Anti-N and anti-Doa immunoglobulin G alloantibody-mediated delayed hemolytic transfusion reaction with hyperhemolysis in sickle cell disease treated with eculizumab and HBOC-201: case report and review of the literature.

BACKGROUND: Delayed hemolytic transfusion reaction (DHTR) with hyperhemolysis is a potentially fatal complication resulting from alloimmunization that can cause severe hemolysis of both transfused and intrinsic red blood cells (RBCs). Patients with sickle cell disease often receive multiple RBC units during their lifetime and thus are likely to develop alloantibodies that increase the risk for DHTR. Treatment to decrease hemolysis includes intravenous immunoglobulin (IVIG), steroids, eculizumab, rituximab, and plasmapheresis in addition to erythropoietin (EPO), intravenous (IV) iron, vitamin B12, and folate to support erythropoiesis. RBC transfusion is preferably avoided in DHTR due to an increased risk of exacerbating the hemolysis. CASE REPORT: We report a rare case of anti-N and anti-Doa immunoglobulin (Ig)G alloantibody-mediated life-threatening DHTR with hyperhemolysis in a patient with hemoglobin SS after RBC transfusion for acute chest syndrome who was successfully treated with eculizumab and HBOC-201 (Hemopure) in addition to steroids, IVIG, EPO, IV iron, and vitamin B12. HBOC-201 (Hemopure) was successfully used as a RBC alternative in this patient. CONCLUSION: Anti-N and anti-Doa IgG alloantibodies can rarely cause severe life-threatening DHTR with hyperhemolysis. HBOC-201 (Hemopure) can be a lifesaving alternative in this scenario. Our report also supports the use of eculizumab in DHTR; however, prospective studies are needed to determine the appropriate dose and sequence of eculizumab administration.

Cytomegalovirus transmission in pediatric renal transplant recipients during the window period.

We report two CMV naïve children who received deceased donor renal transplants from a CMV IgG-negative single donor. CMV IgG in both recipients and the donor were negative immediately prior to transplant. Both recipients had early recurrences of their original disease in their transplants, requiring multiple sessions of plasmapheresis. All blood products used were leukoreduced or CMV seronegative. A few days post-transplant, both recipients developed significant positive CMV viremia. Both required initiation of oral valganciclovir. Case 1 responded to oral valganciclovir only while the case 2 had a delayed response to it and hence required intravenous ganciclovir with good response. When checked retrospectively, CMV IgM in the donor was positive along with positive CMV DNA PCR from the white cells. Here we describe a very unusual scenario of CMV transmission in two pediatric renal transplant recipients from a single donor during the CMV window period.

Dysfibrinogenemia: discrepant results following infusion of purified fibrinogen.

Inherited dysfibrinogenemias are molecular disorders of fibrinogen that affect fibrin polymerization. The majority of cases are asymptomatic, but a significant proportion suffer from increased bleeding or thrombosis. We present two unrelated cases of dysfibrinogenemia, both of whom showed a characteristic discrepancy between fibrinogen activity and the immunologic fibrinogen. In one patient, the dysfibrinogenemia was confirmed by molecular analysis; in the other case, the diagnosis was presumptive based upon laboratory studies. Both patients underwent elective surgery. Both received a highly purified fibrinogen concentrate preoperatively and demonstrated a suboptimal laboratory response to the infusion. Three methods for determining fibrinogen concentration (Clauss fibrinogen, prothrombin-derived fibrinogen, and the viscoelastic functional fibrinogen) were utilized in the case of one patient, and these techniques showed discrepant results with the classic Clauss method giving the lowest concentration. Neither patient experienced excessive bleeding during surgery. Although these discrepancies have been previously described in untreated patients, their manifestation after infusion of purified fibrinogen is less well appreciated.

Evaluation of the efficacy and safety of amustaline/glutathione pathogen-reduced RBCs in complex cardiac surgery: the Red Cell Pathogen Inactivation (ReCePI) study-protocol for a phase 3, randomized, controlled trial.

BACKGROUND: Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. METHODS: ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. DISCUSSION: RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs.

Adding Automation and Independent Dual Verification to Reduce Wrong Blood in Tube (WBIT) Events.

OBJECTIVES: Transfusions remain a complicated procedure involving many disciplines performing various steps. Pretransfusion specimen identification errors remain a concern. Over the past two decades, system changes have been made and minimal improvements in the error rates have been seen. Wrong blood in tube (WBIT) events may lead to mistransfusions of components with life-threatening complications. METHODS: A continuous quality improvement effort involving the introduction of electronic patient identification at the point of pretransfusion specimen collection (an automated system improvement), manual independent dual verification, and periodic education (human process system improvements) were implemented. RESULTS: Both automated and human system process improvements resulted in greater than 10-fold reduction in WBIT events and a 47% reduction in mislabeled specimens. CONCLUSIONS: Diligent improvement and implementation of combination automated system processes and human protocols with continuous monitoring led to great reductions in WBIT error rates and labeling discrepancies, leading to an increase in system safety. These combinations of improvement can lead to more decreased error rates if applied to other critical process steps in the transfusion process.

Effects of a Single Rapid Infusion System on Platelet Function in Stored Whole Blood: An Ex Vivo Study.

Introduction Rapid infusion systems (RIS) are used to warm and rapidly infuse crystalloids and blood products. Current guidelines do not approve of platelet transfusion through a RIS, but data supporting these guidelines are scarce. Our hypothesis was that an infusion of whole blood through a RIS would degrade platelet quantity, impede viscoelastic clot strength, and inhibit platelet aggregation response to adenosine diphosphate pathway (ADP) activation. Methods Ten iterations of a simulated scenario of transfusing whole blood via a single brand and make of RIS (Belmont Fluid Management System 2000, Belmont Medical Technologies, Billerica, MA) were performed. Units of whole blood, which were two to nine days old, were leukoreduced prestorage. Blood was used to prime the RIS and then warmed and infused at 100 mL/min into a reservoir. Blood samples were collected before and immediately after infusion. Samples were tested for platelet count, size, and viscoelastic clot strength using thromboelastographic and aggregation assays. Results The study sample (n = 10) included platelets with an average age of 5.3 days. The infusion through the RIS had a detrimental effect on all the maximal amplitudes (MA) of viscoelastic testing: MA ADP (mean difference = -18.7 mm; 95% CI: -24.1 to -13.3, P = 0.004), MA rapid thromboelastography (MA rTEG) (mean difference = -6.0; 95% CI: -10.0 to -2.0, P = 0.008), MA TEG (mean difference = -7.1; 95% CI: -10.9 to -3.4, P = 0.004), mean platelet volume (MPV) (mean difference = -0.3; 95% CI: -0.6 to -0.1, P = 0.02), and platelet count (mean difference = -68.3 × 103/µL; 95% CI: -86.9 to -49.7, P = 0.004). Conclusions Platelet quantity, viscoelastic clot strength, and platelet aggregation response to ADP each decline after infusion through a RIS. Further studies regarding microaggregates and platelet activation are required.

Bivalirudin May Reduce the Need for Red Blood Cell Transfusion in Pediatric Cardiac Patients on Extracorporeal Membrane Oxygenation.

We retrospectively compared anticoagulation with heparin and bivalirudin for 32 consecutive children under 18 years old during extracorporeal membrane oxygenation (ECMO) in our pediatric cardiac intensive care unit (PCICU). Between September 2015 and January 2018, 14 patients received heparin, 13 venoarterial (VA), and 1 venovenous (VV). From February 2018 to September 2019, 18 received bivalirudin (all VA). The mean (standard deviation [SD]) percentage of time with therapeutic activated partial thromboplastin time and activated clotting time was bivalirudin 54 (14%) and heparin 57 (11%), p = 0.4647, and percentage of time supratherapeutic was bivalirudin 18 (10%) and heparin 27 (12%), p = 0.0238. Phlebotomy-associated blood loss per hour of ECMO was double in the heparin compared with bivalirudin group 1.08 ml/h (0.20 ml/h), compared with 0.51 ml/h (0.07 ml/h), p = 0.0003, as well as interventions to control bleeding. Packed red blood cell (PRBC) transfusions significantly correlated with higher blood loss in the heparin group (Pearson correlation coefficient = 0.49, p = 0.0047). Overall amount of blood product utilization was not different between the groups. Survival to ECMO decannulation was 89% for bivalirudin and 57% for heparin, p = 0.0396, although 6 month survival was not significantly different (67% versus 57%, p = 0.5809). Heparin may increase the need for PRBC transfusions and strategies to attenuate bleeding when compared with bivalirudin for children receiving ECMO in PCICU.

Packed red blood cell donor age affects overall survival in transfused patients undergoing hepatectomy for non-hepatocellular malignancy.

BACKGROUND: Patients undergoing hepatectomy often require packed red blood cell (PRBC) transfusion, which has been associated with worse oncologic outcomes. However, limited data exist regarding the impact of PRBC donor factors. We hypothesized that PRBC donor age impacts survival after hepatectomy for non-hepatocellular malignancies. METHODS: Patients who underwent hepatectomy for non-hepatocellular malignancy from 2005 to 2014 were retrospectively evaluated. Impact of clinicopathologic and PRBC factors on oncologic outcomes were assessed. RESULTS: Of 149 identified patients, 76 received a perioperative PRBC transfusion (median 2 units). Transfusion was associated with increased median length of stay (8 vs. 6 days; p < 0.01) and median operative blood loss (700 vs. 350 mL; p < 0.01) versus non-transfused, respectively. In transfused patients, receipt of PRBC from older donors compared to younger resulted in decreased RFS (0.94 vs. 2.63 years, respectively; p = 0.02) and OS (1.94 vs. 3.44 years, respectively; p = 0.6). The PRBC donor age was an independent predictor of decreased recurrence free survival on multivariate analysis (HR 2.5, p = 0.04). CONCLUSIONS: In patients undergoing hepatectomy for non-hepatocellular malignancies and receiving perioperative transfusion, PRBC donor age may impact survival and warrants further investigation.