Thalassemias are a group of hereditary hemoglobin disorders characterized by mutations on the α- or β-globin chains (resulting in alpha or beta thalassemia). Thalassemias can be further classified according to the specific genotype: the α-chain is coded by four alleles, resulting in four possible variants depending on the number of alleles affected, while the β-chain is coded by two alleles, resulting in two possible variants. The number of alleles affected is directly related to the severity of the disease (minor/intermedia/major). Thalassemia mutations are generally more frequent in areas where malaria is endemic; alpha thalassemias occur most commonly in individuals of Asian or African descent, whereas beta thalassemias are predominant in individuals of Mediterranean descent. The key feature in all forms of thalassemia is microcytic hypochromic anemia (which may be very mild in minor forms), but more severe forms may also manifest with hemolysis, splenomegaly, delay in growth and development, and skeletal deformities. The diagnostic workup for suspected thalassemia includes a blood smear, hemoglobin electrophoresis, high-performance liquid chromatography (HPLC), and, possibly, genetic testing. Minor forms of thalassemia usually require no treatment, while patients with thalassemia intermedia/major typically require regular blood transfusions and management of disease and treatment-related complications (e.g., chelating agent for transfusion-mediated iron overload).
|Overview of thalassemia|
|Type||Mutated gene||Clinical features|
|Alpha thalassemia||Silent carrier|| || |
|Alpha-thalassemia trait|| || |
|Hemoglobin H disease|| |
|Hemoglobin Bart's disease|| |
|Beta thalassemia||Beta-thalassemia minor|| || |
|Beta-thalassemia intermedia|| |
|Beta-thalassemia major|| |
|Sickle cell beta thalassemia|| |
- Beta thalassemia: most commonly seen in people of Mediterranean descent
- Alpha thalassemia: most commonly seen in people of Asian and African descent
- Thalassemia provides partial resistance against malaria.
Alpha thalassemia is common in Asia and Africa.
Epidemiological data refers to the US, unless otherwise specified.
- Cause: gene mutations
- Inheritance pattern: autosomal recessive
In a normal cell, the α-globin chains are coded by a total of four alleles. Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.
- Silent carrier (minima form): one defective allele (-α/αα)
- Alpha-thalassemia trait (minor form)
- Hemoglobin H disease (intermedia form): three defective alleles (--/-α) → results in excessive production of pathologically altered HbH
- Hemoglobin Bart's disease (major form): four defective alleles (--/-‑) → results in excessive production of pathologically altered Hb Bart (consists of four γ-chains ; γ-tetramers)
Beta thalassemia 
- Beta-thalassemia minor (trait): one defective allele
- Beta-thalassemia major (Cooley anemia): two defective alleles
- Sickle cell beta thalassemia: a combination of one defective β-globin allele and one defective HbS allele
- Hemoglobin E/beta thalassemia: a combination of one allele with a hemoglobin E (HbE) variant and one defective β-globin allele. Produces a highly heterogeneous clinical spectrum, and in severe cases patients present with features of beta-thalassemia major. 
- Hemoglobin E disease: a condition characterized by homozygosity to the HbE variant. Patients can present with mild features resembling beta-thalassemia minor (i.e., mild anemia).
Anemia results from a combination of inefficient erythropoiesis and increased hemolysis. The degree to which both mechanisms contribute to the severity of the disease depends on a patient's exact genotype. 
Inefficient erythropoiesis → anemia
- Beta-thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2.
- Alpha-thalassemia intermedia (HbH disease) and alpha-thalassemia major (Bart's disease): faulty α-globin chain synthesis → ↓ → impaired pairing of α-chains with β-chains and γ-chains→ ↑ free β-, γ-chains → ↑ HbH, ↑ Hb-Bart's
- In minor and minima forms, production of the affected chain is reduced, but enough is produced to prevent severe anemia.
- Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis
- Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities
- Minor variant
- Severe that often requires transfusions → secondary iron overload due to hemolysis, transfusion, or both → secondary 
- Growth retardation
- Skeletal deformities (high forehead, prominent zygomatic bones, and maxilla)
- Transient aplastic crisis (secondary to infection with parvovirus B19) 
- Sickle cell beta thalassemia
- Silent carrier: typically no anemia
- Alpha-thalassemia trait: : no or mild anemia
- Hemoglobin H disease
- Hb-Bart's hydrops fetalis syndrome (most severe variant of alpha thalassemia)
Pretest probability 
The presentation of thalassemia is highly variable, ranging from incidental findings to life-threatening forms. Thalassemia is more like to be diagnosed in patients with the following:
- Suggestive clinical features
- Family history of thalassemia
- Asian, African, or Mediterranean ancestry
- Incidental diagnostic findings
Family history plays an important role in diagnosing patients with clinically silent thalassemia. Consider the possibility of minor forms/traits if a family member is diagnosed with a more severe form.
Initial investigations 
- Characteristic finding: microcytic hypochromic anemia (i.e., MCV < 80 fL, MCH < 27 pg/cell) present regardless of Hb level
- Hb levels: variable depending on the subtype
- Other red cell indices
- See also “Diagnostics of anemia” for further evaluation of microcytosis.
- Hemolysis evaluation: nonimmune-mediated hemolytic anemia
- Peripheral blood smear findings include:
CBC parameters can help differentiate thalassemia minor/trait from iron deficiency anemia (IDA), which is frequently associated with a high RDW, low RBC count, and low MCV, typically occurring once Hb is < 10 g/dL. In thalassemia, microcytosis is always present regardless of Hb level, and RDW is normal to increased. Also, RBC count is higher and MCV is lower than in IDA.; Low ferritin suggests iron deficiency anemia and patients should receive iron supplementation. Suspect thalassemia if there is no significant response after three months. 
Confirmatory diagnostic studies 
Detection of hemoglobin variants
- Hb-electrophoresis (qualitative analysis)
- Automated HPLC (qualitative and quantitative analysis)
- Findings (vary depending on the subtype)
|Interpretation of Hb-electrophoresis results for thalassemia |
|Alpha thalassemia||Beta-thalassemia minor/intermedia/major|
|HbH||May be present||Present||Absent|
- Genetic studies: (PCR-based): to determine specific diagnosis and mutations
Bone marrow aspiration (not routinely indicated)
- Usually performed to rule out other hematologic conditions
- Findings in thalassemia are nonspecific (e.g., reactive hyperplasia).
Imaging is not routinely indicated or required for diagnosis. It can be useful in the evaluation of suspected craniofacial abnormalities and extramedullary hematopoiesis.
- Skull x-ray (AP and lateral)
- MRI spine: helpful to evaluate mass effect symptoms due to extramedullary hematopoietic pseudotumors
- All patients
- Thalassemia minor
Thalassemia major and intermedia
- Transfusion therapy (erythrocyte concentrates)
- Surveillance and treatment of complications
- Select patients
Transfusion therapy 
- Transfusion dependency: can fluctuate for individual patients depending on the subtype, severity, and external factors.
- Non-transfusion-dependent patients: only require either occasional or short-term regular blood transfusions for acute needs.
- Transfusion-dependent patients: require lifelong regular transfusions (e.g., every 2–5 weeks).
|Transfusion therapy in thalassemias|
|Non-transfusion-dependent thalassemias (NTDT) ||Transfusion-dependent thalassemias |
|Indications for transfusion|
|Goals of therapy|| || |
Folic acid should be considered in patients with: 
- Thalassemia major or intermedia: regular supplementation
- Thalassemia minor during periods of acute physiological stress (e.g., infections): episodic supplementation
- Fetal hemoglobin induction: hydroxyurea may help induce fetal hemoglobin, reducing symptoms and the need for transfusions
- Limited use: risks may outweigh benefits (see “Asplenia”).
- Indications include:
- Post-operative care: See “Management of asplenic patients.”
- : e.g., , growth delay, signs of organ damage
- General monitoring: serum ferritin
Monitoring for organ damage
- Endocrinopathies: Screen patients for the following conditions and refer to endocrinology as needed.
- Liver cirrhosis and hepatocarcinoma: liver chemistries (every 3 months) and MRI (annually)
- Cardiac siderosis: regular imaging (echocardiogram or MRI) 
Treatment: Chelation therapy is typically recommended when iron accumulates to toxic levels and may be required from a very early age. 
- Deferasirox (first-line)
The objective of chelation therapy is to prevent organ damage resulting from iron overload disease and requires good adherence to treatment, continuous monitoring by specialists, and frequent dosing adjustment.
Other chronic complications
In addition to iron overload disease, patients may develop other long-term complications secondary to the disease or its treatment.
|Common complications in patients with thalassemia |
|Hematologic complications||Hypercoagulable states|
|Hemolytic crisis|| || |
|Extramedullary hematopoietic pseudotumors|| || |
|Chronic leg ulcers|
|Mental health complications|| || |
Hematopoietic stem cell transplant (HSCT)
HSCT can have good outcomes and be considered curative, however, its use is limited due to high mortality and morbidity. Specialist evaluation and (involving patients and/or ) are essential and should weigh each patient's individual risks and benefits. 
- Compatible sibling donor (preferred): most successful alternative; mortality rate of ∼ 5%
- Matched unrelated donor (alternative): can be considered; higher chances of rejection
- Requires the availability of a compatible donor and access to an HSCT specialized center
- Must be performed during early childhood, before iron overload is present (which decreases success) 
- Aggressive pretransplant transfusion requirement → ↑ risk of iron overload disease → ↑
- Posttransplant immunosuppression → ↑ infection risk
Special patient groups
Thalassemia in pregnancy 
- Most patients with thalassemia may suffer from infertility and require assisted reproductive technology to achieve pregnancy.
- Spontaneous fertility may occur in patients who have successfully undergone iron chelation therapy and blood transfusion. 
Pregnancies in patients with thalassemia should be planned, as they are considered high-risk for both the mother and fetus.
- Preconception genetic counseling, close antenatal monitoring and screening, and intrapartum and postpartum management are highly recommended.
- A multidisciplinary team, including a hematologist, cardiologist, endocrinologist, and gynecologist, should be involved in the management of pregnant patients with thalassemia.
Fertility assessment and management
Screening for thalassemia
- Hemoglobinopathy screening should be offered to women with unknown hemoglobinopathy status and normocytic or microcytic anemia.
Partner screening for thalassemia carrier status
- Not a carrier for thalassemia: Follow protocols for spontaneous conception, ovulation induction (e.g., gonadotropins, clomiphene citrate), or in vitro fertilization.
- Carrier of alpha thalassemia: Offer preimplantation genetic testing and in vitro fertilization.
- Partner has thalassemia trait: Advise patients to use donor gametes or a sperm donor.
- If both partners have thalassemia or thalassemia trait: Offer genetic counseling prior to conception. After successful conception, the fetus will undergo thalassemia screening using chorionic villus sampling or amniocentesis.
- If both partners have thalassemia major: Consider alternatives including adoption.
Preconception screening and review: The most important factors to consider during a fertility assessment are cardiac and liver function, and risk of vertical transmission of viral diseases. Diagnostics include:
- Ovarian reserve: anti-Müllerian hormone levels
- CBC (MCH, MCV) and RBC indices
- Hb electrophoresis
- Iron studies
- Cardiac function: echocardiogram, electrocardiogram, T2 star cardiac MRI
- Liver function: liver function tests, liver elastography, liver and gallbladder ultrasound
- Bone density: DEXA scan, vitamin D, calcium levels
- Endocrine function: thyroid function tests, blood glucose levels
- Coagulation studies: PT, INR, protein C, protein S, homocysteine, thrombophilia panel
- Viral infection screening: HBV, HCV, HIV
- Screening for RBC antibodies
- Medication review: folic acid, vitamin D, calcium supplementation, oral iron chelators
- Iron chelation treatment: should be adjusted and closely monitored during pregnancy
- Transfusions: should aim to maintain hemoglobin > 10 g/dL to prevent intrauterine fetal growth restriction
Intrapartum and postpartum management
- Although vaginal delivery is possible, patients usually require cesarean delivery, as those with thalassemia have an increased incidence of cephalopelvic disproportion.
- Breastfeeding should not be discouraged.
- Resume iron chelation therapy, if eligible.
- Continue calcium and vitamin D supplementation.
- Thromboprophylaxis with LMW heparin
- Discuss contraception options (i.e., progesterone-only pill or barrier methods).
- CRISPR-Cas miracle? Report on two successful attempts at treatment : A
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