Hemoglobinopathies

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 of SCD 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.

(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 figure summarizes the genotypes, phenotypes, and transfusion requirements in patients with β-thalassemia:

(Source: Beta-Thalassemia. N Engl J Med 2021.)

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

(Source: Beta-Thalassemia. N Engl J Med 2021.)

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

(Source: Beta-Thalassemia. N Engl J Med 2021.)

Gene therapy: Gene therapies hold promise for treating sickle cell disease and β-thalassemia.

• Lentiviral transduction therapy involves using a modified lentivirus to deliver therapeutic genes into the patient’s cells, potentially correcting the genetic defect causing the disease. The FDA approved betibeglogene autotemcel (beti-cel) uses lentiviral vectors for gene therapy in non-β0/β0, transfusion-dependent β-thalassemia and has been reported to result in transfusion independence in most patients. patients with non-β0/β0, transfusion-dependent β-thalassemia. Lovo-cell (bb1111) is another autologous, lentiviral gene therapy under investigation for treatment of sickle cell disease.

• Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 is a gene-editing technology that allows precise modification of the DNA sequence. In the context of sickle cell disease and β-thalassemia, CRISPR-Cas9 can be used to edit the faulty genes responsible for producing abnormal hemoglobin, thereby correcting the underlying genetic defect.

• Another therapeutic strategy for both sickle cell disease and β-thalassemia is disruption of BCL11a transcription by targeted 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 β-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.