Hematologic Disease: The Hemoglobinopathies

The Hemoglobinopathies

More than 270 million people worldwide are heterozygous carriers of hereditary disorders of hemoglobin, and at least 300,000 affected homozygotes or compound homozygotes are born each year. The hemoglobinopathies include the thalassemias (α-thalassemia, β-thalassemia) and the sickle cell spectrum: sickle cell trait (Hb AS), sickle cell disease (Hb SS), and sickle cell disorders (Hb SC and sickle cell β-thalassemia) (Table 14.1).

Hemoglobin (Hb) consists of four interlocking poly-peptide chains, each of which has an attached heme mol-ecule. The polypeptide chains are called alpha, beta, gamma, delta, epsilon, and zeta. Adult hemoglobins con-sists of two alpha chains and either two beta chains (Hb A), two gamma chains (Hb F), or two delta chains (Hb A₂). The beta chains are the oxygen-carrying subunits of the hemoglobin molecule. Hb F is the primary hemoglobin of the fetus from 12 to 24 weeks of gestation. In the third trimester, production of Hb F decreases as production of beta-chains and Hb A begins.

 α-thalassemia is generally caused by missing copiesof the α-globin gene; however, occasionally point muta-tions can cause functional abnormalities in the protein. Humans normally have 4 copies of the α-globin gene. Those with 3 copies are asymptomatic, those with 2 copies have mild anemia, and those with 1 copy have hemolytic anemia. Individuals in whom the gene is absent have Hb Barts disease, which results in hydrops fetalis and intra-uterine death.

Phenotypic expressions of -thalassemia vary because of the many possible mutations in the β-globin gene. Some mutations cause an absence of the protein, while others result in a defective globin protein. β-thalassemia major occurs in homozygotes and is a severe disease, whereas diagnosis of β-thalassemia minor (heterozygotes) may include asymptomatic to clinically anemic patients.

The sickle cell disorders are autosomal recessive dis-orders caused by point mutations that lead to functional abnormalities in the β-globin chains. Instead of normal Hb A, individuals with this disorder have abnormal Hb S. Hb S is unstable, especially under conditions of low oxy-gen tension. The unstable Hb S causes a structural change resulting in deformity of the normal spheroid shape of the red blood cell into the shape of a “sickle.” These abnor-mally shaped cells lead to increased viscosity, hemolysis, and a further decrease in oxygenation. Sickling that occurs in small blood vessels can cause a vaso-occlusive crisis, in which the blood supply to vital organs is compromised.

Heterozygotic individuals (Hb AS) have sickle celltrait and are asymptomatic. The most severe form of thedisease, which occurs in homozygotic individuals (Hb SS), is called sickle cell anemia. Sickle cell disorders are found not only in patients who have Hb SS, but also in those who have Hb S and one other abnormality of β-globin struc-ture. The most common are Hb SC disease and Hb S/β-thalassemia.

Women of Mediterranean, Southeast Asian, or African descent are at higher risk of being carriers for hemoglobinopathies and should be offered carrier screening. 

If both parents are deemed to be carriers of any hemoglo-binopathy, genetic counseling is recommended. For indi-viduals of non African descent, initial testing should be done by complete blood count (CBC). Because individuals of African de-scent are at high risk for carrying a gene for sickle cell disease, these women should be offered hemoglobin electrophoresis in addition to a CBC. Solubility testing, such as tests for thepresence of Hb S (Sickledex), isoelectronic focusing, and high-performance liquid chromatography (HPLC) are in-adequate for screening and fail to identify important trans-missible hemoglobin gene abnormalities affecting fetal outcome.

Although the course of pregnancy can vary according to the type of hemoglobinopathy, there is also individual variation among patients with the same type of disorder. Besides the genetic implications, patients with the sickle cell trait (Hb AS) have an increased risk of urinary infec-tions but experience no other pregnancy complications. Pregnancies in patients with HbS/β–thalassemia are gen-erally unaffected. Patients who are Hb SS or Hb SC, in contrast, may suffer vaso-occlusive episodes. Infections are also more common due to functional asplenia caused by repetitive end-organ damage to the spleen. Infection should be ruled out before attributing any pain to a vaso-occlusive crisis.

Although prophylactic maternal red cell transfusions for women with hemoglobinopathies have been used in the past, transfusions are, for the most part, reserved for com-plications of hemoglobinopathies such as congestive heart failure, sickle cell disease crises unresponsive to hydration and analgesics, and severely low levels of hemoglobin. Because fetal outcomessuch as preterm labor, intrauterine growth restriction, and low birth weight are more common in women with hemo-globinopathies, except those with sickle cell trait, antenatal assessment of fetal well-being and growth is an important part of managing patients with hemoglobinopathies.