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BackgroundPlatelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion.Study designAn open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality.ResultsBy modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio=0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p= .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p= .151; odds ratio=0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p= .256); and allergic TR were significantly less with PRPC (p= .006). PC and RBC use were not increased with PRPC.DiscussionPRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.

Apheresis platelets (AP) may be contaminated by environmental bacteria via container defects acquired during processing, transport, storage, or transfusion, as highlighted by a recent series of septic reactions related to Acinetobacter spp. and other bacterial strains.The frequency and nature of acquired container defect reports to one manufacturer were evaluated from January 2019 to July 2020. The published incidence of contamination and sepsis due to environmental bacteria with culture screened AP in the United States was reviewed for the period of 2010-2019.Review of a manufacturers' records showed 23 US reports of leaks involving 24 containers attributed to postmanufacturing damage, at a rate of 44 per million distributed storage containers. Analysis of returned containers showed evidence of scratches, impressions, and/or piercings. Literature review of US hemovigilance data revealed that environmental bacteria comprised 7% of confirmed positive primary bacterial culture screens, were responsible for 14%-16% of reported septic, and 8 of 28 (29%) fatal reactions with bacterial-culture screened AP. Sepsis cases have been reported with culture screened, point-of-issue (POI) tested, or pathogen-reduced AP.Environmental contamination of AP is rare but can cause sepsis. Container damage provides a pathway for contamination after culture screening, POI bacteria testing, or pathogen reduction. Blood collectors and transfusion services should have procedures to ensure proper inspection, handling, storage, and transport of AP to avoid damage and should enhance efforts to detect defects prior to release and to eliminate bacteria from all contacting surfaces to minimize the risk of contamination.

The COVID-19 pandemic severely tested the resilience of the US blood supply with wild fluctuations in blood donation and utilisation rates as community donation opportunities ebbed and hospitals post-poned elective surgery. Key stakeholders in transfusion services, blood centres, supply chains and manufacturers reviewed their experiences during the SARS-CoV-2 pandemic as well as available literature to describe successes, opportunities for improvement and lessons learned. The blood community found itself in uncharted territory responding to restriction of its access to donors (approximately 20% decrease) and some supplies; environmental adjustments to address staff and donor concerns about coronavirus transmission; and the development of a new product (COVID-19 convalescent plasma [CCP]). In assuring that the needs of the patients were paramount, the donation process was safe, that clinicians had access to CCP, and vendor relationships aligned, the blood banking community relearned its primary focus: improving patient outcomes.

Amotosalen/UVA pathogen-reduced platelet components (PRPCs) with storage up to 7 days are standard of care in France, Switzerland, and Austria. PRPCs provide effective hemostasis with reduced risk of transfusion-transmitted infections and transfusion-associated graft versus host disease, reduced wastage and improved availability compared with 5-day-stored PCs. This study evaluated the potency of 7-day PRPCs by in vitro characterization and in vivo pharmacokinetic analysis of autologous PCs.The in vitro characteristics of 7-day-stored apheresis PRPCs suspended in 100% plasma or 65% platelet additive solution (PAS-3)/35% plasma, thrombin generation, and in vivo radiolabeled post-transfusion recovery and survival of 7-day-stored PRPCs suspended in 100% plasma were compared with either 7-day-stored or fresh autologous conventional platelets.PRPCs after 7 days of storage maintained pH, platelet dose, in vitro physiologic characteristics, and thrombin generation when compared to conventional 7-day PCs. In vivo, the mean post-transfusion survival was 151.4 ± 20.1 h for 7-day PRPCs in 100% plasma (Test) versus 209.6 ± 13.9 h for the fresh autologous platelets (Control), (T-ΔC: 72.3 ± 8.8%: 95% confidence interval [CI]: 68.5, 76.1) and mean 24-h post-transfusion recovery 37.6 ± 8.4% for Test versus 56.8 ± 9.2% for Control (T-ΔC: 66.2 ± 11.2%; 95% CI: 61.3, 71.1).PRPCs collected in both 100% plasma as well as 65% PAS-3/35% plasma and stored for 7 days retained in vitro physiologic characteristics. PRPCs stored in 100% plasma for 7 days retained in vivo survival. Lower in vivo post-radiolabeled autologous platelet recovery is consistent with reported reduced count increments for allogenic transfusion.

Background Pathogen reduction technology and enhanced bacterial culture screening promise to significantly reduce the risk of transfusion-associated septic reactions due to contaminated platelets. Recent reports suggest that these interventions lack efficacy for post-collection and processing contamination with environmental organisms if the storage bag integrity is compromised. Case report We report a fatal septic transfusion reaction in a 63-year-old patient with chronic kidney and liver disease who received a pathogen reduced platelet transfusion in anticipation of surgery. Methods The residual platelet concentrate was cultured, with the detected microorganisms undergoing 16S genotype sequencing. Separate pathogen reduction studies were performed on the recovered bacteria, including assessment for amotosalen photoproducts. The storage container was subjected to pressure testing and microscopic examination. Environmental culture screening was performed at the hospital. Results Gram negative rods were detected in the platelet unit and cultures of both platelet component and the patient's blood grew Acinetobacter baumannii complex, Leclercia adecarboxylata and Staphylococcus saprophyticus. These strains were effectively inactivated with >7.2, 7.7, and >7.1 log10 kill, respectively. The platelet storage container revealed a leak visible only on pressure testing. Hospital environmental cultures were negative and the contamination source is unknown. A. baumannii complex and S. saprophyticus 16S genotyping sequences were identical to those implicated in a previously reported septic reaction. Conclusion Findings are compatible with post-processing environmental contamination of a pathogen reduced platelet concentrate via a non-visible, acquired storage container leak. Efforts are warranted to actively prevent damage to, and detect defects in, platelet storage containers, and to store and transport components in clean environments.

BACKGROUND Universal pathogen inactivation of platelet concentrates (PCs) using amotosalen/ultraviolet A with 7-day storage was implemented in Switzerland in 2011. Routine-use data were analyzed at the University Hospital Basel, Switzerland. STUDY DESIGN A retrospective two-cohort study of patient and PC characteristics, component usage, patient outcomes, count increments (CIs), and adverse events were analyzed for two consecutive 5-year periods with either 0- to 5-day-old conventional PC (C-PC) (n = 14,181) or 0- to 7-day-old pathogen-inactivated PC (PI-PC) (n = 22,579). RESULTS In both periods, PCs were issued for transfusion on a "first in, first out" basis. With 7-day PI-PC, wastage was reduced from 8.7% to 1.5%; 16.6% of transfused PI-PCs were more than 5 days old. Transfusion of PI-PC more than 5 days old compared with 5 days old or less did not increase platelet and RBC use on the same or next day as an indirect measure of hemostasis and did not increase transfusion reactions. Mean corrected count increments (CCIs) for PI-PC stored for 5 days or less were 22.6% lower than for C-PC (p

WOS: 000478608100031, PubMed ID: 31148155, Transfusion-dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen-reduced (PR) Amustaline-Glutathione (A-GSH) RBCC for TDT. Patients were randomized to a blinded 2-period crossover treatment sequence for six transfusions over 8-10 months with Control and A-GSH-RBCC. The efficacy outcome utilized non-inferiority analysis with 90% power to detect a 15% difference in transfused haemoglobin (Hb), and the safety outcome was the incidence of antibodies to A-GSH-PR-RBCC. By intent to treat (80 patients), 12 center dot 5 +/- 1 center dot 9 RBCC were transfused in each period. Storage durations of A-GSH and C-RBCC were similar (8 center dot 9 days). Mean A-GSH-RBCC transfused Hb (g/kg/day) was not inferior to Control (0 center dot 113 +/- 0 center dot 04 vs. 0 center dot 111 +/- 0 center dot 04, P = 0 center dot 373, paired t-test). The upper bound of the one-sided 95% confidence interval for the treatment difference from the mixed effects model was 0 center dot 005 g/kg/day, within a non-inferiority margin of 0 center dot 017 g/kg/day. A-GSH-RBCC mean pre-transfusion Hb levels declined by 6 center dot 0 g/l. No antibodies to A-GSH-RBCC were detected, and there were no differences in adverse events. A-GSH-RBCCs offer potential to reduce infectious risk in TDT with a tolerable safety profile., Ege University Hospital Blood Centre, Izmir, Turkey

On November 29, 2018, experts in the field of infectious diseases, pathogen reduction technologies (PRTs) and other participants from blood centers, academia, and industry gathered at the Food and Drug Administration (FDA) White Oak Campus in Silver Spring, Maryland, for a 2‐day public workshop entitled “Pathogen Reduction Technologies for Blood Safety.” The workshop opened with welcome remarks from Dr. Nicole Verdun, Director, Office of Blood Research and Review (OBRR), Center for Biologics Evaluation and Research (CBER), FDA, followed by introductory remarks from Dr. Peter Marks, Director, CBER, FDA. The first day of the workshop focused on blood‐borne infectious agents and their impact on blood safety, experiences of the American Red Cross, and other blood establishments in implementing FDA‐approved pathogen inactivation (PI) technology for plasma and platelets (PLTs) in the United States and novel PRTs under consideration for whole blood (WB) and red blood cells (RBCs). The second day opened with welcome remarks from Dr. Chintamani Atreya, Associate Director for Research, OBRR, CBER, FDA. The focus was on emerging innovations relevant to PRTs and potential alternatives to PRTs. The workshop concluded with remarks on insights for future research and development in this area for blood and blood product safety from infectious agents. A brief introduction of each session by the session moderator followed by a summary of the speaker presentation as submitted by the moderator and speaker are reported here.

Background Leukoreduction (LR) of platelet concentrate (PC) has evolved as the standard to mitigate risks of alloimmunization, clinical refractoriness, acute transfusion reactions (ATRs), and cytomegalovirus infection, but does not prevent transfusion-associated graft-versus-host disease (TA-GVHD). Amotosalen-ultraviolet A pathogen reduction (A-PR) of PC reduces risk of transfusion-transmitted infection and TA-GVHD. In vitro data indicate that A-PR effectively inactivates WBCs and infectious pathogens. Study design and methods A sequential cohort study evaluated A-PR without LR, gamma irradiation, and bacterial screening in hematopoietic stem cell transplant (HSCT) recipients. The first cohort received conventional PC (control) processed without LR, but with gamma irradiation and bacterial screening. The second cohort received A-PR PC (test) processed without: LR, bacterial screening, or gamma irradiation. The primary efficacy outcome was the 1-hour corrected count increment. The primary safety outcome was treatment-emergent ATR. Secondary outcomes included clinical refractoriness, and 100-day status for engraftment, TA-GVHD, HSCT-GVHD, infections, and mortality. Results Mean corrected count increment (× 103 ) of 33 test PC recipients was similar (18.9 ± 8.8 vs. 16.6 ± 8.4; p = 0.296) to that of 31 control PC recipients. Test recipients had a reduced, but nonsignificant, incidence of ATR (test = 9.1%, Control = 19.4%; p = 0.296). The frequencies of clinical refractoriness (0 of 33 vs. 4 of 31 patients) and refractory transfusions (6.6% vs. 19.3%) were lower in the test cohort (p = 0.05 and 0.02), respectively. No patient in either cohort had TA-GVHD. Day 100 engraftment, HSCT-GVHD, mortality, and infectious disease complications were similar between cohorts. Conclusions This study indicated that A-PR PC without LR, gamma irradiation, or bacterial screening is feasible for support of HSCT.

Transfusion-associated graft versus host disease (TA-GVHD) is a highly morbid and often fatal adverse event associated with transfusion of cellular blood products [platelets, red blood cells (RBCs) and whole blood] and more rarely with never-frozen plasma products. It is caused by residual viable donor T-lymphocytes that proliferate and actively target recipient tissues. Selective or universal irradiation of blood components using gamma-irradiation and more recently, X-ray irradiation, are the most commonly applied interventions and have been validated by the demonstration of in vitro T-lymphocyte inactivation, in murine models of TA-GVHD and by years of clinical experience. Irradiation, however, has multiple limitations including a sharp dose-response curve that renders quality control of dosage critically important, the use of radioactive radiation sources that are a terrorism risk, and selective implementation in many countries that leads to inadvertent omission and patient risk exposure. Certain pathogen reduction technologies (PRT) for platelets have been approved by regulatory authorities and endorsed by professional societies as an alternative to irradiation for reducing the risk of TA-GVHD, and PRT for RBCs and whole blood are in development. While the mechanism of action of T-lymphocyte inactivation differs from gamma/X-ray irradiation, the impact on T-lymphocyte inactivation for PRT is equivalent or superior to that of irradiation as demonstrated by sensitive in vitro lymphocyte proliferation assays and in vivo mouse models that approximate human TA-GVHD. Clinical trials and cumulative routine-use experience attest to the efficacy of PRT when used as an alternative to irradiation. While T-lymphocyte inactivation efficacy varies between PRT platforms, the implementation of PRT for platelets increases blood safety for patients beyond the mitigation of TA-GVHD, by decreasing the risk of transfusion transmitted infections with known viruses, bacteria and parasites as well as emerging pathogens.

Strategies to reduce platelet (PLT) bacterial contamination include donor screening, skin disinfection, sample diversion, bacterial culture, pathogen reduction (PR), and day-of-transfusion tests. We report bacterial sepsis following a pathogen-reduced PLT transfusion.An adult male with relapsed acute lymphoblastic leukemia was successfully treated for central catheter-associated Staphylococcus aureus bacteremia. A peripherally inserted central catheter (PICC) was placed. Chills, rigors, and flushing developed immediately after PICC-infused pathogen-reduced PLTs, progressing to septic shock requiring intensive care management.PICC and peripheral blood (PB), transfused bag saline flushes (TBFs), environmental samples, and the pathogen-reduced untransfused co-component (CC) were cultured. Plasma metagenomic and bacterial isolate whole-genome sequencing; PLT mitochondrial DNA (mtDNA) testing of untransfused CC and TBF; CC testing for amotosalen (S-59)/S-59 photoproducts; isolate PR studies (INTERCEPT); and TBF polymerase chain reaction for recipient Y-chromosome DNA were performed.PB and PICC cultures grew Acinetobacter calcoaceticus/baumannii complex (ACBC). TBF was gram-positive; mass spectrometry identified ACBC and Staphylococcus saprophyticus (SS). CC Gram stain and cultures were negative. Environmental cultures, some done after decontamination, were ACBC/SS negative. Posttransfusion patient plasma and TBF ACBC sequences were genetically identical. No Y-chromosome signal was detected in TBF. S-59 photoproducts and evidence of mtDNA amplification inhibition were found in the CC. Spiking PR studies showed5.9-log inactivation for both isolates. Donor skin cultures for Acinetobacter were negative.CC sterility, PR studies, residual S-59 photoproducts, and mtDNA amplification inhibition suggest successful PR. Unidentified environmental sources and inherent or acquired bag defects may have contributed to postmanufacturing pathogen-reduced PLT contamination.

Background Strategies to reduce platelet (PLT) bacterial contamination include donor screening, skin disinfection, sample diversion, bacterial culture, pathogen reduction (PR), and day-of-transfusion tests. We report bacterial sepsis following a pathogen-reduced PLT transfusion. Case report An adult male with relapsed acute lymphoblastic leukemia was successfully treated for central catheter-associated Staphylococcus aureus bacteremia. A peripherally inserted central catheter (PICC) was placed. Chills, rigors, and flushing developed immediately after PICC-infused pathogen-reduced PLTs, progressing to septic shock requiring intensive care management. Methods PICC and peripheral blood (PB), transfused bag saline flushes (TBFs), environmental samples, and the pathogen-reduced untransfused co-component (CC) were cultured. Plasma metagenomic and bacterial isolate whole-genome sequencing; PLT mitochondrial DNA (mtDNA) testing of untransfused CC and TBF; CC testing for amotosalen (S-59)/S-59 photoproducts; isolate PR studies (INTERCEPT); and TBF polymerase chain reaction for recipient Y-chromosome DNA were performed. Results PB and PICC cultures grew Acinetobacter calcoaceticus/baumannii complex (ACBC). TBF was gram-positive; mass spectrometry identified ACBC and Staphylococcus saprophyticus (SS). CC Gram stain and cultures were negative. Environmental cultures, some done after decontamination, were ACBC/SS negative. Posttransfusion patient plasma and TBF ACBC sequences were genetically identical. No Y-chromosome signal was detected in TBF. S-59 photoproducts and evidence of mtDNA amplification inhibition were found in the CC. Spiking PR studies showed >5.9-log inactivation for both isolates. Donor skin cultures for Acinetobacter were negative. Conclusion CC sterility, PR studies, residual S-59 photoproducts, and mtDNA amplification inhibition suggest successful PR. Unidentified environmental sources and inherent or acquired bag defects may have contributed to postmanufacturing pathogen-reduced PLT contamination.

Background The INTERCEPT™ Blood System for Red Blood Cells (RBCs) utilizes amustaline (S-303) and glutathione (GSH) to inactivate pathogens and leukocytes in transfused RBCs. Treatment-emergent low titer non-hemolytic antibodies to amustaline/GSH RBC were detected in clinical trials using a prior version of the process. The amustaline/GSH process was re-formulated to decrease S-303 RBC adduct formation. Study design and methods A standard three-cell antibody screening panel was modified to include reagent red cells (RRC) with high (S-303H) or low (S-303L) S-303 adduct density as assessed by flow cytometry, representative of the original and current amustaline/GSH treatment processes, respectively. General hospital and RBC transfusion-dependent patients never exposed, and clinical trial subjects exposed to amustaline/GSH RBC were screened for antibodies to amustaline/GSH RBC using a standardized agglutination assay. Results Twelve (0.1%) of 10,721 general hospital and 5 (0.5%) of 998 repeatedly-transfused patients not previously exposed to amustaline/GSH RBCs expressed natural, low titer (2-32) IgM and/or IgG (non-IgG1 or IgG3 isotype) antibodies with acridine (a structural element of amustaline) (n = 14) or non-acridine (n = 3) specificity. 11 of 17 sera reacted with S-303L panel RRCs. In clinical studies 81 thalassemia and 25 cardiac surgery patients were transfused with a total of 1085 amustaline/GSH RBCs and no natural or treatment-emergent S-303 antibodies were detected. Conclusion Standardized RRC screening panels are sensitive for the detection of natural and acquired S-303-specific antibodies. Natural low titer antibodies to amustaline/GSH RBC are present in 0.15% of naive patients. The clinical relevance of these antibodies appears minimal but is under further investigation.

Background Nucleic acid-targeted pathogen inactivation technology using amustaline (S-303) and glutathione (GSH) was developed to reduce the risk of transfusion-transmitted infectious disease and transfusion-associated graft-versus-host disease with red blood cell (RBC) transfusion. Study design and methods A randomized, double-blind, controlled study was performed to assess the in vitro characteristics of amustaline-treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6-minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline-treated RBCs. Results A total of 774 RBC unis were produced. Mean treatment difference in Hb content was -2.27 g/unit (95% confidence interval, -2.61 to -1.92 g/unit), within the prespecified equivalence margins (±5 g/unit) to declare noninferiority. Amustaline-treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline-treated RBCs. Conclusion Amustaline-treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery.

Background. Platelet transfusion is a critical therapy for hematology-oncology patients at risk of transfusion-transmitted infection (TTI) and pulmonary injury. Amotosalen-UVA pathogen reduction (PR) treatment of apheresis platelet components (PC) in plasma or additive solution (INTERCEPT Blood System for Platelets, Cerus, Concord, CA) is FDA approved to reduce risk of TTI and transfusion associated graft vs. host disease (TA-GVHD). PRPC meet the FDA bacteria risk reduction guidance, and approximately 50% of U.S. PC are PRPC. Amotosalen-UVA PR replaces bacteria screening, gamma irradiation, and CMV serology. PR is performed within 24 hours of collection enabling early release of PRPC with 5-day storage. We tested the hypothesis that PRPC were not inferior to conventional PC(CPC) for the incidence of pulmonary injury. Methods. An open-label sequential cohort study in platelet transfusion dependent hematology-oncology patients was conducted under routine practice conditions in 15 clinical centers. Each site enrolled a CPC cohort followed by a PRPC cohort using 4 primary therapy strata matched ± 10%: chemotherapy without hematopoietic cell transplant (HCT), HCT with myeloablation, HCT with non-myeloablative conditioning, and HCT with reduced intensity conditioning (RIC). Patients were supported with the assigned PC type for up to 21 days with 7 days of surveillance after the last PC exposure. Patients participated in only one cohort. The primary endpoint was treatment emergent assisted mechanical ventilation (TEAMV) by intubation or tight mask with positive end expiration pressure (5cm H 2O) after initiation of study PC. All endpoint patients were adjudicated by a blinded pulmonary expert panel (PEP) for diagnosis of acute respiratory distress syndrome (ARDS) by the Berlin Criteria. Secondary endpoints included: time to initiation of TEAMV, clinically significant pulmonary adverse events (CSPAE, CTCAE ≥ Grade 2), transfusion reactions, and mortality. The incidence of TEAMV by non-inferiority (margin = 2.3%), and secondary endpoints were analyzed by modified intention to treat (mITT) and per protocol (PP). Sensitivity analyses with propensity score matching for key variables were conducted for the primary endpoint. The associations between PC and categorical variables were tested by stratified Cochran-Mantel-Haenszel and continuous variables by ANOVA for two-sided significance p = 0.05. results. A total of 2291 pediatric and adult patients (1068 PRPC and 1223 CPC) were enrolled in the respective cohorts with transfusion of 5,277 PRPC and 5,491 CPC. PC assignment compliance and study completion were > 94%. For the mITT data set, the cumulative incidence of TEAMV was lower for the PRPC cohort (log rank p = 0.039) than the CPC cohort (2.9% versus 4.6%, HR = 0.633: 95% CI 0.408-0.982). PRPC by mITT were non-inferior to CPC for the incidence of TEAMV due to all indications, and for TEAMV with pulmonary dysfunction (PD) by PEP (Table). PP analyses were consistent with mITT. Relative risk (RR) of TEAMV showed significantly (p Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Nooka: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Adaptive technologies: Consultancy; GlaxoSmithKline: Consultancy, Other: Travel expenses; Karyopharm Therapeutics: Consultancy. Uhl: UpToDate: Patents & Royalties; Abbott: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau. Spinella: Secure Transfusion Services: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cerus Corporation: Consultancy, Research Funding. Liu: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Benjamin: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Corash: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company.

BACKGROUND Delayed, large-volume bacterial culture and amotosalen/ultraviolet-A light pathogen reduction are effective at reducing the risk of bacterial proliferation in platelet concentrates (PCs). Hemovigilance programs continue to receive reports of suspected septic transfusion reactions, most with low imputability. Here, we compile national hemovigilance data to determine the relative efficacy of these interventions. STUDY DESIGN AND METHODS Annual reports from the United Kingdom, France, Switzerland, and Belgium were reviewed between 2005 and 2016 to assess the risk of bacterial contamination and septic reactions. RESULTS Approximately 1.65 million delayed, large-volume bacterial culture-screened PCs in the United Kingdom and 2.3 million amotosalen/ultraviolet-A–treated PCs worldwide were issued with no reported septic fatalities. One definite, one possible, and 12 undetermined/indeterminate septic reactions and eight contaminated “near misses” were reported with delayed, large-volume bacterial cultures between 2011 and 2016, for a lower false-negative culture rate than that in the previous 5 years (5.4 vs. 16.3 per million: odds ratio, 3.0; 95% confidence interval, 1.4-6.5). Together, the Belgian, Swiss, and French hemovigilance programs documented zero probable or definite/certain septic reactions with 609,290 amotosalen/ultraviolet-A–treated PCs (

BACKGROUND Plasma thawed and stored at 1 to 6°C for up to 5 days (thawed plasma [TP]) provides rapid availability in emergencies and reduces plasma waste, but it carries risks of coagulation factor loss or activation, bacterial outgrowth, and viral contamination. We characterized changes in amotosalen/ultraviolet A (UVA) light pathogen-reduced, fresh-frozen plasma (FFP) and plasma frozen within 24 hours (PF24) with post-thaw storage. STUDY DESIGN AND METHODS Amotosalen/UVA light-treated FFP and PF24 were thawed after approximately 3 to more than 12 months of frozen storage and held at 1 to 6°C for 5 days. Global assessments of coagulation and hemostatic, antithrombotic, and activation markers indicative of function were assessed. RESULTS Day 5, thawed amotosalen/UVA light-treated FFP and PF24 contained levels of Factors II, V, VIII, IX, X, von Willebrand factor ristocetin cofactor (vWF:RCo), fibrinogen, antithrombin III (ATIII), protein C, and protein S similar to the levels measured in Day 5 TP, as described in the Circular of Information. Thrombin generation was robust on Day 5 (amotosalen/UVA: FFP = 1866 ± 402 nM/minute; PF24 = 1800 ± 277 nM/minute). Most factor activities on Day 5, including von Willebrand factor-cleaving protease (ADAMTS-13), were more than 90% of Day 0 values, except for known labile Factors V and VIII and protein S. All units contained greater than 0.4 IU/mL protein S and α2 plasmin inhibitor on Day 5. Global functional indices, including thrombin-antithrombin complexes, nonactivated thromboplastin time, and thrombin-generation peak height, did not indicate activation of the coagulation cascade, although isolated units showed raised levels of Factor VIIa and Complement 3a. CONCLUSION Amotosalen/UVA light-treated FFP and PF24 demonstrated retention of procoagulant and antithrombotic activity after 5 days post-thaw storage at 1 to 6°C.

Background In 2014, passive immunization by transfusion of Ebola convalescent plasma (ECP) was considered for treating patients with acute Ebola virus disease (EVD). Early Ebola virus (EBOV) seroconversion confers a survival advantage in natural infection, hence transfusion of ECP plasma with high levels of neutralizing EBOV antibodies is a potential passive immune therapy. Techniques to reduce the risk of other transfusion-transmitted infections (TTIs) are warranted as recent ECP survivors are ineligible as routine blood donors. As part of an ongoing clinical trial to evaluate the safety and effectiveness of ECP, the impact of amotosalen/UVA pathogen reduction technology (PRT) on EBOV antibody characteristics was examined. Study design and methods Serum and plasma samples were collected from EVD-recovered subjects at multiple timepoints and evaluated by ELISA for antibodies to recombinant EBOV glycoprotein (GP) and irradiated whole EBOV antigen, as well as for EBOV microneutralization, classic plaque reduction neutralization test (PRNT) and EBOV pseudovirion neutralization assay (PsVNA) activity. Results Six subjects donated 40 individual ECP units. Substantial antibody titers and neutralizing activity results were demonstrated but were generally lower for the ACD plasma samples compared to the serum samples. Anti-EBOV titers by all assays remained essentially unchanged after PRT. Conclusion Treatment of ECP with PRT to reduce the risk of TTI did not significantly reduce EBOV IgG antibody titers or neutralizing activity. Although ECP was used in the treatment of repatriated patients, no PRT units from this study were transfused to EVD patients. This inventory of PRT-treated ECP is currently available for future clinical evaluation.

Background Zika virus (ZIKV) spread to Puerto Rico likely originated from southeastern Brazil approximately 8.5 months earlier than blood donation screening for ZIKV was initiated, but the time of ZIKV introduction in the blood donor population remains unknown. Methods To better understand when arboviral infections first appeared in the blood donor pool in Puerto Rico, we retrospectively screened for ZIKV RNA (as well as chikungunya [CHIKV] and dengue [DENV] viral RNA) a repository of 1186 linked blood donor and recipient samples collected from February 2015 to May 2016 as an endpoint efficacy measure following the introduction of platelet pathogen reduction (PR). Phylogenetic analysis identified relatedness of donor strain to other circulating strains, and molecular clock analysis identified the estimated time of introduction. Results An asymptomatic donor collected in December 2015 was ZIKV RNA confirmed positive, 4 months BEFORE investigational nucleic acid testing (NAT) implementation in April 2016, coincident and related to the first reported autochthonous cases. No CHIKV RNA or DENV RNA reactives were identified in donors or recipients, and no adverse events were reported from PR use in recipients. Phylogenetic analysis confirmed the molecular relatedness of the donor ZIKV strain to the Puerto Rico lineage likely introduced approximately 4.5 months earlier. Conclusion This study identified an asymptomatic ZIKV infection in a blood donor occurring before those previously recognized by blood donation screening. NAT and PR continue to be used as acceptable strategies to prevent transfusion-transmitted arboviral infections worldwide; however, repeated arboviral outbreaks warrant consideration of PR as a more proactive approach.

Clinical governance was first introduced in the U.K. in response to catastrophic failures in a healthcare system focused on efficiency and cost containment. Lessons learned regarding management responsibility for patient outcomes can be applied to transfusion medicine. The concept of clinical governance will be explored in the context of the changing transfusion medicine environment. Blood collectors are regulated using current good manufacturing principles (cGMP) that ensure product quality, and the concepts of organizational corporate governance are well established. In contrast, the process of transfusion is considered medical practice. Clinical governance is a system through which organizations are accountable for continuously improving their patient services and safeguarding high standards of patient care by creating an environment in which clinical excellence will flourish. For transfusion, this incorporates ensuring staff have the appropriate training and their performance is audited. Certification in transfusion principles, continuous education and maintenance of skills are required. The clinical effectiveness of transfusion should be monitored, and research focused on ensuring appropriate transfusion indications. Hemovigilance systems focused on adverse outcomes highlight areas for potential improvement but only if data-based interventions are implemented. An environment is necessary that fosters open reporting and discussion of problems, with formalized corrective action plans leading to continuous clinical quality improvement supported by risk management principles. Clinical governance principles should be applied to transfusion medicine in order to ensure optimum patient outcomes in an environment of limited resources, with responsibility firmly ensconced at the highest level of the organization.

Background and Objectives Blood Centre logistics, staffing and donor scheduling may be optimized if pathogen inactivation (PI) of platelets can be delayed until Day 1, but bacteria may rapidly grow during this time. This study evaluates bacterial PI performed 24 and 30 h after collection. Materials and Methods PAS-3 platelet units were collected on the Amicus and subsequently inoculated (3–53 CFU/unit) with 1of 5 transfusion relevant bacterial species (n = 3/organism). Units were then stored for either 24 ± 0·3 or 30 ± 0·3 h at 20–24°C with agitation, subsequently treated with amotosalen and UVA, and stored for 7 days. Samples were taken before and after inactivation, on Days 2, 5 and 7 for BacT/ALERT testing, and on Days 5 and 7 for plate counts. Results All samples from units taken prior to inactivation either demonstrated positive plate culture counts, or, in untreated positive controls, were culture-positive during storage. All contaminated units treated with amotosalen and UVA 24 after inoculation were culture-negative on all days tested. With inactivation performed 30 h following inoculation, one of 15 units (1-of-3 replicates) was culture-positive with Klebsiella pneumonia (1 × 109 CFU/ml) by Day 5. Conclusion Photochemical treatment did not inactivate 1 of 15 units to sterility in apheresis platelets stored in PAS with a 30-h delay between contamination and treatment, but did inactivate 15 of 15 units with a 24-h delay.

BACKGROUND Innovations in transfusion medicine require randomized controlled clinical trials (RCTs) to demonstrate safety and efficacy before approval; however, these studies are costly and limited in scope and may be underpowered to detect rare adverse events (AEs). Regulatory agencies, such as the Food and Drug Administration, require postmarketing surveillance, hemovigilance (HV), and controlled Phase IV studies to monitor performance and confirm safety. STUDY DESIGN AND METHODS The INTERCEPT Blood System (IBS) is an illustrative model for implementation of a transformative technology for which sponsored active HV, regulatory authority HV, and Phase IV studies were used to extend preapproval efficacy and safety information. RESULTS After CE mark registration in Europe, 13,644 patients received 76,346 IBS components prepared largely without gamma irradiation or bacterial screening in sponsored active HV studies documenting no increased incidence of AEs compared to historical controls and no increased component utilization. National HV systems in France and Switzerland specifically demonstrated no transfusion-associated graft-versus-host disease or increased incidence of transfusion-associated acute lung injury, after transfusion of 317,669 IBS platelet (PLT) components, and significant reduction of transfusion-transmitted bacterial infection as well as acute transfusion reactions. Cumulatively, these studies provide new information about safety and efficacy of IBS PLT and plasma components not obtainable from RCTs. CONCLUSION Although inherently different from RCTs, properly designed postmarketing studies are informative regarding the safety and efficacy of innovative transfusion technologies in large patient populations under conditions of routine use.

Objectifs Le procede INTERCEPT™ pour les concentres de globules rouges (CGR) utilise l’amustaline (S-303) et le glutathion (GSH) pour inactiver un large spectre d’agents pathogenes ainsi que les leucocytes. Des essais cliniques de phase 3 ont ete menes chez des patients thalassemiques (THL) [1] ou en chirurgie cardiovasculaire (CCV) [2] . Methode Les patients CCV ont ete randomises pour recevoir des CGR S-303/GSH « Test » ou non-traites « Controle » (Ctrl) sur une periode de 7 jours pendant et apres la chirurgie. Le critere d’evaluation principal etait le contenu moyen en hemoglobine (Hb) par CGR. Dans l’etude THL, les patients ont subi 6 episodes de transfusion avec des CGR Test et Ctrl sur des periodes de traitement croisees. Le critere d’evaluation principal etait la consommation d’Hb. Les criteres d’evaluation secondaires pour les 2 etudes comprenaient : les evenements indesirables receveurs (EIR) et les anticorps anti-GR emergents du traitement. Resultats La teneur en Hb moyenne des CGR repondait aux criteres d’equivalence dans l’etude CCV1 avec une marge de non inferiorite de 5 g ( Tableau 1 ). L’utilisation moyenne d’Hb ( Tableau 2 ) dans l’etude THL2 etait equivalente pour les 2 types de CGR (marge de non-inferiorite Conclusion L’equivalence des CGR S-303/GSH aux CGR temoins a ete demontree chez des patients CCV et THL. Avec une incidence en EIR equivalente et sans apparition d’anticorps anti-CGR traites, la securite transfusionnelle des CGR traites a ete egalement observee.

Delayed, large-volume bacterial culture and amotosalen/ultraviolet-A light pathogen reduction are effective at reducing the risk of bacterial proliferation in platelet concentrates (PCs). Hemovigilance programs continue to receive reports of suspected septic transfusion reactions, most with low imputability. Here, we compile national hemovigilance data to determine the relative efficacy of these interventions.Annual reports from the United Kingdom, France, Switzerland, and Belgium were reviewed between 2005 and 2016 to assess the risk of bacterial contamination and septic reactions.Approximately 1.65 million delayed, large-volume bacterial culture-screened PCs in the United Kingdom and 2.3 million amotosalen/ultraviolet-A-treated PCs worldwide were issued with no reported septic fatalities. One definite, one possible, and 12 undetermined/indeterminate septic reactions and eight contaminated "near misses" were reported with delayed, large-volume bacterial cultures between 2011 and 2016, for a lower false-negative culture rate than that in the previous 5 years (5.4 vs. 16.3 per million: odds ratio, 3.0; 95% confidence interval, 1.4-6.5). Together, the Belgian, Swiss, and French hemovigilance programs documented zero probable or definite/certain septic reactions with 609,290 amotosalen/ultraviolet-A-treated PCs (1.6 per million). The rates were significantly lower than those reported with concurrently transfused, nonpathogen-reduced PCs in Belgium (4.4 vs. 35.6 per million: odds ratio, 8.1; 95% confidence interval,1.1-353.3) and with historic septic reaction rates in Switzerland (6.0 vs. 82.9 per million: odds ratio, 13.9; 95% confidence interval, 2.1-589.2), and the rates tended to be lower than those from concurrently transfused, nonpathogen-reduced PCs in France (4.7 vs. 19.0 per million: odds ratio, 4.1; 95% confidence interval, 0.7-164.3).Pathogen reduction and bacterial culture both reduced the incidence of septic reactions, although under-reporting and strict imputability criteria resulted in an underestimation of risk.

Nucleic acid-targeted pathogen inactivation technology using amustaline (S-303) and glutathione (GSH) was developed to reduce the risk of transfusion-transmitted infectious disease and transfusion-associated graft-versus-host disease with red blood cell (RBC) transfusion.A randomized, double-blind, controlled study was performed to assess the in vitro characteristics of amustaline-treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6-minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline-treated RBCs.A total of 774 RBC unis were produced. Mean treatment difference in Hb content was -2.27 g/unit (95% confidence interval, -2.61 to -1.92 g/unit), within the prespecified equivalence margins (±5 g/unit) to declare noninferiority. Amustaline-treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline-treated RBCs.Amustaline-treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery.

Background and Objectives Interventions to prevent and detect bacterial contamination of platelet concentrates (PCs) have reduced, but not eliminated the sepsis risk. Standardized bacterial strains are needed to validate detection and pathogen reduction technologies in PCs. Following the establishment of the First International Reference Repository of Platelet Transfusion-Relevant Bacterial Reference Strains (the ‘repository’), the World Health Organization (WHO) Expert Committee on Biological Standardisation (ECBS) endorsed further repository expansion. Materials and Methods Sixteen bacterial strains, including the four repository strains, were distributed from the Paul-Ehrlich-Institut (PEI) to 14 laboratories in 10 countries for enumeration, identification and growth measurement on days 2, 4 and 7 after low spiking levels [10–25 colony-forming units (CFU)/PC bag]. Spore-forming (Bacillus cereusPEI-B-P-07-S, Bacillus thuringiensisPEI-B-P-57-S), Gram-negative (Enterobacter cloacaePEI-B-P-43, Morganella morganiiPEI-B-P-74, PEI-B-P-91, Proteus mirabilisPEI-B-P-55, Pseudomonas fluorescensPEI-B-P-77, Salmonella choleraesuisPEI-B-P-78, Serratia marcescensPEI-B-P-56) and Gram-positive (Staphylococcus aureusPEI-B-P-63, Streptococcus dysgalactiaePEI-B-P-71, Streptococcus bovisPEI-B-P-61) strains were evaluated. Results Bacterial viability was conserved after transport to the participating laboratories with one exception (M. morganiiPEI-B-P-74). All other strains showed moderate-to-excellent growth. Bacillus cereus, B. thuringiensis, E. coli, K. pneumoniae, P. fluorescens, S. marcescens, S. aureus and S. dysgalactiae grew to >106 CFU/ml by day 2. Enterobacter cloacae, P. mirabilis, S. epidermidis, S. bovis and S. pyogenes achieved >106 CFU/ml at day 4. Growth of S. choleraesuis was lower and highly variable. Conclusion The WHO ECBS approved all bacterial strains (except M. morganiiPEI-B-P-74 and S. choleraesuisPEI-B-P-78) for repository enlargement. The strains were stable, suitable for spiking with low CFU numbers, and proliferation was independent of the PC donor.

The BacT/ALERT microbial detection system (bioMerieux, Inc, Durham, NC) is in routine use in many blood centers as a prerelease test for platelet collections. Published reports document wide variation in practices and outcomes. A systematic review of the English literature was performed to describe publications assessing the use of the BacT/ALERT culture system on platelet collections as a routine screen test of more than 10 000 platelet components. Sixteen publications report the use of confirmatory testing to substantiate initial positive culture results but use varying nomenclature to classify the results. Preanalytical and analytical variables that may affect the outcomes differ widely between centers. Incomplete description of protocol details complicates comparison between sites. Initial positive culture results range from 539 to 10 606 per million (0.054%-1.061%) and confirmed positive from 127 to 1035 per million (0.013%-0.104%) donations. False-negative results determined by outdate culture range from 662 to 2173 per million (0.066%-0.217%) and by septic reactions from 0 to 66 per million (0%-0.007%) collections. Current culture protocols represent pragmatic compromises between optimizing analytical sensitivity and ensuring the timely availability of platelets for clinical needs. Insights into the effect of protocol variations on outcomes are generally restricted to individual sites that implement limited changes to their protocols over time. Platelet manufacturers should reassess the adequacy of their BacT/ALERT screening protocols in light of the growing international experience and provide detailed documentation of all variables that may affect culture outcomes when reporting results. We propose a framework for a standardized nomenclature for reporting of the results of BacT/ALERT screening.

Contexte La reduction des agents pathogenes par amotosalen/UVA (INTERCEPT™ (IA)) pour les concentres de plaquettes (CP) dont 80 a 90 % proviennent d’apherese, est utilisee en routine par notre institution. Les CP sont conserves pendant 7 jours maximums. Objectif Evaluer l’impact de la duree de conservation sur l’efficacite therapeutique des CP-IA pour les patients en hematologie-oncologie et ceux subissant une greffe de cellules souches hematopoietiques (GCSH) allogenique. Methodes Les increments plaquettaires (CI) et CI corriges (CCI) ont ete obtenus 1 a 4 heures apres la transfusion. Le risque d’echec de l’hemostase a ete evalue par la necessite d’une transfusion supplementaire de CP ou de concentres de globules rouges (CGR) le jour de la transfusion de CP ou le jour suivant. Resultats Voir Tableau 1 . De 2011 a 2016, 22578 CP ont ete transfuses a 2809 patients. 16,6 % des CP etaient âges de > 5 jours. Les GCSH representaient 14,8 % de la population (13,1 % allogreffes) et ont utilise 50,6 % des CP. La dose moyenne de plaquettes etait de 3,0 ± 0,4 × 10 11 , avec une duree de conservation moyenne de 4,1 ± 1,4 jours. Les CI et CCI ont diminue de facon lineaire avec l’âge des CP. L’utilisation de CP ou de CGR supplementaire(s) le jour meme ou le lendemain d’une transfusion de CP n’a pas augmente avec la duree de stockage. Le delai median avant la prochaine transfusion de CP (1,0 jour) n’etait pas affecte par la duree de conservation du CP. Conclusion L’augmentation de la duree de conservation des CP a ete associee a une diminution des CI et CCI mais n’affecte pas l’hemostase, comme en temoigne l’absence de besoin en CP ou de CGR supplementaires le jour meme ou suivant la transfusion de CP-IA.

BACKGROUND HAIs create a major logistical, financial and patient safety concerns within the healthcare system. Bacterial contamination of platelet components (PCs) is the most common, under recognized, infectious risk of transfusion and contributor to HAIs. Contaminated PCs can lead to central line-associated bloodstream infections, bacteremia, and sepsis, with major long term complications and/or death. While US blood centers employ primary bacterial culture screening (pBCS) today, FDA's Draft Guidance and Blood Products Advisory Committee recommend additional approaches to reduce continued risk including FDA-approved pathogen reduction technology (PRT). Our objective is to determine whether PRT is an effective means to reduce the infectious risk of PCs. METHODS We compiled national hemovigilance (HV) data (2006-2016) from the UK, France, Switzerland, Belgium and the US to examine use of pBCS and PRT with amotosalen/UVA and their associated reports of PC bacterial contamination and sepsis. RESULTS Introduction of pBCS decreased HV reports of PC bacterial contamination in the US by 72.5% (p 700,000 PRT PCs over the same time period. CONCLUSIONS pBCS does not eliminate the risk of bacterial contamination; In its Draft Guidance, FDA acknowledges this shortcoming and recommends further measures. In contrast, PRT inactivates a broad spectrum of pathogens present in PCs, regardless of low level contamination, eliminating the need for pBCS. PRT provides clinicians and patients with transfusion-ready PCs, mitigating the risk of transfusion-transmitted infections and representing an approach to increase hospital safety while reducing the financial challenges of transfusion-related HAIs.

Background Allergic transfusion reaction (ATR) incidence ranges from 1% to 3% of all transfusions. We evaluated the impact of InterSol platelet additive solution (PAS) apheresis platelets (APs) on the incidence of ATRs and the posttransfusion platelet (PLT) increment. Study Design and Methods This retrospective study evaluated all ATRs among patients at a university hospital that maintained a mixed inventory of PAS APs and non-PAS APs (standard plasma-suspended PLTs). Corrected count increments (CCIs) were calculated for AP transfusions of individuals who received both a PAS and a non-PAS AP transfusion within a 7-day period. Hypothesis testing was performed with chi-square test for dichotomous variables and t tests for continuous variables. Results The incidence of ATRs among the non-PAS APs was 1.85% (72 ATRs/3884 transfusions) and 1.01% (12 ATRs/1194 transfusions) for PAS APs (risk ratio [RR], 0.54; 95% confidence interval [CI] = 0.30-0.99; p = 0.04). However, there was no difference in the incidence of febrile nonhemolytic transfusion reactions between non-PAS APs (incidence, 0.70%; 27/3884) compared to PAS APs (incidence, 0.59%; 7/1194; p = 0.69). Among 223 individuals with paired non-PAS and PAS AP transfusions, the mean CCI at 1 to 4 hours after transfusion was 4932 (95% CI, 4452-5412) for non-PAS APs and was lower for PAS APs (CCI, 3766; 95% CI, 3375-4158; p ≤ 0.001). However, there was no significant difference in mean CCI at 12 to 24 hours between non-PAS (CCI, 2135; 95% CI, 1696-2573) and PAS APs (CCI, 1745; 95% CI, 1272-2217; p = 0.14). Conclusions PAS APs substantially reduce the number of ATRs. CCIs for PAS APs were lower immediately after transfusion, but not significantly different at 12 to 24 hours.

Background Posttransfusion sepsis is typically caused by aerobic bacteria in apheresis platelets (PLTs) that escape detection by routine quality control cultures performed on every donation before components are distributed. We report the first case to implicate an anaerobic isolate, Clostridium perfringens, in apheresis PLTs and investigate its detection in vitro by approved tests. Study Design and Methods The C. perfringens strain was inoculated at high (10-100 colony-forming units [CFUs]/mL) or low (1-10 CFUs/mL) concentrations into apheresis PLTs and evaluated for growth over 5 to 7 days by qualitative plate cultures, culture-based assays (BacT/ALERT 3D), and rapid (PLT PGD) tests. Results C. perfringens grew in only 3 of 8 apheresis PLT units after inoculation at either high (2 units) or low (1 unit) concentrations. The PGD test detected the isolate after 5 days in 1 unit with 4.7 × 105 CFUs/mL but failed at five other time points in units with greater than 105 CFUs/mL. Conclusion C. perfringens demonstrated variable growth in spiked PLTs and was not consistently detected by a rapid test even when high levels of contamination were present. The case underscores the importance of direct observation during transfusion, appropriate clinical management, and immediate reporting of suspected septic reactions to the blood center.

Plasma thawed and stored at 1 to 6Amotosalen/UVA light-treated FFP and PF24 were thawed after approximately 3 to more than 12 months of frozen storage and held at 1 to 6Day 5, thawed amotosalen/UVA light-treated FFP and PF24 contained levels of Factors II, V, VIII, IX, X, von Willebrand factor ristocetin cofactor (vWF:RCo), fibrinogen, antithrombin III (ATIII), protein C, and protein S similar to the levels measured in Day 5 TP, as described in the Circular of Information. Thrombin generation was robust on Day 5 (amotosalen/UVA: FFP = 1866 ± 402 nM/minute; PF24 = 1800 ± 277 nM/minute). Most factor activities on Day 5, including von Willebrand factor-cleaving protease (ADAMTS-13), were more than 90% of Day 0 values, except for known labile Factors V and VIII and protein S. All units contained greater than 0.4 IU/mL protein S and α2 plasmin inhibitor on Day 5. Global functional indices, including thrombin-antithrombin complexes, nonactivated thromboplastin time, and thrombin-generation peak height, did not indicate activation of the coagulation cascade, although isolated units showed raised levels of Factor VIIa and Complement 3a.Amotosalen/UVA light-treated FFP and PF24 demonstrated retention of procoagulant and antithrombotic activity after 5 days post-thaw storage at 1 to 6

Innovations in transfusion medicine require randomized controlled clinical trials (RCTs) to demonstrate safety and efficacy before approval; however, these studies are costly and limited in scope and may be underpowered to detect rare adverse events (AEs). Regulatory agencies, such as the Food and Drug Administration, require postmarketing surveillance, hemovigilance (HV), and controlled Phase IV studies to monitor performance and confirm safety.The INTERCEPT Blood System (IBS) is an illustrative model for implementation of a transformative technology for which sponsored active HV, regulatory authority HV, and Phase IV studies were used to extend preapproval efficacy and safety information.After CE mark registration in Europe, 13,644 patients received 76,346 IBS components prepared largely without gamma irradiation or bacterial screening in sponsored active HV studies documenting no increased incidence of AEs compared to historical controls and no increased component utilization. National HV systems in France and Switzerland specifically demonstrated no transfusion-associated graft-versus-host disease or increased incidence of transfusion-associated acute lung injury, after transfusion of 317,669 IBS platelet (PLT) components, and significant reduction of transfusion-transmitted bacterial infection as well as acute transfusion reactions. Cumulatively, these studies provide new information about safety and efficacy of IBS PLT and plasma components not obtainable from RCTs.Although inherently different from RCTs, properly designed postmarketing studies are informative regarding the safety and efficacy of innovative transfusion technologies in large patient populations under conditions of routine use.

Background The American Red Cross began preferentially distributing plasma from male donors in 2007 and subsequently observed an 80% decrease in reported cases of transfusion-related acute lung injury (TRALI) after plasma transfusion. Plasma distributions from male donors now exceed 99% for groups A, B, and O, but only approximately 60% for group AB. We evaluated the ongoing risk of TRALI and the ABO blood group of involved plasma donors. Study Design and Methods The rate of suspected TRALI per distributed components before (2006) and after (2008-2011) implementing the predominantly male-donor plasma strategy is compared. Results The risk of TRALI from the general inventory of distributed plasma decreased significantly from 18.6 cases per million units in 2006 to 4.2 cases per million units in 2008 to 2011 (p

General use of plasma components includes replacement for multiple coagulation factor deficiencies, for treatment of single coagulation factor deficiencies for which a concentrate is unavailable, and as a replacement fluid used in therapeutic plasma exchange for thrombotic thrombocytopenic purpura. Four major products currently transfused are fresh-frozen plasma (FFP), plasma frozen within 24 hours of phlebotomy (FP24), cryoprecipitate-poor plasma (CPP), and thawed plasma. FP24, CPP, and thawed plasma contain decreased amounts of labile coagulation factors. Pathogen reduction technology has included solvent/detergent, methylene blue, and ultraviolet light irradiation with psoralen or riboflavin treatment and is available in Europe but not in the United States. Pathogen-reduced plasma may contain reduced levels of certain coagulant and/or anticoagulant factors compared to FFP. Clinical findings with pathogen-reduced plasma have provided an impetus to the US Food and Drug Administration to promulgate specific requirements for approval of novel plasma products, some of which may be too burdensome for the industry to readily overcome.

H. W. Reesink, J. Lee, A. Keller, P. Dennington, J. Pink, R. Holdsworth, H. Schennach, M. Goldman, T. Petraszko, J. Sun, Y. Meng, K. Qian, V. Rehacek, P. Turek, T. Krusius, E. Juvonen, P. Tiberghien, D. Legrand, G. Semana, J. Y. Muller, J. Bux, A. Reil, C. K. Lin, H. Daly, E. McSweeney, L. Porretti, N. Greppi, P. Rebulla, H. Okazaki, S. A. Sanchez-Guerrero, H. A. Baptista-Gonzalez, C. Martinez-Murillo, A. Guerra-Marquez, H. Rodriguez-Moyado, R. A. Middelburg, J. C. Wiersum-Osselton, A. Brand, C. van Tilburg, D. Dinesh, J. Dagger, P. Dunn, E. Brojer, M. Letowska, K. Maslanka, E. Lachert, M. Uhrynowska, E. Zhiburt, M. Palfi, G. Berlin, B. M. Frey, L. Puig Rovira, E. Muniz-Diaz, E. Castro, C. Chapman, A. Green, E. Massey, N. Win, L. Williamson, C. C. Silliman, D. J. Chaffin, D. R. Ambruso, N. Blumberg, P. Tomasulo, K. J. Land, P. J. Norris, O. C. Illoh, R. J. Davey, R. J. Benjamin, A. F. Eder, L. McLaughlin, S. Kleinman & S. Panzer