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Hematology - Hemoglobinopathies - Fast Facts | NEJM Resident 360

Hemoglobinopathies are a group of genetic disorders that affect the structure of hemoglobin within red blood cells, thereby leading to reduced quality or quantity of effective hemoglobin. Sickle cell disease is a common and well-studied hemoglobinopathy that causes red blood cells to sickle in low-oxygen tension. In contrast, the thalassemia syndromes, of which alpha- and beta-thalassemia are the most common, result from decreased production of the globin protein.

Sickle Cell Disease

Sickle cell disease (SCD) is a multisystem condition that can significantly affect a patient’s quality of life. Homozygous hemoglobin S (HbSS), the most common type of sickle cell disease, is caused by a mutation in the beta-globin gene (HBB). 

Signs and Symptoms

Clinical manifestations vary significantly and can include:

• vaso-occlusive complications

  • painful episodes

  • stroke

  • acute chest syndrome

  • priapism

  • liver disease

  • splenic sequestration

  • leg ulcers

  • osteonecrosis

• complications of hemolytic anemia (e.g., cholelithiasis and aplastic anemia related to parvovirus B19 infection)

• infections associated with encapsulated organisms (e.g., Haemophilus influenzae and Streptococcus pneumoniae); osteomyelitis related to organisms such as Staphylococcus aureus or salmonella

Sickle Cell Vaso-occlusive Episodes 

Management of sickle cell vaso-occlusive episodes involves pain control and fluid resuscitation to attain euvolemia. Pain control is the priority.

• Pain control: Treatment depends on the patient’s symptoms and should be achieved within 30 minutes.

  • Avoid cold compress interventions that may precipitate sickling.

  • Treat with acetaminophen.

  • Intravenous opiates may be required in addition to acetaminophen to help with symptoms during a crisis.

  • Provide patient-controlled analgesia.

• Fluid resuscitation: Episodes can be precipitated by a hypovolemic state. Therefore, fluids should be given with the goal of euvolemia. Volume overload can be dangerous in sickle cell patients and should be avoided.

Clinical Complications of SCD

The following table describes common complications of SCD.

Common Clinical Complications of Sickle Cell Disease

(Source: Sickle Cell Disease. N Engl J Med 2017.)

Acute chest syndrome is a cause of mortality among patients with SCD and should be considered when patients present with individual or combinations of the following symptoms: fever, chest pain, wheeze, cough, and hypoxemia. Acute chest syndrome can be caused by infections (e.g., community-acquired pneumonia) or thromboembolism. Pulmonary infiltrates involving one or more lobes may be seen on imaging. In one study, the National Acute Chest Syndrome Study Group evaluated 671 episodes and outcomes of acute chest syndrome in 538 adults and children with SCD and found that treatment with transfusions, fluid resuscitation, and antibiotics led to clinical response. Plasma exchange transfusion may be required depending on the severity of acute chest syndrome.

Management of SCD

Management of SCD should involve:

• oxygen

• pain control

  • acetaminophen, ketorolac (monitor creatinine and should be time-limited), opiates, ketamine

• fluid resuscitation and maintenance to prevent hypovolemia

• antibiotics

• blood transfusion

  • exchange transfusion required in severe cases

Treatment considerations:

• Hydroxyurea has been shown to prolong survival and reduce the incidence of painful crises and rates of hospitalization. In one observational study, hydroxyurea reduced mortality after 9 years of follow-up.

• Voxelotor is an HbS polymerization inhibitor that binds to hemoglobin and stabilizes the oxygenated state. In a phase 3 study (the HOPE trial), voxelotor increased the hemoglobin level and decreased hemolysis, as compared to placebo.

• Crizanlizumab, a monoclonal antibody to P-selectin, was associated with a lower rate of sickle cell–related pain crises than placebo in a phase 2 study (the SUSTAIN study).

• Hematopoietic stem cell transplantation is a potential treatment option, and currently the only curative option.

• Immunization against encapsulated bacteria should be considered in all patients with SCD.

• Patients should take supplements including folic acid, vitamin D, multivitamin without iron, if their diet is not deemed adequate.

Thalassemia

Alpha- and beta-thalassemia are caused by genetic abnormalities related to hemoglobin synthesis. Patients with beta- and alpha-thalassemia minor may have no symptoms or mild anemia. Patients with beta-thalassemia major may require medical support and frequent blood transfusion.

The following table summarizes the genotypes, phenotypes, and transfusion requirements in patients with β-thalassemia:

Genotypes, Phenotypes, and Transfusion Requirements in Patients with β-Thalassemia

Additional modifiers of phenotype severity may include environmental factors such as coinfection with malaria or polymorphisms that ameliorate the severity of specific complications.16 β-Thalassemia intermedia may be associated with deletion forms of δβ-thalassemia and hereditary persistence of fetal hemoglobin (HbF) or dominant (inclusion-body) β-thalassemia.16 Clinical manifestations of β-thalassemia intermedia and β-thalassemia major at presentation, in addition to anemia, may include jaundice, growth retardation, splenomegaly, and facial and bone deformities. HbE denotes hemoglobin E.
(Source: Beta-Thalassemia. N Engl J Med 2021.)

The following figure describes clinical manifestations and treatment-related complications of β-thalassemia:

Pathophysiology and Clinical Findings of β-Thalassemia

The circled numbers and letters link complications with causal risk factors.
(Source: Beta-Thalassemia. N Engl J Med 2021.)

Treatment of beta-thalassemia is described in the following diagram:

Treatment Options for β-Thalassemia

Panel A shows the treatment options for patients with transfusion-dependent β-thalassemia (TDT). T2-weighted (spin-echo) MRI is used to measure liver iron concentration (LIC), whereas T2-weighted (gradient-echo) MRI can be used to measure both LIC and myocardial iron concentration; measurements are reported in milliseconds and can be converted to milligrams of iron per gram of dry weight. Panel B shows the options for patients with non–transfusion-dependent β-thalassemia (NTDT). 
(Source: Beta-Thalassemia. N Engl J Med 2021.)*

Gene editing: An emerging therapeutic strategy for both sickle cell disease and beta-thalassemia is disruption of BCL11a transcription by targeted clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 cleavage of an erythroid-specific intronic enhancer. Disrupting the BCL11a locus results in an increase in the production of fetal globin. The need for existing treatment for beta-thalassemia (red cell transfusion and iron chelation) and sickle cell disease (pain management, transfusion, and hydroxyurea) may be negated by the use of gene editing technology.

See a NEJM Quick Take video describing a recent study of CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia.

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