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Hemolytic transfusion reactions in SCD
can be further complicated by bystander hemolysis or hyperhemolysis, a process that results in the accelerated clearance of both the transfused RBC and the patient’s own RBC20,21 (Figure 1). Such hyperhemolysis can be par- ticularly fatal in patients with SCD for reasons that remain incompletely understood.
Attention to a high incidence of delayed hemolytic transfusion reactions
While DHTR can be life-threatening, unawareness of their frequency and lack of severity of these transfusion reactions have likely resulted in too little attention regard- ing their potential impact on overall SCD morbidity and mortality. For years, the overall incidence of DHTR per transfusion in SCD was estimated to be around 1:1000.22-24 making it a relatively uncommon transfusion reaction in this population of patients. However, newer reports sug- gest that these data may be misleading. As mentioned pre- viously, given the similarities between the clinical presen- tation of DHTR and the more common complications of vaso-occlusive crises, DHTR can be easily missed.6,7,25 Unless an alloantibody screen is performed, an amnestic alloantibody response will not be detected and a diagnosis of DHTR may not be entertained. Furthermore, as some reports suggest that as many as 30% of DHTR can be alloantibody-negative,14,26 clinicians must rely on HbA measurements obtained within 48 h of the implicated transfusion and at the time of a presumptive DHTR in order to make a reliable diagnosis of DHTR12,27 (Figure 1). Unfortunately, alloantibody screens and HbA values are not routinely ordered following transfusion or in recently transfused patients admitted for acute pain, raising the possibility that the incidence of DHTR in patients with SCD may be much higher than previously appreciated.27
In an effort to assess the incidence of DHTR more accu- rately, a recent prospective study evaluated adult patients after transfusion using total Hb, HbA and HbS quantifica- tion within 48 h after all transfusions and defined DHTR as a significant decrease in HbA (>50%) and/or in total Hb levels (>30%) within 25 days of a trigger transfusion along with hemoglobinuria, symptoms of a vaso-occlu- sive crisis, and/or worsening symptoms of anemia.27 Using this approach, a DHTR was found to occur follow- ing 4.2% of episodic transfusions,27 over ten times more frequently than previously speculated, making DHTR the single most common adverse event following episodic transfusion in patients with SCD. Nearly 11% of all patients with DHTR died,27 suggesting that these reac- tions are not only more common than previously suggest- ed, but also likely to affect SCD mortality significantly. These results provide one possible explanation for the recent observation that alloimmunized patients with SCD have a much higher mortality rate than non-alloim- munized individuals with SCD.28
Comparison of delayed hemolytic transfusion reactions with transfusion-related acute lung injury
There are resemblances between the underappreciated incidence and impact of DHTR in patients with SCD and the history of other transfusion reactions with fatal out- comes.29 Until relatively recently, TRALI was a rarely rec- ognized complication of primarily platelet and plasma transfusion defined by acute lung injury within 6 h of transfusion in the presence of hypoxia, with radiographic evidence of bilateral infiltrates in the absence of circulato-
ry overload.30 Because patients who are susceptible to TRALI often have significant comorbidities, changes in pulmonary function that accompanied transfusion were historically attributed to other etiologies.31 However, once the impact of TRALI was recognized and regulatory agen- cies heightened hemovigilance efforts, TRALI quickly became identified as the most common cause of transfu- sion-related mortality in the USA and Europe.32 Epidemiological studies found associations between blood products donated from multiparous women and other donor factors that increased the likelihood that a recipient would develop TRALI.32 In particular, anti-HLA and other anti-leukocyte alloantibodies that may bind and activate leukocytes intravascularly became implicat- ed in the pathogenesis of TRALI.33-35 Implementation of manufacturing practices that excluded multiparous females and other donors who appeared to increase the risk of TRALI in transfusion recipients has resulted in a significant reduction in TRALI cases.36,37 Thus, TRALI pro- vides a key example of an underappreciated transfusion complication that can result in significant morbidity and mortality and that, upon additional study, improved diag- nostic criteria and changes in clinical practice, has dramat- ically reduced in incidence over time.31
Strategies to prevent delayed hemolytic transfusion reactions
The most effective way to prevent a DTHR is to avoid unnecessary RBC transfusion. When transfusion avoid- ance is not feasible, provision of the most compatible RBC units is recommended. In an effort to reduce the risk of DHTR, transfusion services keep records of previously identified alloantibodies in order to reduce the risk of re- exposure to a particular alloantigen once an alloantibody has been detected. Using this approach, hospital transfu- sion services provide RBC that are negative for the partic- ular alloantigens against which a patient has previously made alloantibodies. However, when patients seek care in multiple healthcare systems this information is often not available.38,39 In this setting, transfusion services can only rely on transfusion histories at the presenting facility or other facilities if obtainable, which are often either not obtained or incomplete.38,39 As this approach often results in inadequate alloimmunization histories,40 multiple encounters in different healthcare systems place patients with SCD at a significantly high risk of DHTR.38 Furthermore, transfusions are often initiated when patients present with acute complications at centers where providers may not be familiar with SCD manage- ment, including transfusion complications. Implemen- tation of healthcare-wide acute care plans for patients with SCD that include consideration of possible transfu- sion complications may provide the type of guidance needed to increase awareness among all providers within a healthcare system.
Nonetheless, despite effective communication between healthcare systems, alloantibodies may not be detected if antibody evaluations are not routinely completed follow- ing transfusion episodes that are at a higher risk of induc- ing alloantibodies. This reflects the ability of newly formed alloantibodies to fall below the level of detection prior to a subsequent transfusion evaluation, which may occur months to years later.41 Thus, RBC alloantibody evanescence can contribute significantly to the risk of DHTR in the absence of systematic post-transfusion sero-
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