Management of hemolytic transfusion reactions.

Delayed hemolytic transfusion reactions (DHTRs) in patients with sickle cell disease are underappreciated and potentially fatal. Patients with DHTRs typically have symptoms of pain or dark urine days to weeks following a red blood cell (RBC) transfusion. In instances of DHTRs with hyperhemolysis, the patient's hemoglobin (Hgb) may be significantly lower than it was pretransfusion, and the Hgb A may drop by more than 50%. In most cases, at least 1 RBC alloantibody and sometimes multiple RBC alloantibodies can be identified during the DHTR, with those antibodies presumably having fallen below the level of detection at the time of the implicated transfusion. However, in up to one-third of cases, no new RBC alloantibodies can be identified posttransfusion. Complement is increasingly being appreciated to play a role in DHTRs and hyperhemolysis, not only due to classic pathway activation (with complement fixed antibody bound to RBCs) but also due to alternative pathway activation (resulting in part from plasma free heme). As such, anti-C5 inhibition has recently been reported to be effective at mitigating hemolysis in the setting of some severe DHTRs. Transfusion avoidance during DHTRs is recommended if possible, with long-term transfusion support advice being less clear; for example, a history of a severe DHTR may lead to questions regarding the safety of transfusions prior to curative therapies such as stem cell transplantation or gene therapy. A better understanding of antibody-positive and antibody-negative DHTRs, including patient- or disease-specific risk factors, is necessary to improve transfusion safety.

Complications of Hemorrhagic Shock and Massive Transfusion-a Comparison Before and After the Damage Control Resuscitation Era.

ABSTRACT: Trauma remains a leading cause of death, and hemorrhage is the leading cause of preventable trauma deaths. Resuscitation strategies in trauma have changed dramatically over the last 20 years. In the pre damage control resuscitation (DCR) era, we used large volume crystalloid resuscitation and packed red blood cells as the primary resuscitative fluids. Now, a 1:1:1 ratio of packed red blood cells, fresh plasma, and platelets with minimal crystalloids is the preferred resuscitative strategy (DCR era). As we have changed how we resuscitate patients, the detrimental effects associated with large volume resuscitation have also changed. In this article, we review the effects of large volume blood product resuscitation, and where possible present a contrast between the pre-DCR era and the DCR era resuscitation strategies.

Massive transfusions and severe hypocalcemia: An opportunity for monitoring and supplementation guidelines.

BACKGROUND: Massive transfusion protocols (MTPs) are associated with severe hypocalcemia, contributing to coagulopathy and mortality in severely injured patients. Severity of hypocalcemia following massive transfusion activation and appropriate treatment strategies remain undefined. STUDY DESIGN AND METHODS: This was a retrospective study of all MTP activations in adult trauma patients at a Level 1 trauma center between August 2016 and September 2017. Units of blood products transfused, ionized calcium levels, and amount of calcium supplementation administered were recorded. Primary outcomes were ionized calcium levels and the incidence of severe ionized hypocalcemia (iCa ≤1.0 mmol/L) in relation to the volume of blood products transfused. RESULTS: Seventy-one patients had an MTP activated during the study period. The median amount of packed red blood cells (PRBCs) transfused was 10 units (range 1-52). A total of 42 (59.1%) patients had periods of severe hypocalcemia. Patients receiving 13 or more units of PRBC had a greater prevalence of hypocalcemia with 83.3% having at least one measured ionized calcium ≤1.0 mmoL/L (p = .001). The number of ionized calcium levels checked and the amount of supplemental calcium given in patients who experienced hypocalcemia varied considerably. DISCUSSION: Severe hypocalcemia commonly occurs during MTP activations and correlates with the number of packed red blood cells transfused. Monitoring of ionized calcium and amount of calcium supplementation administered is widely variable. Standardized protocols for recognition and management of severe hypocalcemia during massive transfusions may improve outcomes.

Association of Veterinary Hematology and Transfusion Medicine (AVHTM) transfusion reaction small animal consensus statement (TRACS). Part 3: Diagnosis and treatment.

OBJECTIVE: To systematically review available evidence to develop guidelines for diagnosis and treatment of transfusion-associated reactions in dogs and cats. DESIGN: Standardized and systemic evaluation of the literature (identified through Medline via PubMed and Google Scholar searches) was carried out for identified transfusion reaction types in dogs and cats. The available evidence was evaluated using PICO (Population, Intervention, Comparison, Outcome) questions generated for each reaction type. The evidence was categorized by level of evidence (LOE) and quality (Good, Fair, or Poor). Guidelines, diagnostic, and treatment algorithms were generated based on the evaluation of the evidence. Consensus on the final guidelines was achieved through Delphi-style surveys. Draft recommendations were disseminated through veterinary specialty listservs for review and comments, which were evaluated and integrated prior to final publication. RESULTS: Medline via PubMed and Google Scholar databases were searched. There were 14 Population Intervention Comparison Outcome questions identified and corresponding worksheets were developed focusing on the diagnosis and treatment of transfusion-associated reactions in dogs and cats. Fourteen guidelines and four algorithms were developed with a high degree of consensus. CONCLUSIONS: This systematic evidence evaluation process yielded recommended diagnostic and treatment algorithms for use in practice. However, significant knowledge gaps were identified, demonstrating the need for additional research in veterinary transfusion medicine.

Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer.

Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.

A case of hyperhaemolysis syndrome in a pregnant Chinese woman with ß-thalassemia during perinatal transfusion.

OBJECTIVES: To report a case of hyperhaemolysis syndrome (HHS) that occurred during perinatal blood transfusion in a pregnant Chinese woman with ß-thalassemia to deepen the understanding of HHS and the risk of transfusion therapy for patients with thalassemia. BACKGROUND: Most HHS cases occur in people with sickle cell disease. So far, no cases of HHS have been reported in the Chinese population. Here, we report a pregnant Chinese women with ß-thalassemia experiencing HHS. METHODS: The patient received ABO- and RhD-matched red blood cell transfusion from six blood donors in four perinatal transfusions. Haemoglobinuria and lower haemoglobin levels compared to those before transfusion were observed after each transfusion, and the lactate dehydrogenase was consistently elevated. The blood samples were collected at different time points during the hospitalisation for direct antiglobulin test (DAT), antibody screening test and acid elution test. The antigens of six blood donors were identified, and the cross-matching tests were repeated using the blood sample of the patient with specific irregular antibodies after the last transfusion. RESULTS: The DAT of the patient was negative for anti-IgG and positive (1+) for anti-C3d, and no red blood cell antibodies were detected in the eluent before, between and after transfusions. Before and between transfusions, blood samples were negative for red blood cell irregular antibodies, whereas IgM anti-P1 and IgG anti-Jka were detected in blood samples the next day after the last transfusion. In the six donors, two were negative for P1 and Jka , one was positive for P1 and negative for Jka , and three were negative for P1 and positive for Jka . The tentative cross-matching tests using the indirect antiglobulin method in saline showed that only agglutination occurred in the blood samples of the patient collected after last transfusion and the three Jka -positive blood donors. DISCUSSION: The clinical manifestations and laboratory test results suggested that HHS occurred in this patient with ß-thalassemia after each transfusion. Clinicians should be aware that HHS can occur with compatible blood transfusion.

[Treatment of transfusional iron overload].

Frequent packed red blood cell (pRBC) transfusion can cause transfusional iron overload. Excess iron generates reactive oxygen species and provokes organ dysfunction. In lower-risk myelodysplastic syndrome (MDS), hyperferritinemia is known as one of the negative prognostic factors. Thus far, iron chelation therapy (ICT) is the only effective treatment for chronic iron overload induced by transfusion. Transfusional iron overload is diagnosed when serum ferritin (SF) levels are ≥500 ng/ml and cumulative volume of pRBC transfusion is ≥20 JPN units. ICT should be initiated when SF levels are ≥1,000 ng/ml and will be further continued until SF levels decline to <500 ng/ml. ICT serves to ameliorate organ dysfunction. A prospective study demonstrated that in patients with lower-risk MDS, ICT can reduce the risk of combined events, including cardiac events, hepatic events, AML transformation, and death of any cause. In some patients, hematological improvement will be observed. However, clinical features underling this hematological phenomenon are not fully understood. Therefore, ICT should not be performed solely for the purpose of hematological recovery.

Cytokine changes in sickle-cell disease patients as markers predictive of the onset of delayed hemolytic transfusion reactions.

BACKGROUND: Changes in cytokine production are known to contribute to the pathogenesis of sickle-cell disease (SCD), particularly in painful acute complications (crises) and episodes of post-transfusion hemolysis. Little is known about cytokine profiles in patients with these complications. STUDY DESIGN AND METHODS: We investigated possible associations between cytokine profile and the onset of delayed hemolytic transfusion reactions (DHTRs), particularly during acute-phase episodes, to improve characterization of the biological parameters predictive of such events. We included SCD patients with severe acute symptoms (n = 36) or steady-state disease (n = 31), both possibly leading to a DHTR (n = 18) event. Luminex® technology was used to determine the plasma concentrations of 23 cytokines. RESULTS: Regardless of clinical context, the concentrations of interleukin (IL)-6, IL-10, inducible protein-10, and macrophage inflammatory protein-1ß were higher in plasma samples from SCD patients than in those from healthy controls. IL-6 and IL-10 concentrations were even higher in acute-phase plasma samples from SCD patients. In addition, IL-27 and TNFα levels were higher, and IL-6 and RANTES levels were lower in acute-phase SCD patients just before the onset of DHTR than in patients experiencing painful occlusive episodes. CONCLUSION: In addition to reporting the plasma cytokine profiles of SCD patients in various clinical phases of the disease, we provide the first evidence of a significant association between low plasma TNFα concentration, high plasma IP-10 concentration and the onset of DHTR in SCD patients.

American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support.

BACKGROUND: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. OBJECTIVE: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. METHODS: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. RESULTS: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. CONCLUSIONS: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

Recapitulation of posttransfusion purpura by cross-strain platelet immunization in mice.

Posttransfusion purpura (PTP) is an uncommon but life-threatening condition characterized by profound thrombocytopenia occurring ∼1 week after a blood transfusion. The hallmark of PTP is a potent immunoglobulin G antibody specific for a transfused platelet-specific alloantigen, usually located on glycoprotein IIb/IIIa (GPIIb/IIIa; αIIb/ß3 integrin). It is widely thought that this alloantibody somehow causes the thrombocytopenia, despite absence from host platelets of the alloantigen for which it is specific. In studies described here, we found that cross-strain platelet immunization in mice commonly induces GPIIb/IIIa-specific alloantibodies combined with platelet-specific autoantibodies and varying degrees of thrombocytopenia, and we identified 1 strain combination (129S1Svlm/PWKPhJ) in which 95% of immunized mice made both types of antibody and developed severe thrombocytopenia. There was a strong inverse correlation between autoantibody strength and platelet decline (P < .0001) and plasma from mice that produced autoantibodies caused thrombocytopenia when transfused to syngeneic animals, arguing that autoantibodies were the cause of thrombocytopenia. The findings define a model in which a routine alloimmune response to platelets regularly transitions to an autoimmune reaction capable of causing severe thrombocytopenia and support the hypothesis that PTP is an autoimmune disorder.

Use of a Transfusion Checklist by Student Nurses to Improve Patient Safety.

Better education around the recognition of transfusion-associated adverse events is warranted. It is unknown if checklist use improves recognition by student nurses. This study examined whether using a checklist could improve transfusion-associated adverse event recognition behaviors. There was an increased frequency of transfusion-associated adverse event management behaviors in the checklist group, but overall recognition was no greater than other groups. A transfusion-associated adverse event checklist may increase patient safety by promoting identification behaviors.

Examining the Role of Complement in Predicting, Preventing, and Treating Hemolytic Transfusion Reactions.

Red blood cell (RBC) transfusion is a critical component of optimal management for a broad range of conditions. Regardless of the indication, pretransfusion testing is required to appropriately match RBC donors and recipients to provide immunologically compatible blood. Although this approach is effective in the vast majority of situations, occasionally, patients will inadvertently receive an incompatible RBC transfusion, which can result in a hemolytic transfusion reaction (HTR). In addition, patients with life-threatening anemia and a complex alloantibody profile, which precludes rapid procurement of compatible RBCs, may also receive incompatible RBCs, placing them at risk for an HTR. Despite the rarity of these clinical situations, when incompatible blood transfusion results in an HTR, the consequences can be devastating. In this review, we will explore the challenges associated with actively preventing and treating acute HTRs following incompatible RBC transfusion. In doing so, we will focus primarily on the role of complement, not only as a key player in HTRs, but also as a potential target for the prevention and treatment of HTRs.

Profound Intraoperative Hypotension Associated With Transfusion via the Belmont Fluid Management System.

This retrospective observational case series conducted at 2 large academic centers over a 4-year period consists of 15 cases of profound hypotension in surgical patients immediately after initiation of the Belmont Fluid Management System for rapid transfusion of blood products. Halting the infusion and administering vasoactive agents led to resolution of hypotension. Repeat transfusion with the Belmont system resulted in repeat hypotension unless counteracted with vasopressors. No etiology was elucidated. This represents the largest documented association of acute hypotensive transfusion reaction with any rapid infusion system in surgical patients.

Transfusion-associated circulatory overload risk mitigation: survey on hospital policies for compliance with AABB Standard 5.9.17.

BACKGROUND: AABB Standards for Blood Banks and Transfusion Services require accredited institutions to have a policy for handling requests for blood components on patients clinically identified as being at high risk for transfusion-associated circulatory overload (TACO; Standard 5.19.7, 31st edition). This survey elucidated how AABB accredited hospital transfusion services/blood banks around the world are complying with this Standard. METHODS: A link to a Web-based survey in English was e-mailed under the auspice of the AABB to each AABB accredited hospital transfusion service/blood bank (n = 851) asking for details on how their institution is complying with this Standard and for general information on any TACO risk mitigation strategies in place. RESULTS: Of the 290 responses received (34% response rate), 282 met the criteria for analysis. There were 174 of 282 (62%) respondents who indicated that their institution has a formal policy for complying with the Standard, and 108 of 282 (38%) who indicated that their institution does not have a formal policy. A diverse range of policies and practices were in place at the institutions with and without a formal policy ranging from writing advice/recommendations in the charts of patients at increased risk of TACO, promulgating policies from the transfusion service/blood bank or institution itself that would reduce the risk, or using decision support tools to provide education about reducing the risk of TACO. CONCLUSIONS: Many but not all AABB accredited institutions have policies to comply with the TACO risk mitigation Standard. However, the vast majority conduct activities that could mitigate risk for TACO.

Implementation of a patient blood management program in hematopoietic stem cell transplantation (Editorial, p. 2763).

BACKGROUND: Recipients of hematopoietic stem cell transplantation (HSCT) are among the highest consumers of allogeneic red blood cell (RBC) and platelet (PLT) components. The impact of patient blood management (PBM) efforts on HSCT recipients is poorly understood. STUDY DESIGN AND METHODS: This observational study assessed changes in blood product use and patient-centered outcomes before and after implementing a multidisciplinary PBM program for patients undergoing HSCT at a large academic medical center. The pre-PBM cohort was treated from January 1 through September 31, 2013; the post-PBM cohort was treated from January 1 through September 31, 2015. RESULTS: We identified 708 patients; 284 of 352 (80.7%) in the pre-PBM group and 225 of 356 (63.2%) in the post-PBM group received allogeneic RBCs (p < 0.001). Median (interquartile range [IQR]) RBC volumes were higher before PBM than after PBM (3 [2-4] units vs. 2 [1-4] units; p = 0.004). A total of 259 of 284 pre-PBM patients (91.2%) and 57 of 225 (25.3%) post-PBM patients received RBC transfusions when hemoglobin levels were more than 7 g/dL (p < 0.001). The median (IQR) PLT transfusion quantities was 3 (2-5) units for pre-PBM patients and 2 (1-4) units for post-PBM patients (p < 0.001). For patients with PLT counts of more than 10 × 109 /L, a total of 1219 PLT units (73.4%) were transfused before PBM and 691 units (48.8%) were transfused after PBM (p < 0.001). Estimated transfusion expenditures were reduced by $617,152 (18.3%). We noted no differences in clinical outcomes or transfusion-related adverse events. CONCLUSION: Patient blood management implementation for HSCT recipients was associated with marked reductions in allogeneic RBC and PLT transfusions and decreased transfusion-related costs with no detrimental impact on clinical outcomes.