Thalassemia: Types, Diagnosis and Management

• Hemoglobinopathies are genetic disorders affecting hemoglobin.
• Hemoglobin is a tetramer with 2 pairs of globin chains, each attached to a heme group containing an iron atom.
• Hemoglobin's main function is the reversible binding and transport of oxygen.
• Different hemoglobin types exist in red blood cells at varying concentrations during different life stages and conditions.

Fetal Switch

• Three major types of hemoglobin are Hb A (αα/ββ), Hb A2 (αα/δδ), and Hb F (αα/γγ).

Hemoglobinopathies Classification

• Hemoglobinopathies encompasses thalassemias and hemoglobin variants.
• Thalassemias involve decreased synthesis of one or more globin chains.
• Alpha and beta thalassemia are types of thalassemias.
• Hemoglobin variants result in structurally abnormal globin proteins.
• Hb S, Hb C, and Hb E are examples of hemoglobin variants.

Alpha Thalassemia Genetics

• Alpha thalassemia often results from deletions of alpha globin genes (HBA1, HBA2) on chromosome 16p13.3.
• It can also arise from non-deletion pathogenic variants.
• Alpha thalassemia affects hemoglobin types A, A2, and F.
• The phenotype depends on the number of deleted genes.

Alpha Thalassemia Forms

• Silent carriers have one alpha globin gene deleted.
• They typically have a normal complete blood count (CBC) and hemoglobin electrophoresis.
• Alpha thalassemia trait involves two alpha globin genes deleted.
• Mild anemia, microcytic-hypochromic RBCs, and a normal Hb Elect are characteristic of alpha thalassemia trait.
• CIS form: East/Southeast Asia.
• TRANS form: Europe, Middle East, Africa, Southern Asia, and Oceania.
• Hemoglobin H disease involves three alpha globin genes deleted.
• Hemoglobin H is present on hemoglobin electrophoresis.
• Hemoglobin H disease is clinically heterogeneous, causing mild to moderate anemia, and may require transfusions.
• Complications include splenomegaly, growth failure, and bony deformities.
• Hemoglobin H-Constant Spring involves two cis alpha globin genes deleted accompanied by the Constant Spring (CS) termination codon variant (α142 STOP→Gln; TAA→CAA) in the third alpha globin gene.
• Hemoglobin H-Constant Spring has a more severe clinical course than deletional Hemoglobin H disease.
• This condition presents a greater likelihood of requiring transfusions.
• Splenomegaly may necessitate splenectomy in over 50% of cases and can cause growth delay.
• Alpha thalassemia major (Hemoglobin Bart's or Hydrops Fetalis) involves deletion of all four alpha globin genes.
• Alpha thalassemia major results in death in utero.
• Serious maternal complications can occur.
• Survival is possible via intrauterine intervention followed by regular transfusion therapy and chelation to prevent iron accumulation after birth.

Beta Thalassemia Genetics

• Beta thalassemia results from single nucleotide pathogenic variants or, less commonly, deletions of the beta globin gene (HBB) on chromosome 11p15.4.
• Pathogenic variants affect beta chain production.
• βº indicates complete absence of beta globin production.
• B+ indicates decreased formation of beta globin.
• Phenotypes include thalassemia trait ("Minor"), thalassemia major ("Cooley's Anemia"), and thalassemia intermedia.

Beta Thalassemia Trait

• Beta Thalassemia Trait is prevalent in Mediterranean countries and islands, the Middle East, North Africa, Eastern Europe, the Indian Subcontinent, Southeast Asia, Melanesia, and the Pacific Islands.
• It is characterized by heterozygosity for a pathogenic variant (β+ or βº).
• Patients present with mild anemia, no disease, and microcytosis (low MCV).
• Hemoglobin electrophoresis shows mildly elevated Hb A2 (> 3.5%) and possible increased Hb F.

Thalassemia Major

• Thalassemia major ("Transfusion Dependent Thalassemia"): results from β+/β° or β°/β° variants, and is usually diagnosed before age 2.
• Severe anemia (fatal if untreated) and secondary iron overload due to hemochromatosis cause organ damage.
• Management includes chronic transfusions, chelation therapy, and monitoring for complications.
• Without transfusions, patients will be severely anemic and have bone marrow hyperplasia, resulting in classic "thal facies" and frontal bossing.
• Splenomegaly, growth retardation, cardiac failure, and death can occur.
• Hemoglobin levels are maintained above 10 g/l via Hypertransfusion Regimens.
• This suppresses bone marrow (ineffective erythropoiesis) and allows for normal growth.
• Proper transfusion regimens prevent bone marrow hyperplasia, osteopenia, cardiomegaly, hepatomegaly, and splenomegaly.
• Secondary hemochromatosis results from transfusion therapy and ineffective erythropoiesis.
• Patients treated with transfusion therapy alone die in their late teens/early twenties; chelation therapy reduces organ damage and prolongs life expectancy.
• Several chelators are available, although compliance is an issue.

Thalassmia Intermedia

• Thalassemia Intermedia ("Transfusion Independent Thalassemia") results from β+/β+ variants and shows genetic heterogeneity.
• There is lesser clinical severity than thalassemia major.
• Onset typically occurs after 2 years of age, up to age 7.
• Characterized by moderate anemia, splenomegaly, moderate to severe hepatomegaly, bony changes, and delayed puberty.
• Transfusions improve quality of life, but are not usually required for survival.
• May be regularly required due to poor growth/development during childhood, skeletal deformity, and to prevent/manage complications.
• Iron overload occurs due to ineffective erythropoiesis, peripheral RBC breakdown, and increased intestinal iron absorption.
• Chelation therapy may be required since iron loading is less accelerated than in transfusion-dependent thalassemia.

Alternative Treatments

• Alternative treatment options include hematopoietic cell transplantation, fetal hemoglobin stimulation, gene therapy, gene editing, and Reblozyl® (Luspatercept).
• Zynteglo is a one-time gene therapy that addresses Beta-Thalassemia at the genetic level.
• Vertex has announced FDA Approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia.

Hemoglobin S

• Hemoglobin S, the most prevalent hemoglobin variant, occurs due to the replacement of glutamic acid by valine at the sixth position in the beta globin gene.
• Red blood cells containing Hemoglobin S "sickle" upon deoxygenation.
• The allele is most common in Africa, countries around the Caribbean Sea (Puerto Rico, Cuba, Haiti, Jamaica), Mediterranean countries (Italy, Greece, Turkey, Syria), Saudi Arabia, and South India.
• Normal red blood cells are disc-shaped, flexible, and flow easily through small blood vessels, with a lifespan of 120 days.
• Sickle cells are sickle-shaped, rigid, sticky, and often get stuck in small blood vessels, with a lifespan of 20 days or less.

Consequences Of Sickling

• Reduced lifespan of red blood cells.
• Vaso-occlusion.
• Ischemia.
• Infarction.
• Hypercoagulable state

Sickle Cell Trait

• Minimal clinical issues with normal overall life expectancy.
• Episodes of hematuria possible.
• There is a risk of increased number of urinary tract infections.
• Extreme lack of oxygen can cause pain episodes or splenic infarctions in rare instances.

Sickle Cell Anemia

• Sickle cell anemia (Sickle Cell Disease/Hb SS Disease) has an onset in early childhood.
• This results in moderate to severe hemolytic anemia and recurrent pain episodes.
• Patients face increased incidence and severity of certain infections.
• Tissue infarction leading to organ damage and failure.
• Complications include: Neurocognitive Dysfunction, Retinopathy, Pulmonary Hypertension, Gallstones, Priapism, Skin Ulcers

Sickle Cell Disease - Management

• Management includes accurate, early diagnosis, education/prompt recognition of complications, prevention/treatment of infections, and aggressive treatment of acute vaso-occlusive events, chronic pain, and hemolytic anemia.
• It is important to screen for organ damage and consider therapeutic intervention.
• LYFGENIA™ (lovotibeglogene autotemcel) has been approved to treat sickle cell disease in patients ages 12 and older with a history of vaso-occlusive events.
• FDA approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Sickle Cell Disease.
• Living and managing sickle cell disease includes appropriate levels of treatment.

Hemogloblin S-beta thalassemia

• Hemoglobin S Beta Thalassemia: Moderate to severe hemolytic anemia and recurrent pain episodes are characterisitic.
• Splenomegaly is apparent.
• Clinical severity depends on the type of beta thalassemia variant inherited.
• Hemoglobin S-β+ thalassemia tends to be less severe than Hemoglobin S-βº thalassemia
• Distinguishing sickle cell disease from Hemoglobin S-βº thalassemia can be difficult on Hb elect.

Hemoglobin C

• Hemoglobin C results from the substitution of lysine for glutamic acid at the sixth position of the Beta globin gene.
• Hemoglobin C is less soluble than Hb A.
• It crystallizes under conditions of dehydration and increased hemoglobin concentrations.
• Hemoglobin C is prevalent in Western Africa, Italy, Greece, Turkey, and the Middle East and is observed among people of Hispanic and Sicilian ancestry.

Hemoglobin C Trait

• Patients are clinically asymptomatic with normal RBC lifespan and slightly low MCV.
• Hemoglobin electrophoresis shows Hb A is approximately 35% HbC.

Hemoglobin C Disease

• Hemoglobin C disease is considered to be one of the most benign hemoglobinopathies; some cases may not be diagnosed until adulthood.
• Patients may have mild, chronic hemolytic anemia, splenomegaly, and sporadic episodes of joint and abdominal pain.
• Potential complications include pigmented gallstones and jaundice.
• Laboratory findings include microcytosis, mild-to-moderate reduction in RBC lifespan, Hb range of 10-12 g/dl, and 100% Hb C on hemoglobin electrophoresis.

Hemoglobin SC Disease

• Hemoglobin SC Disease is milder than sickle cell disease, but there is mild hemolytic anemia accompanied by occasional infarctive crises and splenomegaly.
• Increased viscosity of the blood causes proliferative retinopathy, painful aseptic necrosis of the femoral head (more than in SS disease), and sometimes, acute chest syndrome.

Hemoglobin C-Beta Thalassemia

• In Hemoglobin C-Beta Thalassemia with Beta+ variant, a patient will present mild anemia.
• Laboratory results show low MCV and will show Hb elect 65-70% Hb C, 20-30 Hb A and increased Hb F.
• In Hemoglobin C-Beta Thalassemia with Beta0 variant, a patient will present moderately severe anemia, splenomegaly, possible bone changes, and a Hb elect showing Hb C, no Hb A and increased Hb F.

Hemoglobin E

• Hemoglobin E is the second most common hemoglobin variant.
• The substitution of lysine for glutamic acid at position 26 of the Beta globin gene causes beta + thalassemia phenotype.
• This causes abnormal processing of pre-mRNA to functional mRNA and results in decreased synthesis of Hb E.
• This variant is prevalent in Southeast Asia (Vietnam, Cambodia, Laos, Thailand, Malaysia, Indonesia), India, and China.

Hemoglovin E Trait

• Patients are Asymptomatic
• Normal hemoglobin level
• Microcytosis present without anemia
• Low MCV (average MCV 72 fl)
• On Hb elect: 30-45% Hb E

Hemoglobin E Disease

• Similar to Hb CC disease
• Mild hemolytic anemia
• Mild splenomegaly
• No significant clinical problems
• Labs:
• Normal or slightly low hemoglobin levels
• Low MCV (mean of 67 fl)
• On Hb elect: No HbA, Increased Hb F (10 - 15 %)

Hemoglobin E Beta Thalassemia

• With a Beta0 variant, treatment is similar to beta thalassemia major.
• Patients have severe anemia
• Labs: will have Microcytosis and On Hb elect: Hb E present with significant increase in Hb F (30 - 60%), No Hb A
• With a Betat variant, patients have Moderate anemia, splenomegaly, and Jaundice.
• Labs include: Microcytosis and On Hb elect: ~40% Hb E, 1-30% Hb A and 30-50% Hb F
• Hemoglobin E Sickle Cell: characterized by mild to moderate hemolytic anemia.
• Clinical expression is variable.
• Some patients have no symptoms, whereas others have typical sickle cell-related complications. Less severe compared to other common forms of sickle cell disease.

Hereditary Persistence of Fetal Hemoglobin

• Characterized by persistent high levels of fetal hemoglobin (HbF) in adults.
• Range: 10-40%.
• HbF's presence significantly delays polymerization & increases HbS solubility under deoxygenated conditions.
• Genetic studies have revealed three loci that control HbF levels in adults.
• HBB, specifically Xmn1-HBG2
• HBS1L-MYB
• BCL11A
• No clinical consequences in healthy individuals.
• HPFH co-inheritance with SCD or beta thalassemia alleviates their clinical severity.
• Reactivation of the gamma-globin genes in adults is therefore of significant interest for the clinical management of beta-type hemoglobinopathies.

Screening Tools

• Complete Blood Count (CBC) is used for initial screening.
• Check red blood cell indices: Hemoglobin (HGB), Hematocrit (HCT), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), and Red blood cell (RBC) count.
• Serum Ferritin is used to rule out iron deficiency.
• Serum Ferritin is the most sensitive measure of iron.
• Serum Ferritin level normal ranges: Males = 15 - 300 ng/ml, Females = 12 - 150 ng/ml.
• Alpha/Beta thalassemia trait = Normal values.
• Hemoglobin Electrophoresis(Quantitative) measures and identifies the different types of hemoglobin present in the blood.
• Normal pattern: HbA: 95-98%; HbA2: 2-3%; HbF: 0.8-2%.
• Beta thalassemia trait will show an increased Hb A2 (> 3.5%).
• It may be normal if iron deficient, but will have Possible Increased Hb F (> 2.0%).

Explore the genetic abnormalities and lab findings associated with Hemoglobin Bart's, Beta Thalassemia Trait, and Beta Thalassemia Major. Learn about long-term management strategies, genetic defects, and the importance of hypertransfusion regimens and chelation therapy in thalassemia treatment.