A Newlywed Couple With Questions About Sickle Cell Disease
Ronald N. Rubin, MD—Series Editor
Rubin RN. A newlywed couple with questions about sickle cell disease. Consultant. 2017;57(12):716-717.
A newlywed couple has made an appointment in your office regarding questions about sickle cell disease (SCD). They both are healthy, with no medical issues. However, SCD is present in both of their families—1 cousin each—and previous test results revealed that both of them are heterozygous for hemoglobin S (HbS)—that is, they have sickle cell trait. They realize this finding means that there is a 1 in 4 chance that their future children will have full-blown SCD, and they wish to be informed as best as possible about the condition. They also wish to know about longevity and quality of life issues, the current management schemes available to improve upon both, and what is in development that might become available in the future.
Answer: B is the incorrect statement
The entity in question here is SCD and the genetics and clinical manifestations of the mutant form of hemoglobin, HbS, in contradistinction to normal human hemoglobin A (HbA). SCD represents an amazing demonstration of the power of genes: A single amino acid change occurs in the gene for the β-globin chain (at position 6, valine replaces glutamic acid); from that small biochemical alteration derives protection against malaria in healthy heterozygotes (people with sickle cell trait), coupled with an unfortunately very severe, morbid, and often lethal effect in homozygotes. The malarial protection is so strong that it drives the presence of the mutated gene in the populations of malaria-endemic areas despite near 100% mortality among children with homozygous SCD in lower-income countries.1
However, in higher-income countries such as the United States, slow but steady progress has resulted in great changes in SCD survivorship and quality of life. Several initiatives have been directed toward the most life-threatening and morbidity-causing protean effects of SCD.2 One of the earliest, most effective, and far-reaching maneuvers was to aim at homozygous children’s increased susceptibility to infectious morbidity and death. Homozygous persons virtually always have hyposplenism related to ongoing splenic infarction as a result of SCD polymerization and vaso-occlusion, which predisposes them to sepsis related to encapsulated organisms (eg, pneumococcus), especially in early childhood. Prophylaxis with daily penicillin V until 5 years and strict lifelong adherence to the pneumococcal vaccine schedule have been extremely effective in preventing this cause of early death, such that childhood mortality now approaches that of the general population, and the overall longevity of the SCD population is now above 60 years.1-3 Thus, Answer A is surely an appropriate and absolutely indicated strategy.
Once past childhood, SCD causes myriad effects across all organ systems, with eventual organ failure being the rule. The main pathophysiologic mechanisms are occlusion of major and small vessels due to the defective rheology caused by sickled red blood cells (RBCs), which are rigid and less-deformable than normal RBCs, as well as enhanced membrane adhesiveness of RBCs.4 Stroke is a dreaded central nervous system complication, occurring in as many as 15% of patients with SCD. Well-designed clinical trials have found that strokes can be prevented with aggressive and logistically difficult transfusion regimens.5 However, this approach would expose the entire population with SCD to the difficulties and complications (eg, iron overload, antibody formation) of chronic transfusion. Fortunately, effective screening techniques can help identify patients with SCD at very high risk for stroke. Detecting alterations in blood flow using transcranial Doppler ultrasonography of the major cranial vessels (Answer C), then using transfusion prophylaxis in the high-risk subpopulation of patients with SCD, has been demonstrated to be very effective in preventing the disabling complication of strokes.5
Finally, the use of hydroxyurea, a well-tolerated and nonleukemogenic agent, results in RBCs making more hemoglobin F, which biochemically interferes with HbS, thus preventing tactoid formation and sickling with all of its sequelae.6 Hydroxyurea now has almost 20 years of experience in the clinic.7 Initially, it was shown to decrease morbidity—hospital admissions and painful crises6—but ongoing studies have shown its salutary effects on almost all SCD complications and, indeed, a significant mortality benefit in the entire SCD population.7 Thus, Answer D is correct in that the universal use of hydroxyurea is one of the most effective strategies in current use.
Ongoing pilot studies have recently suggested other strategies that in time may “cure” the SCD phenotype. Hematopoietic stem cell transplantation from haplotype-matched siblings can either ablate or chimerize RBCs in the SCD population to the point of having no clinical disease—a phenotypic cure.8 And even more in the vanguard are gene therapy and gene editing, using viral vector-introduced genetic material, which have been shown to be conceptually possible as a potentially curative treatment for SCD.9
Answer B is not a currently useful strategy. Universal transfusion to a hemoglobin goal above 10 g/dL is overly aggressive and would cause more problems than it fixes. Patients with SCD usually have a baseline hemoglobin level of 7 to 9 g/dL and have adapted to this lower level. Excessively higher hemoglobin levels in these patients can cause symptoms and possibly viscosity problems, as well as the complications of iron overload and RBC antibody formation from the transfusion of so many units. Transfusion in patients with SCD (excluding the subgroup at high risk for stroke) is usually limited to episodic use, such as treating aplastic episodes and in perioperative situations.
The couple was referred to an obstetrics practice with the availability of a medical geneticist and a neonatologist. Subsequently, they had their first child, who was born healthy; sickle cell test results revealed that the child, like both parents, was heterozygous for HbS.
Ronald N. Rubin, MD, is a professor of medicine at the Lewis Katz School of Medicine at Temple University and is chief of clinical hematology in the Department of Medicine at Temple University Hospital in Philadelphia, Pennsylvania.
- Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376(16):1561-1573.
- Gardner K, Douiri A, Drasar E, et al. Survival in adults with sickle cell disease in a high-income setting. Blood. 2016;128(10):1436-1438.
- Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048.
- Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-2031.
- Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results of transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5-11.
- Charache S, Terrin ML, Moore RD, et al; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332(20):1317-1322.
- Wong TE, Brandow AM, Lim W, Lottenberg R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood. 2014;124(26):3850-3857.
- Hsieh MM, Fitzhugh LD, Weitzel RP, et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014;312(1):48-56.
- Ribeil J-A, Hacein-Bey-Abina S, Payen E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376(9):848-855.