Sickle Cell Disease

The only widely used pharmacologic therapy for sickle cell disease is hydroxyurea.^12,48–50 A significant portion of the benefit of hydroxyurea stems from its induction of HbF.⁵¹ HbF does not sickle, and it interrupts the polymerization of HbS in the cell, if present in high enough concentrations.⁵⁰ The level of HbF needed to achieve clinical improvement is not known, but in vitro assays suggest 20% HbF is needed to prevent sickling.^52,53 However, endogenous and hydroxyurea-induced HbF is not distributed evenly through the red cells, so sickling is possible regardless of the level of HbF induced.^54,55 Hydroxyurea likely has other disease-modifying effects as well, including reduction of white blood cell count and reticulocyte count and reduction of red cell adhesion to the endothelium.^56–58 Clinical criteria for initiation of hydroxyurea in adult sickle cell disease patients are shown in Table 4.²⁰ Hydroxyurea is given daily and is dosed to maximum tolerated dose for the individual by following the absolute neutrophil count (ANC). The goal ANC is between 2000 and 4000/µL. At times, absolute reticulocyte count (ARC) can be dose-limiting; goal ARC is greater than 70,000/µL.⁵⁹ Platelet counts may be reduced as well, especially in HbSC patients.^60,61

The only curative therapy for sickle cell disease is hematopoietic stem cell transplant.⁶² Transplant use is limited by availability of matched sibling donors,⁶² and even at experienced centers transplant carries a small risk for mortality, graft rejection, and graft-versus-host disease. Furthermore, consensus on disease complications for which transplant is recommended is also lacking.^63–65 Clinical trials of gene therapy for sickle cell disease and thalassemia are ongoing.⁶⁶

COMPLICATIONS AND DISEASE-SPECIFIC THERAPIES

CASE PRESENTATION

A 26-year-old African-American man who works as a school bus driver presents to an academic center’s emergency department complaining of pain in his left leg, similar to prior pain events. He is described as having sickle cell trait, although no hemoglobin profile is available in his chart. He describes the pain as dull and aching, 10/10 in intensity. A complete blood count (CBC) is obtained; it reveals a hemoglobin of 14.5 g/dL, white blood cell (WBC) count of 5600/µL, and platelet count of 344,000/µL. His CBC is also notable for a mean corpuscular volume (MCV) of 72 fL, a mean corpuscular hemoglobin concentration (MCHC) of 37 g/dL, and a red blood cell distribution width (RDW) of 12. Slide review of a peripheral blood smear shows 2+ target cells (Figure).

The patient is given 6 mg of morphine, which provides some relief of his pain, and is discharged with a prescription for hydrocodone bitartrate/acetaminophen 5/325 mg. The diagnosis given is musculoskeletal pain, and he is instructed to follow-up with a primary care physician. His past medical history is significant for 4 or 5 visits to the emergency department per year in the past 4 years. Prior to 4 years ago, he rarely required medical attention.

• What laboratory and clinical features might lead you to question the diagnosis of sickle cell trait in this patient?

The patient’s hemoglobin is within normal range, which is consistent with sickle cell trait; however, he is microcytic, with a normal RDW. It is possible to be mildly microcytic in the early stages of iron deficiency, prior to the development of anemia, but the RDW would typically be elevated, demonstrating the presence of newer, smaller cells produced under conditions of iron deficiency.⁶⁷ It is also possible that his microcytosis with a normal RDW could represent sickle cell trait with co-inheritance of β-thalassemia. Up to 30% of African Americans have β-thalassemia,² and 1 in 10 have sickle cell trait.⁶⁸ However, a high MCHC, indicating the presence of dense cells, and target cells noted on slide review are most consistent with HbSC.⁹ HbSC patients, especially males, can have hemoglobin levels in the normal range.⁴ The biggest inconsistency with the diagnosis of sickle cell trait is his history of frequent pain events. Individuals with sickle cell trait rarely present with pain crises, except under extreme conditions of dehydration or high altitude.⁶⁸ Sickle cell trait is generally regarded as a benign condition, although a study of U.S. military recruits found a 30-fold higher risk of sudden death during basic training in persons with sickle cell trait.⁶⁹ Additional sickle cell trait–related complications include hematuria, risk of splenic sequestration or infarct under extreme conditions and high altitude, and a rare and usually fatal renal malignancy, renal medullary carcinoma, which is vanishingly rare in individuals without sickle cell trait.^70,71 Although the patient reported having sickle cell trait, this diagnosis should have been verified with a hemoglobin panel, given his atypical presentation.²⁰