Marilyn J. Telen, MD – Division of Hematology and Duke Comprehensive Sickle Cell Center, Duke University
Patients with sickle cell disease (SCD) continue to be transfused at a high rate, compared to the general population. In the USA, approximately 25% of all hospital admissions of SCD patients involve transfusion. Both historical and more recent data also document the relatively high rate of alloimmunization in SCD. Rosse et al. found that 18.6% of patients were alloimmunized in the Cooperative Study of Sickle Cell Disease, which included patients of all ages. In our more recent study of adult patients, we found an alloimmunization rate of 27%, probably reflecting the older average patient age.
Frequency of transfusion, along with differences between prevalent antigen phenotypes among SCD patients as compared to donors, contribute to this rate of alloimmunization. Many but by no means all centers prospectively match red cell transfusions for C, E, and K antigens, while a few provide more extensively phenotypically matched blood. In Africa, prospective matching for S is becoming more common where practicable. However, this practice is both expensive and potentially limiting in some patient care settings. Once alloantibodies appear, they clearly complicate transfusion practice. First, they limit blood availability, especially in community hospitals not equipped to perform extensive antigen typing and crossmatching. Second, appearance of new alloantibodies and re-appearance of previously formed alloantibodies result in significant morbidity and mortality. Awareness of the risk of DHTR and familiarity with means of diagnosing DHTR are critical when a patient is transfused as well as when a patient presents with a vaso-occlusive pain episode days to weeks after transfusion. Moreover, the phenomenon of massive hemolysis in the setting of DHTR in SCD is a potentially life-threatening emergency that does not always respond to transfusion of compatible blood but can be treated with a variety of other modalities.
Autoantibody formation is an unusual but recognized complication of alloimmunization. In our recent study of adult SCD patients, 25% of alloimmunized patients also developed warm autoantibodies. Comparison of baseline hemoglobin levels was significantly lower in the patients with autoantibodies than in patients without autoantibodies, suggesting that such autoantibodies are not benign, although appropriate treatment remains to be defined.
Furthermore, although alloimmunization is not associated with the frequency or severity of vaso-occlusive episodes, a higher percentage of alloimmunized patients have chronic pain, as defined by daily narcotic. Additionally, alloimmunized patients have poorer survival (HR=1.92, p=0.01) and are more likely to have avascular necrosis (p=0.024), end-organ damage (p=0.049) and red cell autoantibodies (p<0.001). These associations remain, even after controlling for the effects of age, gender, and hemoglobin diagnosis.
Alloimmunization against red cell antigens remains an important obstacle to being able to offer patients the best treatments for their disease and may also be a marker of disease severity. There is still much we do not understand about why some patients become alloimmunized, while others do not. And we as yet have only unsatisfactory methods for overcoming alloimmunization when it occurs.