Timing of hypotensive adverse events in U.S. source plasma donors: Exploratory analysis from the IMPACT trial.

BACKGROUND AND OBJECTIVES: There is less robust data describing adverse events (AEs) in source plasma donors than in whole blood donors, particularly regarding time to AEs (TAEs). We, therefore, sought to characterize TAE and the influence of donor characteristics in a large-scale clinical trial dataset. MATERIALS AND METHODS: TAE was calculated utilizing data from the IMPACT (IMproving PlasmA CollecTion) trial, with linear regression analyses performed to determine the influence of donor parameters on TAE. RESULTS: Linear regression revealed that repeat donors tended to have AEs ~6 min later than naïve donors in the IMPACT trial; however, this was not statistically significant (p = 0.781). Besides this, gender showed greatest difference in TAE; however, no covariates were statistically significant. AE rates were relatively constant throughout the donation process with higher rates beginning 40 min after initiation; no initial peak was observed (first 10-15 min). CONCLUSION: AEs occurred throughout the donation process. None of the analyzed factors could fully explain the difference in the dynamics of AE timing with that of whole blood donation, particularly the missing early peak. Therefore, other factors, e.g., expectation and attitude towards donating plasma and potential events during plasma collection, may explain this difference and should be the focus of future studies.

Spray-dried plasma: A post-traumatic blood "bridge" for life-saving resuscitation.

Massive bleeding remains a major source of morbidity and mortality worldwide. Recent studies have shed light on the pathophysiology of traumatic-induced coagulopathy and the central role of endotheliopathy. Transfusion therapy has changed dramatically in the last decade with use of red cells and plasma in a 1:1 ratio. The use of early transfusion increases the likelihood of a favorable outcome. Early intervention-preferably less than 60 min of injury-is a major factor in improved survival. Experience with dried plasma products-lyophilized or freeze-dried-in Europe and South Africa has demonstrated both safety and efficacy. Dry plasma products are not available in the United States but several products are in development. Spray-dried plasma contains clinically meaningful levels of coagulation activity and in vitro data suggest robust ability to generate thrombus. The decentralized, blood-center based manufacturing model of spray-dried plasma offers advantages for availability to meet routine and extraordinary demands.

Repeat donation and deferral rates in US source plasma donors: Exploratory analysis from the IMPACT trial.

BACKGROUND: The IMPACT trial demonstrated the safety of a new personalized nomogram for plasma donation and provided an opportunity to explore short- to mid-term impact on repeat donation and deferral rates, and factors affecting these. STUDY DESIGN AND METHODS: In the IMPACT trial, participants were randomized to donate plasma using an established weight-based nomogram (control) versus a new personalized nomogram incorporating height, weight, and hematocrit (experimental). In this exploratory analysis, repeat donations (per donor, by study arm) were analyzed using negative binomial generalized linear regression models and descriptive statistics. The mean number of donor deferral events was compared between the two arms using logistic regression and count data modeling approaches and were analyzed by lead cause. RESULTS: The predicted mean number of repeat donations was similar between the control and experimental arms (6.82 vs. 6.62, respectively; p = .22). Overall, the predicted mean number of repeat donations was significantly higher in males compared with females (p < .0001). Naïve donors had on average 2.8/2.7 (control/experimental) fewer repeat donations compared with experienced donors. In 23, 137 donations from 3443 donors, 798 donors (376 control, 422 experimental, p = .80) had at least one deferral (for any cause). The predicted mean number of deferrals in all categories of interest was not statistically different between the study arms. CONCLUSION: Similar repeat donation and deferral rates between arms suggest that the new nomogram did not result in disruptions to subsequent donation. Further longitudinal research on mid- to long-term effects is warranted.

Personalized collection of plasma from healthy donors: A randomized controlled trial of a novel technology-enabled nomogram.

BACKGROUND: Source plasma is essential to support the growing demand for plasma-derived medicinal products. Supply is short, with donor availability further limited by the coronavirus disease 2019 (COVID-19) pandemic. This study examined whether a novel, personalized, technology-based nomogram was noninferior with regard to significant hypotensive adverse events (AEs) in healthy donors. STUDY DESIGN AND METHODS: IMPACT (IMproving PlasmA CollecTion) was a prospective, multicenter, double-blinded, randomized, controlled trial carried out between January 6 and March 26, 2020, in three U.S plasma collection centers. Donors were randomly assigned to the current simplified 1992 nomogram (control) or a novel percent plasma nomogram (PPN) with personalized target volume calculation (experimental). Primary endpoint was the rate of significant hypotensive AEs. Noninferiority (NI) was tested with a margin of 0.15%. Collected plasma volume was a secondary endpoint. RESULTS: A total of 3443 donors (mean [SD] BMI: 32 [7.74] kg/m2 ; 65% male) underwent 23,137 donations (median [range]: 6 [1-22] per subject). Ten significant hypotensive AEs were observed (six control; four experimental), with model-based AE incidence rate estimates (95% CI) of 0.051% (0.020%-0.114%) and 0.035% (0.010%-0.094%), respectively (p = .58). NI was met at an upper limit of 0.043% versus the predefined margin of 0.15%. There was no statistical difference between total AEs (all AE types: p = .32). Mean plasma volume collected was 777.8 ml (control) versus 841.7 ml (experimental); an increase of 63.9 ml per donation (8.2%; p < .0001). CONCLUSION: This trial showed that a novel personalized nomogram approach in healthy donors allowed approximately 8% more plasma per donation to be collected without impairing donor safety.

A microfluidic analysis of thrombus formation in reconstituted whole blood samples comparing spray-dried plasma versus fresh frozen plasma.

BACKGROUND: Prompt resuscitation with plasma and other blood products reduces trauma-related morbidity and mortality. Standard storage and preparation techniques for frozen plasma limit its utility in the pre-hospital setting. Plasma can be dehydrated using hot air (spray-dried plasma), stored at room temperature and rehydrated quickly for use. The spray-dry process decreases high-molecular-weight multimers of von Willebrand factor compared with conventional plasma. The objective of this study was to compare platelet adhesion and thrombus formation in a microfluidic perfusion assay facilitated by spray-dried compared with frozen plasma using a non-inferiority design. STUDY DESIGN AND METHODS: Whole blood was centrifuged to obtain red cell concentrate, and a platelet pellet that was suspended in either spray-dried or frozen plasma to create recombined whole blood. Platelets were fluorescently labelled, and samples were flowed through a collagen-coated microchannel. Surface area coverage by platelets and thrombi was analysed and compared between each spray-dried and frozen plasma pair. RESULTS: Compared with whole blood samples containing frozen plasma, samples with spray-dried plasma had similar surface area coverage of platelets and thrombi after 180 s of flow. Even when diluted with von Willebrand factor-free plasma, there was no reduction thrombus formation. CONCLUSION: Spray-dried plasma is not inferior in supporting haemostasis compared with fresh frozen plasma in a paired analysis. It offers advantages with respect to portability and ease of preparation over frozen plasma in the pre-hospital setting. This study supports development of clinical studies to evaluate the efficacy and safety of spray-dried plasma in trauma patients.

Clinical Utility of Autologous Salvaged Blood: a Review.

INTRODUCTION: Autologous salvaged blood, commonly referred to as "cell saver" or "cell salvage" blood, is an important method of blood conservation. Understanding the mechanism of action and summarizing the existing evidence regarding the safety, efficiency, and the relative costs of cell salvage may help educate clinicians on how and when to best utilize autotransfusion. METHODS: This review focuses on issues concerning the quality of red blood cells (RBC), efficiency, and the cost effectiveness relative to autotransfusion. The key considerations of safe use and clinical applicability are described along with the challenges for wider dissemination. RESULTS: Cell salvage can reduce requirements for allogeneic transfusions, along with the associated risks and costs. Autologous salvaged RBCs provide high-quality transfusion, since the cells have not been subjected to the adverse effects of storage as occurs with banked blood. The risks for RBC alloimmunization and transfusion-related infectious diseases are also avoided. With a careful selection of cases, salvaged blood can be more cost effective than donor blood. Cell salvage may have a role in cardiac, major vascular, orthopedic, transplant, and trauma surgeries. However, there remain theoretical safety concerns in cases with bacterial contamination or in cancer surgery. CONCLUSION: In addition to other methods of blood conservation used in patient blood management programs, autologous salvaged blood adds value and is cost effective for appropriate surgical cases. Evidence suggests that autologous salvaged blood may be of higher quality and confer a cost reduction compared with the allogeneic banked blood, when used appropriately.

Electronic remote blood issue supports efficient and timely supply of blood and cost reduction: evidence from five hospitals at different stages of implementation.

BACKGROUND: This multicenter international study evaluated electronic remote blood issue (ERBI) for blood unit collection in hospitals. STUDY DESIGN AND METHODS: Retrospective data were collected from the ERBI software databases and blood bank information systems. Prospective "time-and-motion" data collection methods simulated the delivery of red blood cell units to determine the staff time for each step. RESULTS: The main benefit of ERBI was found in two hospitals where the blood unit was issued and collected at refrigerators remote from the blood bank (closer to the clinical area) compared with the standard process of blood bank issue (BBI) and blood unit collection in the blood bank. There was a reduction in the time for blood to reach patients (2.02 min compared to 8.43 min at one site [p ≤ 0.0001], 1.57 min compared to 6.54 min at the other [p ≤ 0.0001]). However, there was no reduction in time where ERBI was conducted in the blood bank or where a blood unit issued by the standard BBI was collected at remote refrigerators. In the three hospitals where ERBI was conducted at remote refrigerators, there was an improved issue:transfusion ratio (range of 1.02-1.09 for ERBI compared to 1.48-1.58 for BBI) and a reduction in staff time and costs of between $5,000 and $10,000/year. CONCLUSION: This multicenter international study builds on findings from studies in single hospitals that ERBI at remote refrigerators improves the efficiency of transfusion by reducing the time taken for blood units to reach patients, staff time, and costs.

Rat red blood cell storage lesions in various additive solutions.

BACKGROUND: Small rodent models are routinely used to evaluate the safety and efficacy of blood transfusions. Limited comprehensive literature exists about effect of different storage solutions in rat red blood cells (RBCs) characteristics. RBCs undergo time dependent biochemical and biophysical changes during storage known as hypothermic storage lesions (HSLs). OBJECTIVE: This study evaluates the effects of RBC additive solutions (AS) during storage of rat RBCs. METHODS: Blood was leukoreduced and stored as per manufacturer instructions at 4°C up to 42-days. Three solutions, CPDA-1; AS-1; and AS-7 (SOLX), were evaluated. Biochemical parameters measured included extracellular K+, pH, hemolysis, 2,3-diphosphoglycerate (2,3-DPG), oxygen affinity, ATP, and lactate. Mechanical properties measured included RBC deformability, elongation index (EI), RBC membrane shear elastic modulus (SEM), mean corpuscular volume (MCV), viscosity, and aggregability. RESULTS: There were no differences in biochemical or mechanical parameters at baseline or after one week of storage. However, after two weeks, AS-7 preserved biochemical and mechanical properties as compared to CPDA-1 and AS-1. Changes were observed to be significant after 14-days of storage. AS-7 prevented extracellular K+ increase, reduced acidosis, showed lower hemolysis, preserved ATP and 2,3-DPG levels (consequently oxygen affinity), and reduced lactate. AS-7, when compared to CPDA-1 and AS-1, prevented the reduction in RBC deformability and was found to preserve the EI at multiple shear stresses, the membrane SEM, the aggregability and viscosity. DISCUSSION: Rat RBCs stored with AS-7 presented reduced changes in biochemical and mechanical parameters, when compared with rat RBCs stored in CPDA-1 and AS-1, after as early as two weeks of storage.

New-Generation Thromboelastography: Comprehensive Evaluation of Citrated and Heparinized Blood Sample Storage Effect on Clot-Forming Variables.

CONTEXT: - Thromboelastography (TEG) is a whole blood, real-time analyzer measuring the viscoelastic properties of the hemostasis process and allowing for individualized goal-directed therapy. However, routine use of TEG requires validation of sample storage effect on clot parameters. OBJECTIVES: - To establish the minimum time required for equilibration time and the maximum time for sample storage for all commercially available TEG tests for the new-generation TEG 6s and to determine how those times compare with the older generation TEG 5000. DESIGN: - Citrated and heparinized whole blood samples obtained from 20 healthy donors were analyzed for clot parameters at multiple time points for both the TEG 6s and the TEG 5000. Samples were activated with the citrated multichannel cartridge or the platelet-mapping cartridge in the TEG 6s or with recalcified kaolin in the TEG 5000. RESULTS: - All blood samples yielded TEG parameter results within reference ranges and had a tendency toward hypercoagulable profiles with increased storage time. Sample storage resulted in increased platelet inhibition with significant differences at 4 hours in the platelet-mapping cartridge (arachidonic acid percentage of inhibition, P = .002; adenosine diphosphate percentage of inhibition, P = .02). CONCLUSIONS: - For nonemergent cases or in a central laboratory setting, all tests provided reliable results for up to 4 hours in the citrated multichannel cartridge and for 3 hours for platelet function information in the platelet-mapping cartridge. In emergent/urgent situations in which the sample needs to be run immediately, RapidTEG and functional fibrinogen tests may be preferred.

In a canine pneumonia model of exchange transfusion, altering the age but not the volume of older red blood cells markedly alters outcome.

BACKGROUND: Massive exchange transfusion of 42-day-old red blood cells (RBCs) in a canine model of Staphylococcus aureus pneumonia resulted in in vivo hemolysis with increases in cell-free hemoglobin (CFH), transferrin-bound iron (TBI), non-transferrin-bound iron (NTBI), and mortality. We have previously shown that washing 42-day-old RBCs before transfusion significantly decreased NTBI levels and mortality, but washing 7-day-old RBCs increased mortality and CFH levels. We now report the results of altering volume, washing, and age of RBCs. STUDY DESIGN AND METHODS: Two-year-old purpose-bred infected beagles were transfused with increasing volumes (5-10, 20-40, or 60-80 mL/kg) of either 42- or 7-day-old RBCs (n = 36) or 80 mL/kg of either unwashed or washed RBCs with increasing storage age (14, 21, 28, or 35 days; n = 40). RESULTS: All volumes transfused (5-80 mL/kg) of 42-day-old RBCs resulted in alike (i.e., not significantly different) increases in TBI during transfusion as well as in CFH, lung injury, and mortality rates after transfusion. Transfusion of 80 mL/kg RBCs stored for 14, 21, 28, and 35 days resulted in increased CFH and NTBI in between levels found at 7 and 42 days of storage. However, washing RBCs of intermediate ages (14-35 days) does not alter NTBI and CFH levels or mortality rates. CONCLUSIONS: Preclinical data suggest that any volume of 42-day-old blood potentially increases risks during established infection. In contrast, even massive volumes of 7-day-old blood result in minimal CFH and NTBI levels and risks. In contrast to the extremes of storage, washing blood stored for intermediate ages does not alter risks of transfusion or NTBI and CFH clearance.

Use of Thromboelastography (TEG) for Detection of New Oral Anticoagulants.

CONTEXT: The clinical introduction of new oral anticoagulants (NOACs) has stimulated the development of tests to quantify the effects of these drugs and manage complications associated with their use. Until recently, the only treatment choices for the prevention of venous thromboembolism in orthopedic surgical patients, as well as for stroke and systemic embolism in patients with atrial fibrillation, were vitamin K antagonists, antiplatelet drugs, and unfractionated and low-molecular-weight heparins. With the approval of NOACs, treatment options and consequent diagnostic challenges have expanded. OBJECTIVE: To study the utility of thromboelastography (TEG) in monitoring and differentiating between 2 currently approved classes of NOACs, direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). DESIGN: Blood samples from healthy volunteers were spiked with each NOAC in both the presence and absence of ecarin, and the effects on TEG were evaluated. RESULTS: Both the kaolin test reaction time (R time) and the time to maximum rate of thrombus generation were prolonged versus control samples and demonstrated a dose response for apixaban (R time within the normal range) and dabigatran. The RapidTEG activated clotting time test allowed the creation of a dose-response curve for all 3 NOACs. In the presence of anti-Xa inhibitors, the ecarin test promoted significant shortening of kaolin R times to the hypercoagulable range, while in the presence of the direct thrombin inhibitor only small and dose-proportional R time shortening was observed. CONCLUSIONS: The RapidTEG activated clotting time test and the kaolin test appear to be capable of detecting and monitoring NOACs. The ecarin test may be used to differentiate between Xa inhibitors and direct thrombin inhibitors. Therefore, TEG may be a valuable tool to investigate hemostasis and the effectiveness of reversal strategies for patients receiving NOACs.

Washing older blood units before transfusion reduces plasma iron and improves outcomes in experimental canine pneumonia.

In a randomized controlled blinded trial, 2-year-old purpose-bred beagles (n = 24), with Staphylococcus aureus pneumonia, were exchanged-transfused with either 7- or 42-day-old washed or unwashed canine universal donor blood (80 mL/kg in 4 divided doses). Washing red cells (RBC) before transfusion had a significantly different effect on canine survival, multiple organ injury, plasma iron, and cell-free hemoglobin (CFH) levels depending on the age of stored blood (all, P < .05 for interactions). Washing older units of blood improved survival rates, shock score, lung injury, cardiac performance and liver function, and reduced levels of non-transferrin bound iron and plasma labile iron. In contrast, washing fresh blood worsened all these same clinical parameters and increased CFH levels. Our data indicate that transfusion of fresh blood, which results in less hemolysis, CFH, and iron release, is less toxic than transfusion of older blood in critically ill infected subjects. However, washing older blood prevented elevations in plasma circulating iron and improved survival and multiple organ injury in animals with an established pulmonary infection. Our data suggest that fresh blood should not be washed routinely because, in a setting of established infection, washed RBC are prone to release CFH and result in worsened clinical outcomes.

Hemotherapy bedside biovigilance involving vital sign values and characteristics of patients with suspected transfusion reactions associated with fluid challenges: can some cases of transfusion-associated circulatory overload have proinflammatory aspects?

BACKGROUND: Monitoring of patients' vital sign values (VSVs) during hemotherapy may have an important role in the recognition and mitigation of transfusion-associated circulatory overload (TACO). Knowledge regarding VSVs and other patient characteristics in bedside-reported TACO or fluid challenge-suspected transfusion reactions (TACO/FC-STRs) is limited. STUDY DESIGN AND METHODS: We performed a retrospective observational cohort study of cases of uncomplicated red blood cell (RBC) transfusions (UCTs) and reported suspected transfusion reaction (STR) cases investigated by our hospital's transfusion medicine service (TMS) from January 1, 2005, to February 29, 2008, using data obtained from TMS consult reports and quality improvement databases examining VSVs and patient characteristics in TACO/FC-STRs. RESULTS: The frequency of TACO/FC-STRs was 0.19% per all RBC units transfused (1:530 units transfused). Both clinically and statistically (p≤0.05) significant changes were encountered in all VSVs in patients experiencing TACO/FC-STRs either at the 15-minute time interval or at the end-of-transfusion time points. Measured and derived VSVs related to the patients' blood pressure in the peritransfusion period were consistently increased. Approximately two-thirds of TACO/FC-STR patients also exhibited inflammatory related signs and symptoms at STR bedside presentation. Differences (all p≤0.050) between UCT and TACO/FC-STR cohorts were seen for patient mean weights (80 kg vs. 72 kg), mean minutes to transfusion completion (121 min vs. 83 min), and mean storage age of suspected sentinel RBC unit (22.5 days vs. 25.2 days). CONCLUSION: Trend monitoring of peritransfusion VSVs, especially blood pressures, may aid in the bedside recognition of TACO/FC-STRs. A subset of these patients may also present with febrile and/or inflammatory signs and symptoms.

Clinical utility of thromboelastography: one size does not fit all.

Coagulation management requires the balancing of different components that contribute to clot formation. These components include the interactions between platelets, procoagulant, anticoagulant, and fibrinolytic factors. The cause of bleeding or thrombotic events is often multifactorial; however, the tests clinicians most frequently use to assess hemostasis do not reflect the complexity of the coagulation system. The paucity of global measurements of hemostasis has resulted in either an empirical or a one-size-fits-all approach to treatment. In contrast, thromboelastography is a test that monitors the different phases of clot formation and lysis, providing the clinician with a tool for making informed therapeutic decisions. This review provides an overview of thromboelastography in the management of hypocoagulable and hypercoagulable conditions.