Reconsidering Fresh Frozen Plasma Availability to Reduce Blood Product Waste During Massive Transfusion Events in Trauma.

BACKGROUND: Within component therapy of massive transfusion protocol (MTP) in trauma, thawed plasma is particularly susceptible to expiring without use given its short 5-day shelf life. Optimizing the number of thawed products without compromising safety is important for hospital resource management. The goal is to examine thawed plasma utilization rates in trauma MTP events and optimize the MTP cooler content at our Level I trauma center. METHODS: Trauma MTP activations from 01/2019 to 12/2022 were retrospectively reviewed. During the study period, blood products were distributed in a 12:12:1 ratio of packed red blood cells (pRBC): plasma: platelets per cooler, with up to 4 additional units of low-titer, group O whole blood (LTOWB) available. The primary measure was percent return of unused, thawed plasma. RESULTS: There were 367 trauma MTP activations with a median (IQR) activation call-to-first cooler delivery time of 8 (6-10) minutes. 73.0% of thawed plasma was returned to the blood bank unused. In one third of MTP activations, all dispensed plasma was returned. The majority (74.1%) of patients required 6 or fewer units of plasma. In 81.5% of activations, 10 or fewer units of plasma and 10 or fewer units of pRBC were used. DISCUSSION: The majority of trauma MTP requirements may be accommodated with a reduced cooler content of 6 units pRBC, 6 units plasma, and 1 pheresis platelets, buffered by up to 4 units LTOWB (approximates 4 units of pRBC/4 units plasma), in conjunction with a sub-10min cooler delivery time. Follow-up longitudinal studies are needed.

Correction to: Amanita Mushroom Toxin Poisoning in Los Angeles County.

[This corrects the article DOI: 10.14309/crj.0000000000001246.].

Amanita Mushroom Toxin Poisoning in Los Angeles County.

Mushroom (amatoxin) poisoning from ingestion is a rare but life-threatening medical emergency characterized by gastrointestinal symptoms before progression to multisystem organ failure in severe cases. Many therapies of amatoxin intoxication have been described, including supportive care, medical therapies, detoxification strategies, and liver transplant. The evidence supporting these therapies remains limited due to the rarity of amatoxin poisoning and challenge of a timely diagnosis. We report a case of amatoxin poisoning in Los Angeles causing severe liver injury without acute liver failure treated successfully using medical therapies, gallbladder drainage, and plasma exchange.

Durable remission of thrombotic thrombocytopenic purpura in the setting of pembrolizumab therapy.

BACKGROUND: There is a small but growing number of thrombotic thrombocytopenic purpura (TTP) cases attributed to immune checkpoint inhibitor therapy, with nivolumab and ipilimumab therapy being the most frequently described in the literature. STUDY DESIGN AND METHODS: This report evaluates the course of a patient with a history of metastatic adenocarcinoma of the lung who developed TTP following treatment with the PD-1 inhibitor Pembrolizumab. The patient was treated with six sessions of therapeutic plasma exchange and appeared to be in remission. Exacerbation occurred 4 days later, and seven more sessions of plasma exchange were performed along with four total doses of Rituximab, and a steroid taper with monitoring of platelet counts and ADAMTS13 activity. RESULTS: His platelet count recovered to a peak of 318,000 UL with an ADAMTS13 activity of 77% at the time of discharge. The patient has been following up regularly for outpatient testing with no TTP relapse as of the completion of this report. DISCUSSION: This is one of a few cases of Pembrolizumab-associated TTP reported in the literature with successful complete remission following treatment. Plasma exchange in this setting may be an especially beneficial therapeutic intervention because of the removal of both the anti-ADAMTS13 antibody as well as the immune system upregulating anti-PDL1 monoclonal antibody with replacement of ADAMTS13 from donor plasma. Longer duration of plasma exchange and monitoring for normalization of ADAMTS13 levels in addition to platelet count before cessation of treatment may improve durable remission rates in this entity.

Successful autologous hematopoietic stem cell transplants using Salmonella positive products collected from asymptomatic donors.

BACKGROUND: Bacterial contamination of hematopoietic stem cell (HSC) products is most commonly due to normal skin flora. Salmonella in HSC products is rare, and to our knowledge safe administration of an autologous HSC product containing Salmonella has not been reported. STUDY DESIGN AND METHODS: We describe two patients undergoing autologous HSC transplant: peripheral blood HSC collection was performed by leukapheresis, and samples were cultured according to standard institutional protocol. Subsequent microorganism identification was performed using MALDI-TOF (Bruker Biotyper). Strain-relatedness was investigated by infrared spectroscopy using the IR Biotyper (Bruker). RESULTS: The patients were asymptomatic throughout the collection process; however, HSC products collected on two consecutive days from each patient were positive for Salmonella. Isolates from both cultures were further characterized as Salmonella enterica serovar Dublin by the local public health department. Antibiotic susceptibility testing revealed different sensitivity patterns for the two strains. IR Biotyper demonstrated significant discriminatory power among the clinically significant Salmonella enterica subspecies, serogroups B, C1, and D. The patient strains were similar as both belonged to Group D Salmonella enterica serovar Dublin but were not identical. The Salmonella positive autologous HSC products were infused to both patients following administration of empiric antibiotic therapy. Both patients successfully engrafted and did well. CONCLUSION: Salmonella is rarely seen in cellular therapy products and positivity may be the result of asymptomatic bacteremia at the time of collection. We present two instances of autologous HSC products containing Salmonella that were infused, along with prophylactic antimicrobial therapy without significant adverse clinical effects.

Blood Type A1 Mismatch Does Not Affect Heart Transplant Outcomes at One Year.

There are subtypes within blood type A, termed non-A1, that have reduced expression of A antigen on cell surfaces. This can result in the development of anti-A1 antibodies. There is limited information regarding the impact of this in heart transplant (HTx) recipients. We conducted a single-center cohort study of 142 Type A HTx recipients in which we compared outcomes of a match group (an A1/O heart into an A1 recipient or a non-A1/O heart into a non-A1 recipient) with a mismatch group (an A1 heart into a non-A1 recipient or a non-A1 heart into an A1 recipient). At one year post-transplant, there were no differences between the groups in survival, freedom from non-fatal major adverse cardiovascular events, freedom from any treated rejection, or freedom from cardiac allograft vasculopathy. There was an increased hospital length of stay in the mismatch group (13.5 vs. 17.1 days, p = 0.04). Our study showed that A1 mismatch was not associated with worse outcomes at one year post-HTx.

Overtransfusion of packed red blood cells during massive transfusion activation: a potential quality metric for trauma resuscitation.

Objectives: The goal of this study was to explore the incidence of overtransfusion in trauma patients requiring massive transfusion protocol (MTP) activation and identify modifiable risk factors. We hypothesized that overtransfusion is common after MTP activation. Methods: Patients admitted to a level I trauma center from July 2016 to December 2019 and who required MTP activation were selected. The primary outcome was overtransfusion, defined as a hemoglobin (Hg) ≥11 g/dL at 24 hours (±2 hours). A Cox regression model was used to identify independent risk factors for overtransfusion. Results: 140 patients met inclusion criteria. The median age was 39.0 years, with the majority (74.3%) being male. The median (IQR) Injury Severity Score (ISS) was 24.0 (58.0) and 38.4% had a penetrating mechanism. The median (IQR) admission Hg was 12.6 (11.7) g/dL. Overall, 71.4% of patients were overtransfused by the conclusion of MTP, 43.6% 24 hours later, and 29.5% at discharge. Overtransfusion did not correlate with the number of units of blood transfused nor with the duration of MTP. Overtransfused patients at 24 hours after the conclusion of MTP were significantly more likely to present with a penetrating injury (52.5% vs. 27.3%, p=0.003) and have a significantly lower ISS (median (IQR) 18.5 (44.0) vs. 26.0 (58.0), p=0.035.) In a Cox regression model, penetrating mechanism (adjusted HR (AHR): 2.93; adjusted p=0.004) and admission base excess (BE) (AHR: 1.15; adjusted p=0.001) were the only variables independently associated with overtransfusion. Conclusions: Overtransfusion of trauma patients requiring MTP activation is highly common, leading to overutilization of a limited resource. Penetrating trauma and BE may be modifiable risk factors that can help limit overtransfusion. Overtransfusion should be tracked as a data point by blood banks and trauma centers and be further studied as a potential quality metric for the resuscitation of massively transfused trauma patients. Level of evidence: III.

Implementation of a low-titer stored whole blood transfusion program for civilian trauma patients: Early experience and logistical challenges.

INTRODUCTION: Cold-stored low titer group O whole blood (LTOWB) is increasingly utilized in the initial resuscitation of exsanguinating trauma patients. We report on our early experience with LTOWB, focusing on logistics, implementation challenges, and outcomes. METHODS: In February, 2019, LTOWB was incorporated into the massive transfusion protocol (MTP) activated for trauma patients in the emergency department (ED.) Up to 4 units of LTOWB were included in the MTP cooler, depending on availability, and were transfused prior to transfusion of any other blood products from the MTP cooler. Demographics, injury characteristics, and outcomes were obtained, and the logistics of LTOWB availability were reviewed. RESULTS: Over a 12-month period, MTP was activated for 74 trauma patients. Of those, 38 (51%) MTP included at least one unit of LTOWB, with 19/38 (50%) including 4 LTOWB units. A total of 177 units of LTOWB were purchased during the study period, and of those, 74 (42%) expired before use. Patients who received LTOWB had a similar mortality compared to those who received component therapy (39% vs. 47%; Odds Ratio [95% CI]: 0.7 [0.3, 2.0]; p = 0.72,) however, they were able to achieve a significantly higher plasma:pRBC ratio during the duration of MTP activation (mean [SD] 0.8 [0.2] vs. 0.4 [0.4]; mean difference [95% CI]: 0.4 [0.2, 0.5]; p < 0.01.) CONCLUSIONS: Our early experience with LTOWB transfusion demonstrates feasibility, but also highlights challenges with inventory management. These findings triggered changes to our protocol aiming at minimizing wastage. The use of LTOWB may yield a higher plasma:pRBC ratio early during the resuscitation period. Further investigation is required to explore whether this may yield a survival advantage. LEVEL OF EVIDENCE: III (Therapeutic/Care Management).

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD. METHODS: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression. RESULTS: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD. CONCLUSIONS: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.

Blood group O convalescent plasma donations have significantly lower levels of SARS-CoV-2 IgG antibodies compared to blood group A donations.

BACKGROUND: COVID-19 convalescent plasma (CCP) is plasma collected from individuals who have recovered from SARS-CoV-2 infection. The FDA Emergency Use Authorization restricts use of CCP to high-titer units only. The purpose of this study was to determine if donor ABO blood group was associated with SARS-CoV-2 antibody response, and subsequent qualification as high-titer CCP. METHODS: All CCP donations collected from April 21, 2020 to September 1, 2020 were included. The Abbott ARCHITECT semi-quantitative chemiluminescent microparticle immunoassay was used to assess IgG antibodies to the nucleocapsid protein of SARS-CoV-2. Units with a S/C value ≥4.5 were considered high titer. RESULTS: A total of 232 CCP donations were evaluated. There were no significant differences in the distribution of sex, age, and interval from symptom resolution to donation by ABO blood group. The mean SARS-CoV-2 IgG antibody S/C value was significantly lower in blood group O donations (3.6), compared to blood group A (5.0) donations (p < .001). There was no difference in antibody response between the other blood group pairings. Blood group O donations resulted in a lower percentage of high-titer units (35%), compared to blood group A (60%), B (58%), and AB (65%) donations. CONCLUSION: Blood group O donations were found to have significantly lower levels of SARS-CoV-2 IgG nucleocapsid antibodies compared to blood group A donations and were less likely to produce CCP units that qualified as high titer. These findings may aid donor recruitment to promote availability of high-titer CCP to meet patient needs.

SARS-CoV-2 specific antibody and neutralization assays reveal the wide range of the humoral immune response to virus.

Development of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n = 115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.

Altered type 1 interferon responses in alloimmunized and nonalloimmunized patients with sickle cell disease.

Patients with sickle cell disease (SCD) have a high prevalence of RBC alloimmunization. However, underlying mechanisms are poorly understood. Given that proinflammatory type 1 interferons (IFNα/ß) and interferon stimulated genes (ISGs) promote alloimmunization in mice, we hypothesized that IFNα/ß may contribute to the increased frequency of alloimmunization in patients with SCD. To investigate this, expression of ISGs in blood leukocytes and peripheral blood mononuclear cells (PBMCs) of previously transfused SCD patients with or without alloimmunization and race-matched healthy controls were quantified, and IFNα/ß gene scores were calculated. IFNα/ß gene scores of SCD leukocytes and plasma cytokines were elevated, compared to controls (gene score, p < 0.01). Upon stimulation with IFNß, isolated PBMCs from patients with SCD had elevated ISGs and IFNα/ß gene scores (p < 0.05), compared to stimulated PBMCs from controls. However, IFNß-stimulated and unstimulated ISG expression did not significantly differ between alloimmunized and non-alloimmunized patients. These findings indicate that patients with SCD express an IFNα/ß gene signature, and larger studies are needed to fully determine its role in alloimmunization. Further, illustration of altered IFNα/ß responses in SCD has potential implications for IFNα/ß-mediated viral immunity, responses to IFNα/ß-based therapies, and other sequelae of SCD.

Comparison of the platelet activation status of single-donor platelets obtained with two different cell separator technologies.

BACKGROUND: The microparticle content (MP%) of apheresis platelets-a marker of platelet activation-is influenced by donor factors and by external stressors during collection and storage. This study assessed the impact of apheresis technology and other factors on the activation status (MP%) of single-donor apheresis platelets. STUDY DESIGN AND METHODS: Data from six US hospitals that screened platelets by measuring MP% through dynamic light scattering (ThromboLUX) were retrospectively analyzed. Relative risks (RRs) were derived from univariate and multivariable regression models, with activation rate (MP% ≥15% for plasma-stored platelets; ≥10% for platelet additive solution [PAS]-stored platelets) and MP% as outcomes. Apheresis platform (Trima Accel vs Amicus), storage medium (plasma vs PAS), pathogen reduction, storage time, and testing location were used as predictors. RESULTS: Data were obtained from 7511 platelet units collected using Trima (from 16 suppliers, all stored in plasma, 20.0% were pathogen-reduced) and 2456 collected using Amicus (from four different collection facilities of one supplier, 65.0% plasma-stored, 35.0% PAS-stored, none pathogen-reduced). Overall, 30.0% of Trima platelets were activated compared to 45.6% of Amicus platelets (P < .0001). Multivariable analysis identified apheresis platform as significantly associated with platelet activation, with a lower activation rate for Trima than Amicus (RR: 0.641, 95% confidence interval [CI]: 0.578; 0.711, P < .0001) and a 6.901% (95% CI: 5.926; 7.876, P < .0001) absolute reduction in MP%, when adjusting for the other variables. CONCLUSION: Trima-collected platelets were significantly less likely to be activated than Amicus-collected platelets, irrespective of the storage medium, the use of pathogen reduction, storage time, and testing site.

Novel SARS-CoV-2 specific antibody and neutralization assays reveal wide range of humoral immune response during COVID-19.

Development of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n=115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.

Probable transfusion transmission of West Nile virus from an apheresis platelet that screened non-reactive by individual donor-nucleic acid testing.

BACKGROUND: Despite West Nile virus (WNV) blood donation screening using nucleic acid testing (NAT), donors with low viral loads not detected by mini-pool-NAT have led to transfusion transmitted (TT)-WNV infection. We describe a probable case of fatal TT-WNV infection from an individual donor (ID)-NAT non-reactive apheresis platelet donation. STUDY DESIGN AND METHODS: An apheresis platelet donation was WNV ID-NAT reactive and prior donations from the same donor were investigated. A WNV ID-NAT non-reactive apheresis platelet unit collected 26 days earlier was transfused during heart transplantation to a patient who subsequently developed WNV neuroinvasive disease and expired. The source of the recipient's WNV infection was investigated. RESULTS: Twenty-six days after collection of the suspect platelet unit, a donation from the same donor was WNV ID-NAT reactive and WNV IgM and IgG positive. In addition to the suspect platelet unit, the heart transplant recipient who developed WNV infection received 17 blood components from 24 donors. Serologic testing performed on 11 of the remaining 24 donors (46%) was WNV IgM negative. Pre-transplant recipient and heart donor samples tested WNV RNA and IgM negative. CONCLUSION: A probable case of fatal neuroinvasive TT-WNV was linked to an infectious apheresis platelet unit undetected by WNV ID-NAT. It is hypothesized that the suspect unit was collected early in the viremic period when viral RNA was below the limit-of-detection of the ID-NAT assay. Implementation of ID-NAT screening of blood donors has not entirely eliminated the risk of TT-WNV infections, which may best be addressed by pathogen inactivation technologies.

Critical developments of 2018: A review of the literature from selected topics in transfusion. A committee report from the AABB's Clinical Transfusion Medicine Committee.

BACKGROUND: The AABB compiles an annual synopsis of the published literature covering important developments in the field of transfusion medicine. An abridged version of this work is being made available in TRANSFUSION, with the full-length report available as Appendix S1 (available as supporting information in the online version of this paper). STUDY DESIGN AND METHODS: Papers published in late 2017 and 2018 are included, as well as earlier papers cited for background. Although this synopsis is comprehensive, it is not exhaustive, and some papers may have been excluded or missed. RESULTS: The following topics are covered: "big data" and "omics" studies, emerging infections and testing, platelet transfusion and pathogen reduction, transfusion therapy and coagulation, transfusion approach to hemorrhagic shock and mass casualties, therapeutic apheresis, and chimeric antigen receptor T-cell therapy. CONCLUSION: This synopsis may be a useful educational tool.

RHD genotyping of serologic RhD-negative blood donors in a hospital-based blood donor center.

BACKGROUND: Serologic RhD-negative blood donors are tested by a method known to detect weak D antigen expression. Serology does not detect all red blood cells with RhD expression and RHD genotyping has been used to identify variant RHD alleles, which may lead to some RhD expression. The aim of this study was to determine the frequency of RHD variant alleles in serologic RhD-negative blood donors at a hospital-based donor center in Los Angeles. STUDY DESIGN AND METHODS: RHD genotyping of serologic RhD-negative blood donors over a 20-month period was performed using the Immucor RHD BeadChip assay. DNA sequencing was performed when the RHD BeadChip assay failed to assign a genotype. For RHD variants known or suspected to result in RhD expression, recipients of previous blood donations were investigated for alloimmunization. RESULTS: RHD genotyping was performed in 1174 RhD-negative blood donors, and 1122 were genotyped for RHCE variants. Eleven donors (0.94%) harbored mutations predicted to yield RhD expression. The predicted phenotypes were, in decreasing frequency, DEL, partial, and weak D phenotypes. Anti-D was not detected in 16 patients who had received blood from these donors after an average follow up of 182 days. CONCLUSION: Genotyping can be used to identify donors with the potential to sensitize RhD-negative recipients. In this limited study, 0.94% of serologic RhD-negative blood donors were found to have variant RHD alleles that might cause alloimmunization in RhD-negative recipients. To our knowledge, a study of this nature has not been reported in the United States.