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Challenges in preventing and treating hemolytic complications associated with red blood cell transfusion
Transfusion Clinique et Biologique 26 (2019) 130–134
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Original article
Challenges in preventing and treating hemolytic complications associated with red blood cell transfusion Défis dans la prévention et le traitement des complications hémolytiques associées à la transfusion de globules rouges Satheesh Chonat a , Connie M. Arthur b , Patricia E. Zerra b , Cheryl L. Maier b , Ryan P. Jajosky b , Marianne E.M. Yee a , Maureen J. Miller b , Cassandra D. Josephson a,b , John D. Roback b , Ross Fasano a,b,∗ , Sean R. Stowell b,∗ a Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA b Center for Transfusion Medicine and Cellular Therapies, Department of Laboratory Medicine and Pathology, Emory University School of Medicine, 101, Woodruff Circle, 30322 Atlanta, GA, USA
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Article history: Available online 25 March 2019 Keywords: Sickle cell disease Transfusion Allo-immunization Hemolysis Prevention Diagnosis treatment
a b s t r a c t Red blood cell (RBC) transfusion support represents a critical component of sickle cell disease (SCD) management. However, as with any therapeutic intervention, RBC transfusion is not without risk. Repeat exposure to allogeneic RBCs can result in the development of RBC alloantibodies that can make it difficult to find compatible RBCs for future transfusions and can directly increase the risk of developing acute or delayed hemolytic transfusion reactions, which can be further complicated by hyperhemolysis. Several prophylactic and treatment strategies have been employed in an effort to reduce or prevent hemolytic transfusion reactions. However, conflicting data exist regarding the efficacy of many of these approaches. We will explore the challenges associated with predicting, preventing and treating different types of hemolytic transfusion reactions in patients with SCD in addition to describing future strategies that may aid in the management of the complex transfusion requirements of SCD patients. © 2019 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Drépanocytose Transfusion Allo-immunisation Hémolyse Prevention Diagnostic Traitement
Le support transfusionnel est un composant majeur de la prise en charge thérapeutique au cours de la drépanocytose. Ceci étant, comme toute thérapeutique, la transfusion n’est pas sans risque. L’exposition répétée à des globules rouges transfusés peut aboutir à terme à la production d’allo-anticorps érythrocytaires, responsables dans certains cas d’accidents immuno-hémolytiques gravissimes. Des stratégies prophylactiques et thérapeutiques ont été mises en place pour limiter ou prévenir ces accidents, mais des données contradictoires existent concernant ces différentes approches. Dans ce manuscrit nous explorons les challenges associés à la prédiction, la prévention et le traitement de cette complication hémolytique, ainsi que de futures stratégies possibles et la nécessité aussi de disposer de CGR compatibles pour les patients drépanocytaires. ´ ´ es. © 2019 Elsevier Masson SAS. Tous droits reserv
∗ Corresponding authors at: Center for Transfusion Medicine and Cellular Therapies, Department of Laboratory Medicine and Pathology, Emory University School of Medicine, 101, Woodruff Circle, 30322 Atlanta, GA, USA. E-mail addresses: [email protected] (R. Fasano), [email protected] (S.R. Stowell). https://doi.org/10.1016/j.tracli.2019.03.002 1246-7820/© 2019 Elsevier Masson SAS. All rights reserved.
S. Chonat et al. / Transfusion Clinique et Biologique 26 (2019) 130–134
1. Introduction Red blood cell transfusion represents one of the most common therapeutic interventions in hospitalized patients. While RBC transfusion can certainly be beneficial [1–3], as with any therapeutic intervention, RBC transfusion is not without risk. RBC transfusion can result in the formation of RBC alloantibodies that can make it difficult to find compatible RBCs for future transfusions and directly increase the risk of transfusion-related complications [4,5]. The ensuing complications that RBC alloimmunization can cause are particularly apparent in patients with chronic anemic states that require frequent RBC transfusions, such as sickle cell disease (SCD), thalassemia and some bone marrow failure syndromes, such as myelodysplasia [4,6–11]. The propensity of SCD patients to develop RBC alloantibodies in part reflects differences in alloantigen expression that often occurs between RBC donors and patients with SCD [12]. RBC matching protocols have been employed to address this issue and therefore reduce alloimmunization rates [12–17]. However, even when these strategies are implemented, high rates of RBC alloimmunization in SCD patients can still occur [18]. In addition, unlike many other anemic conditions requiring RBC transfusion, the indications for transfusion in SCD are often accompanied by significant inflammation. Several studies in SCD patients and animal models suggest that inflammation may indeed increase the probability of alloantibody formation following RBC exposure [19–22]. These considerations, in addition to other genetic and environmental factors [23,24], may be responsible for the increased risk of RBC alloimmunization in patients with SCD. Regardless of the exact cause of the higher RBC alloimmunization prevalence in SCD, patients who develop RBC alloantibodies have a higher overall mortality rate [25]. The higher mortality that alloimmunized SCD patients experience may reflect underlying factors that contribute to both increased mortality and enhanced RBC alloimmunization in addition to potential complications RBC alloimmunization can cause [25,26]. While alloimmunization against common alloantigens, such as D, C, E, KEL and Duffy, may slightly delay the ability to procure crossmatch compatible RBCs prior to transfusion, the majority of patients who only develop alloantibodies against one or two of these and similar antigens can be safely transfused in a timely manner. However, alloimmunization can compromise optimal transfusion support in patients who develop complex multi-alloantibody profiles and/or form alloantibodies against high incidence alloantigens [26]. In these situations, the inherent infrequency of potential donors can make it difficult to quickly secure compatible RBCs [27,28]. This can especially be challenging when patients present with an acute need for RBC transfusion. In countries where healthcare systems do not readily communicate transfusion histories, these challenges can quickly become magnified as the information and time required to identify rare donors may preclude the identification of compatible RBCs in time for a needed transfusion. Similarly, while recent advances in molecular approaches for genotype matching of SCD patients are promising [16,29–33], transfusions can still be delayed when no prior genotype or phenotype is available for a given patient to facilitate alloantibody identification, especially when a warm autoantibody may be present [34]. 1.1. Hemolytic complications of RBC transfusion In addition to producing challenges in the identification of compatible RBCs for transfusion, alloimmunization can increase the likelihood of acute hemolytic transfusion reactions (AHTRs) and delayed hemolytic transfusion reactions (DHTRs). While AHTRs are uncommon secondary to thorough alloantibody identification and RBC matching prior to transfusion, DTHRs occur
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much more frequently with equally challenging outcomes [35,36]. Recent studies suggest that DHTRs can occur in up to 4% of all transfusion episodes in SCD patient [37–39]. While centralized alloimmunization repositories hold promise in reducing DHTR rates [40], incomplete alloimmunization histories, which are more likely to occur when patients are treated in multiple healthcare systems, likely increase the incidence of DHTRs [38,39]. However, even if alloantibody histories are accurately obtained, as many as 30% of DHTRs can occur in the absence of any detectable alloantibody [41]. Whether these “alloantibody-negative” DHTRs reflect a true absence of alloantibody formation, inadequate sensitivity of clinical assays, or actual gaps in alloantibody detection remains to be determined. Regardless, the inability to detect alloantibodies using routine clinical approaches can make it difficult to accurately predict and prevent DHTRs following an otherwise compatible RBC transfusion. Recent algorithms, which include monitoring HbA values immediately following transfusion and obtaining patients’ histories of such reactions, have been developed in an attempt to address this very issue [41]. In addition to experiencing AHTR or DHTR, patients with SCD are also prone to developing hyperhemolytic reactions, otherwise known as hyperhemolysis syndrome (HHS), following RBC transfusion. HHS is typically characterized by the accelerated clearance of the patient’s own RBCs in addition to the transfused RBCs [42–48]. As the strongest indicators for transfusion in SCD are themselves associated with significant complications (e.g. stroke, acute chest syndrome, multi-organ failure, etc.), the rapid drop in Hb that SCD patients can experience during HHS can significantly exacerbate underlying SCD complications [26,49,50]. As a result, HHS can be particularly life-threatening. Similar to DHTRs, HHS can occur in patients with no detectable alloantibody, making it difficult to predict which patients are at risk for developing this complication. 1.2. Strategies used to prevent and treat HTRs Given the potential consequences of AHTR, DHTRs and HHS, providers can face challenging situations when seeking to balance the potential benefits of RBC transfusion with the possible implications of unpredictable transfusion complications [51,52]. This can be particularly apparent for SCD patients who present with an incomplete transfusion history, yet have an acute need for transfusion. As previously mentioned, a complex alloantibody profile requiring rare RBC donors often precludes the rapid identification of compatible blood [27,28]. In these situations, the patient’s response to supportive care is often carefully monitored while ongoing attempts to identify compatible RBCs continue [26]. Occasionally, if anemia and its associated consequences are deemed to be life-threatening, incompatible RBC transfusion may be considered [26]. However, effective strategies designed to prevent or reduce the probability of an AHTR in this setting remain enigmatic. Similarly, when SCD patients are transfused compatible RBCs, yet develop DHTRs with or without accompanying HHS, determining what treatment options may be most beneficial can likewise be challenging. When life threatening anemia necessitates RBC transfusion support and only incompatible RBC are available (and the clinical significance of a patient’s alloantibodies remain unknown), or when the patient developed DHTRs with or without HHS, several strategies have been employed in an effort to reduce, prevent, or treat a hemolytic transfusion reaction. Most, if not all, of these strategies are aimed at preventing antibody-mediated removal of the transfused RBCs [51–53] (Fig. 1). For example, intravenous (IV) steroids have been given with the intention of reducing phagocytic processes that may facilitate the removal of antibody opsonized RBCs [54,55]. Steroids may also reduce the inflammatory response that is thought to occur during accelerated hemolysis [56]. In
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Fig. 1. Strategies previously used to target antibody effector function in an effort to prevent or reduce hemolytic transfusion reactions. A variety of strategies, ranging from steroids, IVIg, bortezomib and eculizumab have been used to in an effort to prevent a hemolytic transfusion in patients with life-threatening anemia and no compatible RBCs are available or in patients who develop delayed-type transfusion reactions following RBC transfusion. While the proposed mechanisms of action are depicted in the figure, very little data demonstrates that any or all of these approaches will effectively prevent or treat a hemolytic transfusion reaction. Additional approaches designed to prevent antibody formation or reduce antibody production once formed are not included.
addition to IV steroids, IVIg is often provided in an attempt to likewise reduce antibody-mediated RBC removal. Although many different mechanisms have been postulated whereby IVIg may favorably modulate antibody-mediated disease [57,58], how IVIg prevents or at least reduces RBC clearance following an incompatible RBC transfusion remains unknown. More recently, use of proteasome inhibitors, plasmapheresis, and eculizumab have been considered. While proteasome inhibitors, such as bortezomib, are often used to target plasma cells and therefore may result in a long-term decline in alloantibody production [59–61], they fail to reduce the levels of existing antibodies whose long half-lives can complicate acutely needed transfusions. However, bortezomib may impact other aspects of immune function, such as the phagocytic activity of macrophages, that may in turn reduce their ability to clear RBCs [62,63]. While repetitive plasmapheresis can reduce the levels of existing antibodies, this procedure is typically not an option because it can be difficult to safely perform in severely anemic patients. Eculizumab prevents complement activation and would therefore be predicted to be most useful in patients with existing alloantibodies presumed to mediate RBC destruction through a complement-dependent process [64,65]. Despite attempts to use all or various iterations of these strategies to prevent antibody-mediated RBC removal, it is difficult to gauge the effectiveness of these strategies [38,39,66–68]. A variety of case reports and case series provide some data suggesting that steroids, IVIg, bortezomib, eculizumab, or some combination of these or other strategies all together, may be effective at preventing or treating antibody-mediated removal of RBCs [38,39,51,52,66–68]. However, as noted previously, patients have received incompatible RBC transfusions without evidence of a HTR while many cases of DHTR resolve spontaneously with only supportive care [37–39,52]. As a result, it can be difficult to know if a given prevention or treatment strategy favorably influences outcomes in these settings or whether a positive outcome publication bias has prevented a clear understanding of the actual efficacy of these approaches. There are indeed reports that indicate that use of some of these strategies fail to universally prevent the devastating consequences of alloantibody-mediated RBC hemolysis [26]. Challenges associated with accurately predicting which prophylactic or treatment options may be effective at preventing
or treating antibody-mediated RBC removal may in part reflect the diversity of RBC alloantigen targets. Unlike transplantation, where human leukocyte antigen (HLA) antigens are extremely polymorphic, but structurally very similar, RBC alloantigens can differ in structure, distribution, density and overall engagement by potential alloantibodies [69,70]. Differences in alloantigen structure, variations in the titer, subclass distribution, alloantibody glycosylation and, the status and overall activity of a patient’s reticuloendothelial system, likely converge to dictate whether a given alloantibody will result in RBC clearance [70,71]. Alloantibody functional tests, such as the monocyte monolayer test, can aid in predicting the clinical significance of a particular alloantibody [72,73]. However, the relatively slow turnaround time can preclude the use of this option in the acute setting. Furthermore, this test does not provide information regarding all the mechanisms that may be involved in RBC clearance in a particular clinical setting and therefore the most appropriate strategy to prevent or treat a HTR. As a consequence of distinct alloantibody effector mechanisms and recipient variables, it is hard to envision a prophylactic or treatment approach that will uniformly apply to all antibody-mediated HTRs when antibody effector function is the therapeutic target. Instead, an understanding of the distinct pathways alloantibodies can employ to facilitate RBC clearance will likely be needed if effective approaches designed to routinely prevent or treat alloantibody-mediated HTRs are to be realized. As intentional transfusion of incompatible RBCs in patients for experimental purposes is considered unethical, directly examining the mechanisms of alloantibody-induced RBC removal and the efficacy of different prevention and treatment strategies is challenging. Despite the potentially devastating consequences of HTRs clinically, the limited frequency with which these reactions occur coupled with the diversity of alloantigens involved, makes a definitive randomized control trial examining prophylactic options challenging. However, various animal models do provide some insight into the complexities of incompatible RBC transfusion and suggest that several forms of antibody-mediated removal can occur [74–79]. Each of these antibody-mediated clearance mechanisms would be predicted to be differentially susceptible to strategies designed to prevent or treat HTRs. Thus, alloantibody and patient
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specific approaches to preventing antibody-mediated removal of RBCs may be required to produce the most effective outcomes. In contrast to targeting alloantibody-mediated removal, recent studies suggest that at least in the setting of HHS, exuberant activation of the alternative complement pathway may contribute to ongoing hemolysis [49,50]. While several studies indicate that HHS may in part reflect enhanced macrophage activation and erythrophagocytosis [43,46,67], recent studies have demonstrated that free heme can directly activate complement [80]. These data suggest that hemolysis may result in complement activation, which in turn could cause further hemolysis. Such a positive feedback loop of free heme release, complement activation and additional RBC hemolysis is consistent with the severe anemia observed in patients with HHS. Recent results targeting complement appear to corroborate this possibility, with patients experiencing HHS treated with eculizumab displaying a rapid reduction in complement activation that is accompanied by decreased hemolysis and overall clinical improvement [49,50]. 2. Conclusions While HTRs are uncommon following transfusion in the general population, these reactions occur with much higher frequency in patients with SCD with potentially devastating consequences. Although alloantigen matching protocols can reduce alloimmunization, SCD patients who receive extended phenotype matched RBCs can continue to develop RBC alloantibodies [18]. Even if fully matched RBCs could be provided [29], up to 30% of SCD patients can develop DHTRs in the absence of detectable alloantibodies [41], strongly suggesting that extensive alloantigen matching protocols alone will not likely eliminate HTRs in this patient population. While a variety of studies are beginning to elucidate various factors that may regulate RBC alloimmunzation [81–85], additional studies are needed, both at a mechanistic level and clinically, to understand how these alloantibodies may contribute to HTRs in patients with SCD in an effort to more effectively predict, prevent and treat AHTR, DHTR and HHS. Funding This work was supported in part by the Burroughs Wellcome Trust Career Award for Medical Scientists, the National Institutes of Health (NIH) Early Independence grant DP5OD019892, R01HL135575, and P01HL132819 to SS. Disclosure of interest The authors declare that they have no competing interest. References [1] Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5–11. [2] DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 2014;371:699–710. [3] Beverung LM, Strouse JJ, Hulbert ML, et al. Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy. Am J Hematol 2015;90:139–43. [4] Chou ST, Liem RI, Thompson AA. Challenges of alloimmunization in patients with haemoglobinopathies. Br J Haematol 2012;159:394–404. [5] Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood 2012;120:528–37. [6] Hillyer CD, Shaz BH, Winkler AM, Reid M. Integrating molecular technologies for red blood cell typing and compatibility testing into blood centers and transfusion services. Transfus Med Rev 2008;22:117–32. [7] Rosse WF, Gallagher D, Kinney TR, et al. Transfusion and alloimmunization in sickle cell disease. The Cooperative Study of Sickle Cell Disease. Blood 1990;76:1431–7.
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Challenges in preventing and treating hemolytic complications associated with red blood cell transfusion Défis dans la prévention et le traitement des complications hémolytiques associées à la transfusion de globules rouges Satheesh Chonat a , Connie M. Arthur b , Patricia E. Zerra b , Cheryl L. Maier b , Ryan P. Jajosky b , Marianne E.M. Yee a , Maureen J. Miller b , Cassandra D. Josephson a,b , John D. Roback b , Ross Fasano a,b,∗ , Sean R. Stowell b,∗ a Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA b Center for Transfusion Medicine and Cellular Therapies, Department of Laboratory Medicine and Pathology, Emory University School of Medicine, 101, Woodruff Circle, 30322 Atlanta, GA, USA
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Article history: Available online 25 March 2019 Keywords: Sickle cell disease Transfusion Allo-immunization Hemolysis Prevention Diagnosis treatment
a b s t r a c t Red blood cell (RBC) transfusion support represents a critical component of sickle cell disease (SCD) management. However, as with any therapeutic intervention, RBC transfusion is not without risk. Repeat exposure to allogeneic RBCs can result in the development of RBC alloantibodies that can make it difficult to find compatible RBCs for future transfusions and can directly increase the risk of developing acute or delayed hemolytic transfusion reactions, which can be further complicated by hyperhemolysis. Several prophylactic and treatment strategies have been employed in an effort to reduce or prevent hemolytic transfusion reactions. However, conflicting data exist regarding the efficacy of many of these approaches. We will explore the challenges associated with predicting, preventing and treating different types of hemolytic transfusion reactions in patients with SCD in addition to describing future strategies that may aid in the management of the complex transfusion requirements of SCD patients. © 2019 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Drépanocytose Transfusion Allo-immunisation Hémolyse Prevention Diagnostic Traitement
Le support transfusionnel est un composant majeur de la prise en charge thérapeutique au cours de la drépanocytose. Ceci étant, comme toute thérapeutique, la transfusion n’est pas sans risque. L’exposition répétée à des globules rouges transfusés peut aboutir à terme à la production d’allo-anticorps érythrocytaires, responsables dans certains cas d’accidents immuno-hémolytiques gravissimes. Des stratégies prophylactiques et thérapeutiques ont été mises en place pour limiter ou prévenir ces accidents, mais des données contradictoires existent concernant ces différentes approches. Dans ce manuscrit nous explorons les challenges associés à la prédiction, la prévention et le traitement de cette complication hémolytique, ainsi que de futures stratégies possibles et la nécessité aussi de disposer de CGR compatibles pour les patients drépanocytaires. ´ ´ es. © 2019 Elsevier Masson SAS. Tous droits reserv
∗ Corresponding authors at: Center for Transfusion Medicine and Cellular Therapies, Department of Laboratory Medicine and Pathology, Emory University School of Medicine, 101, Woodruff Circle, 30322 Atlanta, GA, USA. E-mail addresses: [email protected] (R. Fasano), [email protected] (S.R. Stowell). https://doi.org/10.1016/j.tracli.2019.03.002 1246-7820/© 2019 Elsevier Masson SAS. All rights reserved.
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1. Introduction Red blood cell transfusion represents one of the most common therapeutic interventions in hospitalized patients. While RBC transfusion can certainly be beneficial [1–3], as with any therapeutic intervention, RBC transfusion is not without risk. RBC transfusion can result in the formation of RBC alloantibodies that can make it difficult to find compatible RBCs for future transfusions and directly increase the risk of transfusion-related complications [4,5]. The ensuing complications that RBC alloimmunization can cause are particularly apparent in patients with chronic anemic states that require frequent RBC transfusions, such as sickle cell disease (SCD), thalassemia and some bone marrow failure syndromes, such as myelodysplasia [4,6–11]. The propensity of SCD patients to develop RBC alloantibodies in part reflects differences in alloantigen expression that often occurs between RBC donors and patients with SCD [12]. RBC matching protocols have been employed to address this issue and therefore reduce alloimmunization rates [12–17]. However, even when these strategies are implemented, high rates of RBC alloimmunization in SCD patients can still occur [18]. In addition, unlike many other anemic conditions requiring RBC transfusion, the indications for transfusion in SCD are often accompanied by significant inflammation. Several studies in SCD patients and animal models suggest that inflammation may indeed increase the probability of alloantibody formation following RBC exposure [19–22]. These considerations, in addition to other genetic and environmental factors [23,24], may be responsible for the increased risk of RBC alloimmunization in patients with SCD. Regardless of the exact cause of the higher RBC alloimmunization prevalence in SCD, patients who develop RBC alloantibodies have a higher overall mortality rate [25]. The higher mortality that alloimmunized SCD patients experience may reflect underlying factors that contribute to both increased mortality and enhanced RBC alloimmunization in addition to potential complications RBC alloimmunization can cause [25,26]. While alloimmunization against common alloantigens, such as D, C, E, KEL and Duffy, may slightly delay the ability to procure crossmatch compatible RBCs prior to transfusion, the majority of patients who only develop alloantibodies against one or two of these and similar antigens can be safely transfused in a timely manner. However, alloimmunization can compromise optimal transfusion support in patients who develop complex multi-alloantibody profiles and/or form alloantibodies against high incidence alloantigens [26]. In these situations, the inherent infrequency of potential donors can make it difficult to quickly secure compatible RBCs [27,28]. This can especially be challenging when patients present with an acute need for RBC transfusion. In countries where healthcare systems do not readily communicate transfusion histories, these challenges can quickly become magnified as the information and time required to identify rare donors may preclude the identification of compatible RBCs in time for a needed transfusion. Similarly, while recent advances in molecular approaches for genotype matching of SCD patients are promising [16,29–33], transfusions can still be delayed when no prior genotype or phenotype is available for a given patient to facilitate alloantibody identification, especially when a warm autoantibody may be present [34]. 1.1. Hemolytic complications of RBC transfusion In addition to producing challenges in the identification of compatible RBCs for transfusion, alloimmunization can increase the likelihood of acute hemolytic transfusion reactions (AHTRs) and delayed hemolytic transfusion reactions (DHTRs). While AHTRs are uncommon secondary to thorough alloantibody identification and RBC matching prior to transfusion, DTHRs occur
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much more frequently with equally challenging outcomes [35,36]. Recent studies suggest that DHTRs can occur in up to 4% of all transfusion episodes in SCD patient [37–39]. While centralized alloimmunization repositories hold promise in reducing DHTR rates [40], incomplete alloimmunization histories, which are more likely to occur when patients are treated in multiple healthcare systems, likely increase the incidence of DHTRs [38,39]. However, even if alloantibody histories are accurately obtained, as many as 30% of DHTRs can occur in the absence of any detectable alloantibody [41]. Whether these “alloantibody-negative” DHTRs reflect a true absence of alloantibody formation, inadequate sensitivity of clinical assays, or actual gaps in alloantibody detection remains to be determined. Regardless, the inability to detect alloantibodies using routine clinical approaches can make it difficult to accurately predict and prevent DHTRs following an otherwise compatible RBC transfusion. Recent algorithms, which include monitoring HbA values immediately following transfusion and obtaining patients’ histories of such reactions, have been developed in an attempt to address this very issue [41]. In addition to experiencing AHTR or DHTR, patients with SCD are also prone to developing hyperhemolytic reactions, otherwise known as hyperhemolysis syndrome (HHS), following RBC transfusion. HHS is typically characterized by the accelerated clearance of the patient’s own RBCs in addition to the transfused RBCs [42–48]. As the strongest indicators for transfusion in SCD are themselves associated with significant complications (e.g. stroke, acute chest syndrome, multi-organ failure, etc.), the rapid drop in Hb that SCD patients can experience during HHS can significantly exacerbate underlying SCD complications [26,49,50]. As a result, HHS can be particularly life-threatening. Similar to DHTRs, HHS can occur in patients with no detectable alloantibody, making it difficult to predict which patients are at risk for developing this complication. 1.2. Strategies used to prevent and treat HTRs Given the potential consequences of AHTR, DHTRs and HHS, providers can face challenging situations when seeking to balance the potential benefits of RBC transfusion with the possible implications of unpredictable transfusion complications [51,52]. This can be particularly apparent for SCD patients who present with an incomplete transfusion history, yet have an acute need for transfusion. As previously mentioned, a complex alloantibody profile requiring rare RBC donors often precludes the rapid identification of compatible blood [27,28]. In these situations, the patient’s response to supportive care is often carefully monitored while ongoing attempts to identify compatible RBCs continue [26]. Occasionally, if anemia and its associated consequences are deemed to be life-threatening, incompatible RBC transfusion may be considered [26]. However, effective strategies designed to prevent or reduce the probability of an AHTR in this setting remain enigmatic. Similarly, when SCD patients are transfused compatible RBCs, yet develop DHTRs with or without accompanying HHS, determining what treatment options may be most beneficial can likewise be challenging. When life threatening anemia necessitates RBC transfusion support and only incompatible RBC are available (and the clinical significance of a patient’s alloantibodies remain unknown), or when the patient developed DHTRs with or without HHS, several strategies have been employed in an effort to reduce, prevent, or treat a hemolytic transfusion reaction. Most, if not all, of these strategies are aimed at preventing antibody-mediated removal of the transfused RBCs [51–53] (Fig. 1). For example, intravenous (IV) steroids have been given with the intention of reducing phagocytic processes that may facilitate the removal of antibody opsonized RBCs [54,55]. Steroids may also reduce the inflammatory response that is thought to occur during accelerated hemolysis [56]. In
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Fig. 1. Strategies previously used to target antibody effector function in an effort to prevent or reduce hemolytic transfusion reactions. A variety of strategies, ranging from steroids, IVIg, bortezomib and eculizumab have been used to in an effort to prevent a hemolytic transfusion in patients with life-threatening anemia and no compatible RBCs are available or in patients who develop delayed-type transfusion reactions following RBC transfusion. While the proposed mechanisms of action are depicted in the figure, very little data demonstrates that any or all of these approaches will effectively prevent or treat a hemolytic transfusion reaction. Additional approaches designed to prevent antibody formation or reduce antibody production once formed are not included.
addition to IV steroids, IVIg is often provided in an attempt to likewise reduce antibody-mediated RBC removal. Although many different mechanisms have been postulated whereby IVIg may favorably modulate antibody-mediated disease [57,58], how IVIg prevents or at least reduces RBC clearance following an incompatible RBC transfusion remains unknown. More recently, use of proteasome inhibitors, plasmapheresis, and eculizumab have been considered. While proteasome inhibitors, such as bortezomib, are often used to target plasma cells and therefore may result in a long-term decline in alloantibody production [59–61], they fail to reduce the levels of existing antibodies whose long half-lives can complicate acutely needed transfusions. However, bortezomib may impact other aspects of immune function, such as the phagocytic activity of macrophages, that may in turn reduce their ability to clear RBCs [62,63]. While repetitive plasmapheresis can reduce the levels of existing antibodies, this procedure is typically not an option because it can be difficult to safely perform in severely anemic patients. Eculizumab prevents complement activation and would therefore be predicted to be most useful in patients with existing alloantibodies presumed to mediate RBC destruction through a complement-dependent process [64,65]. Despite attempts to use all or various iterations of these strategies to prevent antibody-mediated RBC removal, it is difficult to gauge the effectiveness of these strategies [38,39,66–68]. A variety of case reports and case series provide some data suggesting that steroids, IVIg, bortezomib, eculizumab, or some combination of these or other strategies all together, may be effective at preventing or treating antibody-mediated removal of RBCs [38,39,51,52,66–68]. However, as noted previously, patients have received incompatible RBC transfusions without evidence of a HTR while many cases of DHTR resolve spontaneously with only supportive care [37–39,52]. As a result, it can be difficult to know if a given prevention or treatment strategy favorably influences outcomes in these settings or whether a positive outcome publication bias has prevented a clear understanding of the actual efficacy of these approaches. There are indeed reports that indicate that use of some of these strategies fail to universally prevent the devastating consequences of alloantibody-mediated RBC hemolysis [26]. Challenges associated with accurately predicting which prophylactic or treatment options may be effective at preventing
or treating antibody-mediated RBC removal may in part reflect the diversity of RBC alloantigen targets. Unlike transplantation, where human leukocyte antigen (HLA) antigens are extremely polymorphic, but structurally very similar, RBC alloantigens can differ in structure, distribution, density and overall engagement by potential alloantibodies [69,70]. Differences in alloantigen structure, variations in the titer, subclass distribution, alloantibody glycosylation and, the status and overall activity of a patient’s reticuloendothelial system, likely converge to dictate whether a given alloantibody will result in RBC clearance [70,71]. Alloantibody functional tests, such as the monocyte monolayer test, can aid in predicting the clinical significance of a particular alloantibody [72,73]. However, the relatively slow turnaround time can preclude the use of this option in the acute setting. Furthermore, this test does not provide information regarding all the mechanisms that may be involved in RBC clearance in a particular clinical setting and therefore the most appropriate strategy to prevent or treat a HTR. As a consequence of distinct alloantibody effector mechanisms and recipient variables, it is hard to envision a prophylactic or treatment approach that will uniformly apply to all antibody-mediated HTRs when antibody effector function is the therapeutic target. Instead, an understanding of the distinct pathways alloantibodies can employ to facilitate RBC clearance will likely be needed if effective approaches designed to routinely prevent or treat alloantibody-mediated HTRs are to be realized. As intentional transfusion of incompatible RBCs in patients for experimental purposes is considered unethical, directly examining the mechanisms of alloantibody-induced RBC removal and the efficacy of different prevention and treatment strategies is challenging. Despite the potentially devastating consequences of HTRs clinically, the limited frequency with which these reactions occur coupled with the diversity of alloantigens involved, makes a definitive randomized control trial examining prophylactic options challenging. However, various animal models do provide some insight into the complexities of incompatible RBC transfusion and suggest that several forms of antibody-mediated removal can occur [74–79]. Each of these antibody-mediated clearance mechanisms would be predicted to be differentially susceptible to strategies designed to prevent or treat HTRs. Thus, alloantibody and patient
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specific approaches to preventing antibody-mediated removal of RBCs may be required to produce the most effective outcomes. In contrast to targeting alloantibody-mediated removal, recent studies suggest that at least in the setting of HHS, exuberant activation of the alternative complement pathway may contribute to ongoing hemolysis [49,50]. While several studies indicate that HHS may in part reflect enhanced macrophage activation and erythrophagocytosis [43,46,67], recent studies have demonstrated that free heme can directly activate complement [80]. These data suggest that hemolysis may result in complement activation, which in turn could cause further hemolysis. Such a positive feedback loop of free heme release, complement activation and additional RBC hemolysis is consistent with the severe anemia observed in patients with HHS. Recent results targeting complement appear to corroborate this possibility, with patients experiencing HHS treated with eculizumab displaying a rapid reduction in complement activation that is accompanied by decreased hemolysis and overall clinical improvement [49,50]. 2. Conclusions While HTRs are uncommon following transfusion in the general population, these reactions occur with much higher frequency in patients with SCD with potentially devastating consequences. Although alloantigen matching protocols can reduce alloimmunization, SCD patients who receive extended phenotype matched RBCs can continue to develop RBC alloantibodies [18]. Even if fully matched RBCs could be provided [29], up to 30% of SCD patients can develop DHTRs in the absence of detectable alloantibodies [41], strongly suggesting that extensive alloantigen matching protocols alone will not likely eliminate HTRs in this patient population. While a variety of studies are beginning to elucidate various factors that may regulate RBC alloimmunzation [81–85], additional studies are needed, both at a mechanistic level and clinically, to understand how these alloantibodies may contribute to HTRs in patients with SCD in an effort to more effectively predict, prevent and treat AHTR, DHTR and HHS. Funding This work was supported in part by the Burroughs Wellcome Trust Career Award for Medical Scientists, the National Institutes of Health (NIH) Early Independence grant DP5OD019892, R01HL135575, and P01HL132819 to SS. Disclosure of interest The authors declare that they have no competing interest. References [1] Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5–11. [2] DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 2014;371:699–710. [3] Beverung LM, Strouse JJ, Hulbert ML, et al. Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy. Am J Hematol 2015;90:139–43. [4] Chou ST, Liem RI, Thompson AA. Challenges of alloimmunization in patients with haemoglobinopathies. Br J Haematol 2012;159:394–404. [5] Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood 2012;120:528–37. [6] Hillyer CD, Shaz BH, Winkler AM, Reid M. Integrating molecular technologies for red blood cell typing and compatibility testing into blood centers and transfusion services. Transfus Med Rev 2008;22:117–32. [7] Rosse WF, Gallagher D, Kinney TR, et al. Transfusion and alloimmunization in sickle cell disease. The Cooperative Study of Sickle Cell Disease. Blood 1990;76:1431–7.
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