Transfusion management of patients with sickle cell disease: the continuing dilemma
2009; Wiley; Volume: 50; Issue: 1 Linguagem: Inglês
10.1111/j.1537-2995.2009.02527.x
ISSN1537-2995
Autores Tópico(s)Erythrocyte Function and Pathophysiology
ResumoThis issue of TRANSFUSION includes two articles that highlight some of the remaining issues related to transfusion support for patients with sickle cell disease (SCD) in two very dichotomous settings, varying dramatically in terms of their depth of resources. On one extreme, Tournamille and colleagues1 from France report their findings evaluating patients with SCD for partial C status using molecular testing methods. They conclude that this technologically sophisticated testing is needed to optimally prevent alloimmunization. At the other end of the resource spectrum, Natukunda and colleagues2 provide an overview of transfusion management for patients with SCD in Uganda, with specific data on alloimmunization in their patient population. As the reader will find, these articles portray very different approaches to transfusion management of the same disease, in large part because of the differences in resource availability. It is likely that some portion of this journal's readership has available resources that are either at one of these extremes or some place in the middle, spanning the gamut between the extremes that these authors represent. Taken together, these articles emphasize the medical management decisions that must be made to optimally utilize the available resources in the best interest of patient care. One of the most perplexing aspects of caring for patients with SCD is the fact that a single gene mutation can result in a spectrum of disease severity and manifestations. Hemoglobin S, the hallmark of SCD, is due to a single β-globin gene mutation. Patients with SCD may have relatively mild disease with occasional complications requiring hydration, pain medications, episodic transfusion, and uncommon hospitalization. In contrast, the same gene mutation in other patients results in severe disease with life-threatening complications, requiring regular transfusions, numerous hospitalizations, and even surgical interventions. For these severely affected patients, the disease and its often escalating complications become an obstacle for accomplishing desired life goals. Despite advances in therapeutic options and improvement in comprehensive health care with a focus on preventive care, there is no reliable predictor for severity of SCD. If there were a marker to predict which patients were at the highest risk for the most severe complications such as acute chest syndrome, multiorgan failure syndrome, or end-stage renal disease, these particularly high-risk patients could be preferentially counseled to consider progenitor cell transplantation. Without such a marker, it is difficult to consider the risks of transplantation in a patient who has not yet had numerous complications, but the patient who has already had numerous complications may no longer be the optimal transplant candidate. Thus, this variability of disease severity and the lack of a prognostic or predictive indicator contribute to the difficulties of medical management and, consequently, impact transfusion management. Not only does the disease vary in severity, but the need for transfusion and the immune response to transfusion vary as well. Red blood cell (RBC) transfusion (chronic or acute transfusion) is essential for the medical management of the complications of SCD. Because of the risk of alloimmunization and potentially severe hemolytic transfusion reactions, providing compatible blood to meet the needs of patients with SCD is one of the most difficult challenges confronting transfusion services and donor centers. Alloimmunization rates in patients with SCD in the United States have been well documented. In 12 reports reviewed by Garratty,3 the frequency of alloantibodies ranged from 8% to 35% of transfused patients with a mean and median of 25%. The cause of this high incidence of alloimmunization is probably multifactorial, although one contributing factor is clearly the disparity in antigen frequencies in patients and donors.4 The majority of patients with SCD are of African descent, whereas the majority of blood donors in the United States are white. Natukunda and coworkers2 report an alloimmunization rate of only 6.1% in Ugandan patients with SCD, which may reflect a more homogeneous population of patients and donors or the fact that the transfusion volumes and episodes were low, limiting antigen exposure. Similar to the United States, anti-E and anti-C were among the most commonly encountered antibodies in the Uganda study.2 The immune response to transfusion in patients with SCD is unpredictable and poorly understood. Some patients may produce only a single antibody specificity despite exposure to multiple alloantigens in repeated transfusions, while others may produce a spectrum of alloantibody specificities that become increasingly complex with each subsequent transfusion episode. Although the explanation for this variable response to transfusion is still unclear, a recent study in a murine model indicates that inflammation may play a regulatory role in alloimmunization.5 Since SCD is characterized by chronic inflammation,6,7 this finding is particularly intriguing and awaits further elucidation. As one might predict, the high incidence of alloantibodies in patients with SCD is accompanied by a high risk of delayed hemolytic transfusion reactions (DHTRs), and these reactions can be severe with life-threatening or even fatal anemia.3 Although the antibody(-ies) implicated in severe DHTR may be obvious from posttransfusion serologic tests, there are inexplicable cases where no antibody responsible for the reaction can be detected.8 Several possible mechanisms for the profound anemia that may occur in DHTR in SCD have been proposed.8-10 In at least some cases, there is a loss of autologous RBCs in addition to the expected destruction of transfused donor RBCs during DHTRs.8 Bystander hemolysis, the immune destruction of "innocent bystander" (autologous) cells, may be involved in this process. Alternatively, Petz and colleagues9 found that the anemia increases in severity after hemolysis of transfused donor RBCs in DHTRs, because there is suppression of erythropoiesis, as commonly occurs as a result of transfusion or concomitant illness. Recently, Chadebech and coworkers11 have suggested another mechanism where increased phosphatidylserine during DHTR may signal excessive eryptosis (suicidal RBC death) resulting in hemolysis. In addition, alloimmunization and DHTRs may be further complicated with the production of autoantibodies and in some cases the development of posttransfusion autoimmune hemolysis.12,13 Prevention of alloimmunization and DHTRs in SCD has been primarily focused on the provision of donor RBCs that are prophylactically antigen-matched with the recipient's phenotype. A survey of 1182 North American laboratories published in 2005 revealed remarkably diverse practices.14 Surprisingly, the majority (743/1182 or 62.9%) typed patients with SCD only for ABO and D antigens.14 Approximately 28% of laboratories typed patients for C, E, and K antigens.14 Perhaps the most widely practiced transfusion protocol in the United States is the prophylactic antigen matching of donor RBCs with the recipients' phenotype for C, E, and K antigens to prevent alloimmunization to the most commonly encountered alloantibodies.14-16 The work by Tournamille and colleagues1 in this issue underscores one of the pitfalls in this transfusion practice. That is, patients with SCD may be typed as C+ by routine serologic tests, but may actually have a partial C phenotype and, therefore, may be at risk for developing anti-C. We have advocated determining a complete or extensive RBC phenotype (i.e., CcEe, K, Fya, Fyb, Jka, Jkb, S, s) on all patients with SCD at presentation to the transfusion service.17 The reference laboratory can utilize the patient's phenotype as an aid in antibody identification studies. With the advent and availability of molecular testing methods, we now maintain that all patients with SCD would benefit from RBC antigen genotyping.18 Consequently, we have initiated this testing for all of our patients. RBC antigen genotyping can now be applied to circumvent difficulties in serologic testing due to interference caused by the presence of transfused donor RBCs or antibody sensitization of the patient's RBCs.19,20 Genotyping can also provide important information for the resolution of complex antibody problems, such as the presence of the r's type and other blood group antigens (e.g., Jsa/Jsb, Doa/Dob) that are not included in a routine complete phenotype.21 Further, genotyping patients allows assessment of the risk of alloimmunization against antigens in the Duffy system due to regulation of antigen expression determined by the GATA-1 box.22 Although there has been much interest in the role of molecular testing techniques in evaluating the patient with SCD, these techniques also promise to enhance donor identification and management. Platforms for rapid-throughput RBC antigen genotyping have significantly improved the search for blood donors to meet the needs of patients with SCD, particularly highly alloimmunized patients who may require uncommon or rare blood types.23 The question of whether patients without alloantibodies should receive antigen-matched blood to prevent the formation of antibodies or whether those donors should be reserved for alloimmunized patients who can only receive antigen-negative blood continues to be debated. Unfortunately, we cannot yet distinguish immune responders from nonresponders. Although approximately 25% of patients with SCD become alloimmunized, there are approximately 75% of patients who do not become alloimmunized despite heavy transfusion burdens. Consequently, we do not provide prophylactically antigen-matched RBCs for patients who have not developed an antibody.17 We utilize the detection of an initial alloantibody (or autoantibody24) as an indicator of immune responsiveness, signaling a patient who may be at increased risk for developing multiple antibodies with subsequent transfusion episodes.17 When an at-risk patient is identified, we provide RBCs that are negative for the immunizing antigen, as well as extensively antigen matched with the patient's phenotype and/or genotype.17 In summary, many experts have developed all-inclusive management protocols to prevent RBC alloimmunization in a disease that is highly unpredictable. Although these protocols utilize significant resources, the success of these strategies has been difficult to establish. With limited resources, Natukunda and coworkers2 have confirmed that alloimmunization is an issue in Uganda despite a homogeneous population and low transfusion rate. They are striving to decrease alloimmunization through improvements in immunohematologic testing. As shown by Tournamille and colleagues1 very sophisticated techniques can identify a group at risk, but implementation of their protocol is hindered by a lack of donor availability. Although optimal protocols to prevent alloimmunization will continue to be debated, ultimately, the most appropriate transfusion management approach is dependent on the specific resources and needs of each community.
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