Eculizumab for management of hyperhemolysis syndrome in pediatric patients with sickle cell disease: A single-center case series.

Chronic hemolytic anemia and vascular occlusion are hallmarks of sickle cell disease (SCD). Blood transfusions are critical for supportive and preventive management of SCD complications. Patients with SCD are at risk for hyperhemolysis syndrome (HHS), a subtype of delayed hemolytic transfusion reactions. HHS management includes intravenous immunoglobulin, corticosteroids, and avoidance of further transfusions. Not all patients respond to first-line agents. Eculizumab, which blocks terminal complement activation, has been proposed as second-line management of HHS. We describe two patients who received eculizumab for refractory HHS. In our experience, eculizumab is a safe and effective option for refractory pediatric HHS.

Role of anti-allergic agents on attenuating transfusion reactions in adults: A systematic review and meta-analysis.

BACKGROUND: Anti-allergic agents (e.g. dexamethasone, chlorpheniramine or promethazine) are commonly administered to patients prior to blood product transfusions. However, the use of these agents is largely experience-based instead of evidence-based. This meta-analysis aimed to explore the evidence behind using anti-allergic agents to attenuate transfusion reactions. MATERIALS AND METHODS: The Pubmed, EMBASE, Cochrane Library, Wanfang, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical literature (CMB) databases were all queried for related articles. Data from groups treated with and without anti-allergic agents were collected for meta-analysis using RevMan 5.3. Baseline characteristics and univariate statistics between groups were compared using SPSS 19.0. RESULTS: Eight eligible articles (six case control studies and two randomized controlled trials, all with high risks of bias) were identified (22060 total cases). Administered anti-allergic agents in these studies only included dexamethasone, chlorpheniramine or promethazine. Baseline characteristics showed no significant age or gender differences between treatment or control groups. There were no significant differences between the pooled experimental or control groups (for each of the three medications) in terms of fever, pruritis, rash, airway spasm or overall transfusion reaction rates. CONCLUSION: There is no evidence that dexamethasone, chlorpheniramine or promethazine can prevent transfusion reactions. Avoiding the arbitrary use of such anti-allergic agents before blood transfusions may potentially avoid needless adverse drug reactions.

Posttransfusion hyperhemolysis is arrested by targeting macrophage activation with novel use of Tocilizumab.

BACKGROUND: Hyperhemolysis syndrome (HHS) is a posttransfusion complication most frequently seen in sickle cell disease (SCD), characterized by rapid destruction of transfused and autologous red blood cells (RBCs), resulting in reticulocytopenia and a decrease in hemoglobin to below pretransfusion levels. Additional RBC transfusion can be life threatening. Most patients improve with intravenous immune globulin and steroids, but in refractory cases, hyperhemolysis may result in multiorgan failure and death in the absence of salvage therapy. The exact pathophysiology of HHS remains uncertain, yet new insights suggest that RBC destruction is driven by activated macrophages. Therefore, we propose that antimacrophage therapy may represent an effective treatment. CASE REPORT: A case of life-threatening HHS, refractory to intravenous immune globulin and steroids, in a patient with SCD is presented. Marked elevation in ferritin, an indirect marker of macrophage activation, a negative direct antiglobulin test, and the absence of RBC alloantibodies was noted. A hemoglobin nadir of 2.1 g/dL and resultant hypoxemia-induced organ failure prompted the use of tocilizumab, an interleukin-6 receptor monoclonal antibody. Hemoglobin-based oxygen carrier-201, a cell-free polymerized bovine hemoglobin, was used to support the patient during critical anemia. RESULTS: Hemolysis resolved and ferritin dramatically decreased after administration of tocilizumab, which was well tolerated. A full recovery was achieved. CONCLUSION: This case highlights both a novel and successful approach to managing refractory transfusion-induced hyperhemolysis with tocilizumab and provides further evidence supporting the role for macrophage activation in the destruction of RBCs in antibody-negative HHS. We propose that tocilizumab is an effective and rapid salvage therapy for refractory HHS.

A suspected septic transfusion reaction associated with posttransfusion contamination of a platelet pool by vancomycin-resistant Enterococcus faecium.

BACKGROUND: Vancomycin-resistant enterococci (VRE) are antibiotic-resistant organisms associated with both colonization and serious life-threatening infection in health care settings. Contamination of platelet concentrates (PCs) with Enterococcus can result in transfusion-transmitted infection. CASE PRESENTATION: This report describes the investigation of a septic transfusion case involving a 27-year-old male patient with relapsed acute leukemia who was transfused with a 5-day-old buffy coat PC pool and developed fever and rigors. DISCUSSION: Microbiology testing and pulse-field gel electrophoresis (PFGE) was done on patient blood cultures obtained from peripheral and central lines. Microbiology and molecular testing were also performed on the remaining posttransfusion PC pool, which was refrigerated for 24 hours before microbiology testing. Red blood cell (RBC) and plasma units associated with the implicated PCs were screened for microbial contamination. Patient blood cultures obtained from peripheral and central lines yielded vancomycin-resistant Enterococcus faecium. Gram stain of a sample from the platelet pool was negative but coagulase-negative Staphylococcus (CNST) and VRE were isolated on culture. Antibiotic sensitivity and PFGE profiles of several VRE isolates from the patient before and after transfusion, and the PC pool, revealed that all were closely related. Associated RBC and plasma components tested negative for microbial contamination. CONCLUSIONS: Microbiological and molecular investigations showed a relationship between VRE isolated from the patient before and after transfusion, and therefore it is postulated that a patient-to-PC retrograde contamination (from either blood or skin) occurred. As the CNST isolated from the PC pool was not isolated from patient samples, its implication in the transfusion event is unknown.

Strategies for managing transfusional iron overload: conventional treatments and novel strategies.

PURPOSE OF REVIEW: For individuals who have transfusion-dependent anemia, iron overload is the long-term complication, which results in significant morbidity. Ameliorating this is now the biggest unmet need. This review specifically addresses this issue. RECENT FINDINGS: Over the last decade or so, major advances in the treatment of these individuals, has resulted from novel strategies aimed at reducing transfusion requirement as well as optimizing chelation therapy. This review will summarize these advances and provide insights into some of the therapies in the pipeline. Strategies aimed at reducing transfusion requirement include modulation of erythropoietic regulation by reducing ineffective red cell production through activin trapping, as well as stem cell gene modification approaches, which aim for a cure, and transfusion independence. Refined means of assessing tissue iron and the introduction of oral chelators have facilitated tailoring chelation regimens with closer monitoring and improved compliance. Newer approaches to ameliorate iron toxicity have focused on the hepcidin pathway, all of which would result in increased hepcidin levels and reduction of iron absorption from the intestine, sequestration of iron in normal storage sites and reduced exposure of more susceptible organs, such as the heart and endocrine organs, to the toxic effects of increased iron. SUMMARY: These advances offer the promise of improved management of transfusion-dependent individuals.

Complications of a severe autoimmune hemolytic anemia crisis: transfusional iron overload and gangrenous cholecystitis.

BACKGROUND: Evans syndrome is a rare autoimmune disorder that is defined by the simultaneous or sequential presence of two or more cytopenias without an obvious underlying precipitating cause. Evans syndrome usually follows a chronic relapsing and remitting course and is quite rare, making it difficult to evaluate in clinical studies. CASE REPORT: A 66-year-old male patient with a 17-year history of Evans syndrome presented with fulminant autoimmune hemolytic anemia (AIHA). He presented with a markedly elevated C-reactive protein (CRP; 46 mg/L [normal, 0-5 mg/L]) before onset of a decrease in hemoglobin. He required the transfusion of 20 units of red blood cells while awaiting response to aggressive immunosuppressive therapy including high-dose corticosteroids, intravenous immunoglobin therapy, and rituximab. He achieved a complete hematologic response. RESULTS: His postdischarge course was complicated by acute cholecystitis requiring laparoscopic cholecystectomy. In addition, his transfusional iron overload requiring 16 phlebotomies to reduce his ferritin level from 4933 µg/L to 326 µg/L, with phlebotomies ongoing every 2 weeks to achieve a ferritin level of less than 100 µg/L. CONCLUSION: Neither transfusional iron overload nor acute cholecystitis are well-recognized complications of a severe episode of AIHA. An elevated CRP has been recently recognized as an important prognostic marker in patients with immune thrombocytopenic purpura and this case suggests a need to evaluate its utility in AIHA.

Transfusion-associated circulatory overload prevention: a retrospective observational study of diuretic use.

BACKGROUND AND OBJECTIVES: Approaches to preventing transfusion-associated circulatory overload (TACO) include the use of diuretics. The purpose of this study was to determine how commonly diuretics are prescribed in patients receiving a red-blood-cell (RBC) transfusion. MATERIALS AND METHODS: This was a retrospective study of 200 adult inpatient RBC transfusion orders, 50 consecutive at each of four academic institutions. Only the first transfusion order for each patient was included. Only 1 or 2 unit orders were included. The primary outcome was the percentage of patients receiving furosemide peri-transfusion. Secondary objectives included the dose, route, and timing of furosemide and the association of clinical factors with ordering furosemide. RESULTS: The median age was 62·5 years (IQR 53, 73), and 52% were female. Peri-transfusion furosemide was ordered in 16% (95% CI 11-21%). The most common dose was 20 mg (55%), the route intravenous (90%) and timing post-transfusion (74%). At least one risk factor for TACO was present in 55% of patients: renal dysfunction (33%), older than 70 years (28%), history of congestive heart failure (18%), ejection fraction <60% (16%) and diastolic dysfunction (5%). Low haemoglobin as an indication for transfusion (OR 4·2; 95% CI 1·4-12·8) and diuretics on admission (OR 3·5; 95% CI 1·5-8·0) were associated with ordering furosemide peri-transfusion. CONCLUSIONS: Furosemide is not routinely ordered for RBC transfusion, even in patients with risk factors for TACO. Studies assessing the safety, efficacy, optimal dose, and timing of furosemide in preventing TACO are justified.

Posterior reversible encephalopathy syndrome following blood transfusion in a patient with factor X deficiency: Is it an unusual systemic manifestation of an adverse transfusion reaction?

Adverse neurological transfusion reactions including posterior reversible encephalopathy syndrome (PRES) following blood transfusion are rare. Our case an 18-year-female with known Factor X deficiency with menorrhagia developed severe hypertension, followed by generalised tonic clonic convulsions apparently after blood component transfusion. She had earlier received 4 units of red blood cells (RBC) for anaemia and 10 units of fresh frozen plasma (FFP) for menorrhagia (with prolonged PT and APTT) within short span of time at another hospital. There was no history of hypertension, convulsions, any cardiovascular, renal or neurological disease before transfusion. The clinical features and magnetic resonance imaging findings led to the diagnosis of PRES. Abnormal electroencephalogram and a hypercoagulable haemostatic profile on thromboelastography along with derangement in blood glucose and liver function tests were also observed. Patient responded well to the anticonvulsants and antihypertensive agents prescribed and was discharged in a stable condition. Our patient had a systemic transfusion reaction involving predominantly neurological system, however, cardiovascular, hepatic, haemostatic and endocrine systems were also affected. This case is unusual being the first report of PRES occurring in a patient with factor X deficiency presenting with an array of clinical and laboratory features which have not been reported in earlier studies involving PRES. Presumably the initial aggressive red cell transfusion to treat anaemia initiated the crisis and further large volumes of transfused FFP contributed to this adverse transfusion reaction in our case. Clinicians and Transfusion Medicine specialists should be aware about this uncommon clinical entity.

A national survey of premedication for transfusion reactions in Japan.

BACKGROUND: Premedication before transfusion is commonly administered in clinical practice despite a lack of evidence for its efficacy. The aim of this study was to clarify the status of premedication and evaluate expert opinions regarding its use in Japanese medical institutions. METHOD: Between May and July 2016, we conducted a questionnaire survey on premedication before transfusion in 252 medical institutes that were certified by an academic society or employed transfusion experts. RESULTS: A total of 141 institutes (54.2%) responded, and hematologists (n=113) comprised the most frequent respondents. The purpose of premedication was to prevent urticaria, pruritus, and fever, and washed blood products were used for anaphylactic shock or refractory transfusion reactions before. Drugs for premedication were intravenously administered either just before or 30min before transfusion. Both inpatients and outpatients were premedicated in a similar manner, and institutional guidelines were not established. More than half of the experts recognized premedication as efficient and necessary, and premedication for previous transfusion reactions was frequently implemented, particularly for platelet transfusion or in patients with hematological diseases. Some institutions administered one or more drugs for premedication from the first transfusion. Antihistamines and hydrocortisone were the most frequently used as premedication. CONCLUSION: Our study reports the current status of premedication for transfusion in Japan. Antihistamines and hydrocortisone were most commonly used for premedication despite a lack of evidence of their use. These findings may help clarify the indications for premedication and the use of washed blood products.

Peptide inhibitor of complement C1 modulates acute intravascular hemolysis of mismatched red blood cells in rats.

BACKGROUND: Acute hemolytic transfusion reactions have a broad clinical presentation from mild and transitory signs and symptoms to shock, disseminated intravascular coagulation, renal failure, and death. We have recently developed a rat model of acute intravascular hemolysis showing that the classical complement pathway mediates antibody-dependent hemolysis. The objective of this study was to evaluate the role of the classical pathway inhibitor peptide inhibitor of complement C1 (PIC1) in this animal model. STUDY DESIGN AND METHODS: Male Wistar rats received a 15% transfusion of human red blood cells (RBCs) and blood was isolated from the animals up to 120 minutes. Animals received PIC1 either 2 minutes before or 0.5 minutes after transfusion. Sham-, vehicle-, and cobra venom factor (CVF)-treated animals were used as control groups with a subset of rats also receiving an equivalent dose of intravenous immunoglobulin (IVIG) before transfusion. Blood was analyzed for transfused RBC survival by flow cytometry and free hemoglobin (Hb) in isolated plasma by spectrophotometry. RESULTS: Vehicle-treated rats showed decreased human RBC survival and increased free Hb as expected. Rats receiving PIC1 before transfusion showed increased human RBC survival and decreased Hb similar to CVF-treated rats. Notably, rats receiving PIC1 after initiation of transfusion showed similar decreases in hemolysis as animals receiving PIC1 before transfusion. Compared to IVIG and saline controls, PIC1-treated animals demonstrated decreased hemolysis and protection from acute kidney injury. CONCLUSIONS: These results demonstrate that PIC1 has efficacy in an animal model of acute intravascular hemolysis in both prevention and rescue scenarios.

Delayed haemolytic transfusion reaction in adults with sickle cell disease: a 5-year experience.

Delayed haemolytic transfusion reactions (DHTR) are potentially life-threatening complications in patients with sickle cell disease (SCD). Between 1 August 2008 and 31 December 2013, 220 of 637 adult patients in our centre had at least one red blood cell (RBC) transfusion in 2158 separate transfusion episodes. Twenty-three DHTR events occurred in 17 patients (13 female) including 15 HbSS, one HbSC and one HbSß(0) thalassaemia, equating to a DHTR rate of 7·7% of patients transfused. Mean interval from RBC transfusion to DHTR event was 10·1 ± 5·4 d, and typical presenting features were fever, pain and haemoglobinuria. Twenty of the 23 (87·0%) DHTR episodes occurred following transfusion in the acute setting. Notably, 11/23 (47·8%) of DHTRs were not diagnosed at the time of the event, most were misdiagnosed as a vaso-occlusive crisis. 16/23 DHTRs had 'relative reticulocytopenia', which was more common in older patients. Seven of 23 episodes resulted in alloantibody formation, and three caused autoantibody formation. DHTRs are a severe but uncommon complication of RBC transfusion in SCD and remain poorly recognized, possibly because they mimic an acute painful crisis. Most of the DHTRs are triggered by RBC transfusion in the acute setting when patients are in an inflammatory state.

Hyperhemolysis syndrome in a patient without a hemoglobinopathy, unresponsive to treatment with eculizumab.

BACKGROUND: Hyperhemolysis is a serious transfusion reaction, most often described in patients with hemoglobinopathies. Hyperhemolysis is characterized by the destruction of host red blood cells (RBCs), in addition to donor RBCs, via an unknown mechanism. STUDY DESIGN AND METHODS: We present the case of a 58-year-old woman with treated human immunodeficiency virus and a normal hemoglobin (Hb) electrophoresis who developed hyperhemolysis in the setting of a delayed hemolytic transfusion reaction (DHTR). RESULTS: The patient was ABO group B and had a previously identified anti-Fy(b) alloantibody. After transfusion of Fy(b)--RBCs, she developed a DHTR and was found to have anti-E, anti-C(w), anti-s, and an additional antibody to an unrecognized high-frequency RBC alloantigen. Subsequent transfusion of ABO-compatible RBCs that were negative for Fy(b), E, C(w), and s antigens resulted in immediate intravascular hemolysis. In the absence of bleeding, her hematocrit (Hct) decreased to 10.2%. An extensive serologic evaluation failed to identify the specificity of the high-frequency antibody. Severe hemolytic reactions also occurred despite pretransfusion conditioning with eculizumab. The Hct and clinical symptoms slowly improved after the cessation of transfusions and treatment with erythropoietin and steroids. This case demonstrates several noteworthy features including hyperhemolysis in a patient without a Hb disorder, the development of an antibody to an unknown RBC antigen, and the failure of eculizumab to prevent intravascular hemolysis after transfusion. CONCLUSION: Hyperhemolysis is not restricted to patients with hemoglobinopathies. Whether eculizumab offers any benefit in the hyperhemolysis syndrome or in the prevention of intravascular hemolysis due to RBC alloantibodies remains uncertain.

Successful use of eculizumab for treatment of an acute hemolytic reaction after ABO-incompatible red blood cell transfusion.

BACKGROUND: Transfusion of ABO major-incompatible red blood cells (RBCs) can activate the complement system and can cause severe and even lethal acute hemolytic reactions. The activation of the complement system with formation of C3a and C5a (anaphylatoxins) and the release of hemoglobin from the lysed RBCs are thought to mediate clinical signs like fever, hypotension, pain, and acute renal failure. Therapeutic inhibition of the complement cascade in case of ABO-incompatible RBC transfusion would be desirable to ameliorate the signs and symptoms and to improve the outcome of the reaction. STUDY DESIGN AND METHODS: A patient with blood group B was erroneously transfused with a unit of group A2 RBCs. Within 1 hour after transfusion she received eculizumab, a monoclonal antibody that binds to the complement component C5 and blocks its cleavage. Clinical and immunohematologic observations are reported here. RESULTS: Hemoglobinemia and hemoglobinuria were present for several hours after transfusion, but she developed no hypotension, no renal failure, and no disseminated intravascular coagulation. As shown by flow cytometry, group A cells survived in the peripheral blood for more than 75 days. No immunoglobulin G was detectable by column agglutination technique on these cells. CONCLUSION: A low isoagglutinin titer and blood group A2 of the erroneously transfused cells most likely were the reason for the absence of clinical signs during and immediately after the ABO-incompatible transfusion. In the further course, eculizumab successfully protected the incompatible RBCs from hemolysis for several weeks.

The effect of C1-inhibitor in a murine model of transfusion-related acute lung injury.

BACKGROUND AND OBJECTIVE: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Specific therapy is lacking. We assessed whether C1-inhibitor attenuates lung injury in a 'two-hit' TRALI model. METHODS: Mice were primed with lipopolysaccharide, subsequently TRALI was induced by MHC-I antibodies. In the intervention group, C1-inhibitor was infused concomitantly. Mice were supported with mechanical ventilation. After 2 h, mice were killed, lungs were removed and bronchoalveolar lavage fluid (BALF) was obtained. RESULTS: Injection of MHC-I antibodies induced TRALI, illustrated by an increase in wet-to-dry ratio of the lungs, in BALF protein levels and in lung injury scores. TRALI was further characterized by complement activation, demonstrated by increased BALF levels of C3a and C5a. Administration of C1-inhibitor resulted in increased pulmonary C1-inhibitor levels with high activity. C1-inhibitor reduced pulmonary levels of complement C3a associated with improved lung injury scores. However, levels of pro-inflammatory mediators were unaffected. CONCLUSION: In a murine model of TRALI, C1-inhibitor attenuated pulmonary levels of C3a associated with improved lung injury scores, but with persistent high levels of inflammatory cytokines.

Successful management of severe allergic reactions to platelet transfusion with omalizumab: A case report.

RATIONALE: An allergic transfusion reaction is a common side effect of transfusions of red blood cells. Using washed red blood cells is the most effective method for preventing such a reaction. However, the availability of other washed transfusion components, including platelets, is limited. PATIENT CONCERNS: A 69-year-old patient with acute myeloid leukemia progressed from myelodysplastic syndrome and was treated with azacitidine. She experienced a minor reaction to platelet transfusion that initially responded to the administration of corticosteroids and antihistamines. However, she worsened even after subsequent preventive treatments and was referred to the emergency department due to anaphylaxis. The patient developed hypotension, chest pain, and dyspnea 10 minutes after the initiation of platelet transfusion. DIAGNOSES: She was diagnosed with platelet-induced anaphylaxis. INTERVENTIONS: In an attempt to prevent anaphylaxis, 150 mg of omalizumab was prescribed 1 week prior to transfusion. However, she experienced anaphylaxis again and was administered intramuscular epinephrine. For the following transfusion, we treated her with a 300 mg dose of omalizumab 24 hours before the transfusion. OUTCOMES: She tolerated well and continued to receive further chemotherapy and platelet transfusion with premedication. LESSONS: This case suggests that omalizumab is a good candidate for the management of severe allergic transfusion reactions.