide)
    2. Myocardial fibrosis
    3. Cardiomyopathy
    4. Heart Failure
    5. Pulmonary Hypertension
    6. Cardiac Dysrhythmia
    7. Valvular heart disease
    8. Pericarditis
    9. Myocarditis
  3. Liver Disease (decreased with iron chelation)
    1. Cirrhosis (2 to 7% of Transfusion Dependent Thalassemia)
    2. Hepatocellular Carcinoma (<3.5%)
    3. Hepatitis C risk increases due to frequent transfusion

XXI. Prognosis

  1. Normal Lifespan
    1. Asymptomatic Thalassemia (trait, carrier)
    2. Alpha Thalassemia Intermedia (Deletional HbH Disease)
  2. Possibly Reduced Lifespan
    1. Hemoglobin Constant Spring (Non-Deletional HbH Disease)
      1. Associated with increased transfusions and related complications
  3. Reduced Lifespan
    1. Beta Thalassemia Major
      1. Average lifespan to age 50 years
      2. Improved from prior 17-30 year lifespan with transfusions and prevention of Iron Overload
    2. Beta Thalassemia Minor
      1. Average lifespan to age 57 years
      2. Average lifespan also improved from prior with transfusions and prevention of Iron Overload
  4. Neonatal mortality
    1. Alpha Thalassemia Major (Hemoglobin Bart, Non-Immune Hydrops Fetalis)
      1. Had been uiniformy fatal before the use of intrauterine transfusions
      2. Intrauterine transfusions have allowed for initial survival approacing 100%
      3. Intrauterine Bone Marrow Transplantation is being explored as of 2022

XXII. Prevention

  1. See Thalassemia
  2. Preconception Genetic Counseling for parents with Thalassemia
  3. Chorionic Villus Sampling can diagnose Thalassemia in first trimester
  4. Preimplantation Genetic Testing can predict Thalassemia prior to in vitro fertilization

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