Challenges associated with access to plasma-derived medicinal products in low middle-income and low-income countries.

BACKGROUND AND OBJECTIVES: Plasma-derived medicinal products (PDMPs) are essential to treat many chronic conditions such as haemophilia and primary immunodeficiency. Patients living in low middle-income and low-income countries (LMICs and LICs, respectively) have limited access to PDMPs. The aim of this article is to explore the challenges of accessing PDMPs in LMICs and LICs. MATERIALS AND METHODS: A review of the literature and reports on blood safety, plasma production and its utilization to produce PDMPs in LMICs and LICs was carried out. RESULTS: There is huge wastage of recovered plasma in LMICs and LICs as a result of a lack of good manufacturing practice (GMP) in the production of plasma for fractionation. Together with the high cost of imported PDMP procurement, patients have limited access to such products. CONCLUSION: There is a need to improve the situation by using domestically sourced plasma through the initiation of local plasma programmes through a stepwise approach to improve access to PDMPs in LMICs and LICs.

Viral reduction of human blood by ultraviolet A-photosensitized vitamin K5.

Blood product transfusion can transmit viral pathogens. Pathogen reduction methods for blood products have been developed but, so far, are not available for whole blood. We evaluated if vitamin K5 (VK5) and ultraviolet A (UVA) irradiation could be used for virus inactivation in plasma and whole blood. Undiluted human plasma and whole blood diluted to 20% were spiked with high levels of vaccinia or Zika viruses. Infectious titers were measured by standard TCID50 assay before and after VK5/UVA treatments. Up to 3.6 log of vaccinia and 3.2 log of Zika were reduced in plasma by the combination of 500 µM VK5 and 3 J/cm2 UVA, and 3.1 log of vaccinia and 2.9 log of Zika were reduced in diluted human blood (20%) by the combination of 500 µM VK5 and 70 J/cm2 UVA. At end of whole blood treatment, hemolysis increased from 0.18% to 0.41% but remained below 1% hemolysis, which is acceptable to the Food and Drug Administration for red cell transfusion products. No significant alteration of biochemical parameters of red blood cells occurred with treatment. Our results provide proof of the concept that a viral pathogen reduction method based on VK5/UVA may be developed for whole blood.

The impact of the sample time of secondary bacterial culture on the risk of exposure to contaminated platelet components: A mathematical analysis.

BACKGROUND: The US Food and Drug Administration (FDA) issued a guidance for bacterial risk control strategies for platelet components in September 2019 that includes strategies using secondary bacterial culture (SBC). While an SBC likely increases safety, the optimal timing of the SBC is unknown. Our aim was to develop a model to provide insight into the best time for SBC sampling. STUDY DESIGN AND METHODS: We developed a mathematical model based on the conditional probability of a bacterial contamination event. The model evaluates the impact of secondary culture sampling time over a range of bacterial contamination scenarios (lag and doubling times), with the primary outcome being the optimal secondary sampling time and the associated risk. RESULTS: Residual risk of exposure decreased with increasing inoculum size, later sampling times for primary culture, and using higher thresholds of exposure (in colony-forming units per milliliter). Given a level of exposure, the optimal sampling time for secondary culture depended on the timing of primary culture and on the expiration time. In general, the optimal sampling time for secondary culture was approximately halfway between the time of primary culture and the expiration time. CONCLUSION: Our model supports that the FDA guidance is quite reasonable and that sampling earlier in the specified secondary culture windows may be most optimal for safety.

The current state of the platelet supply in the US and proposed options to decrease the risk of critical shortages.

Due to circumstances such as increased demand and an aging donor pool, the likelihood of critical platelet shortages is increasing. The platelet supply could be improved through the expansion of the donor pool, the identification and sustained utilization of high-quality donors, and changes in component processing and storage that result in a longer platelet shelf-life. Refrigerated platelets, stored at 1° to 6°C, have the potential to improve patient safety by decreasing the risk of bacterial contamination while concurrently allowing for a longer storage period (eg, 14 days) and improved hemostatic effectiveness in actively bleeding patients. An approach utilizing remuneration of apheresis platelet donors combined with pathogen reduction of the platelet components could be used as a means to increase the donor pool and identify and sustain safe, reliable, high-quality donors. Remuneration might provide an incentive for underutilized populations (eg, individuals <30 years old) to enter the apheresis platelet donor population resulting in a significant expansion of the platelet donor pool. Over time, approaches such as the use of refrigerated platelets, platelet donor remuneration, and the application of pathogen reduction technology, might serve to attract a large, reliable, and safe donor base that provides platelet collections with high yields, longer shelf-lives and, excellent hemostatic function.

Public Policy Impact of the COVID-19 Pandemic on Blood Supply in the United States.

The COVID-19 pandemic has precipitated an acute blood shortage for medical transfusions, exacerbating an already tenuous blood supply system in the United States, contributing to the public health crisis, and raising deeper questions regarding emergency preparedness planning for ensuring blood availability. However, these issues around blood availability during the pandemic are related primarily to the decline in supply caused by reduced donations during the pandemic rather than increased demand for transfusion of patients with COVID-19.The challenges to ensure a safe blood supply during the pandemic will continue until a vaccine is developed, effective treatments are available, or the virus goes away. If this virus or a similar virus were capable of transmission through blood, it would have a catastrophic impact on the health care system, causing a future public health emergency that would jeopardize the national blood supply.In this article, we identify the impact of the COVID-19 pandemic on blood supply adequacy, discuss the public health implications, propose recovery strategies, and present recommendations for preparing for the next disruption in blood supply driven by a public health emergency.

Blood Donation and COVID-19: Reconsidering the 3-Month Deferral Policy for Gay, Bisexual, Transgender, and Other Men Who Have Sex With Men.

In April 2020, in light of COVID-19-related blood shortages, the US Food and Drug Administration (FDA) reduced the deferral period for men who have sex with men (MSM) from its previous duration of 1 year to 3 months.Although originally born out of necessity, the decades-old restrictions on MSM donors have been mitigated by significant advancements in HIV screening, treatment, and public education. The severity of the ongoing COVID-19 pandemic-and the urgent need for safe blood products to respond to such crises-demands an immediate reconsideration of the 3-month deferral policy for MSM.We review historical HIV testing and transmission evidence, discuss the ethical ramifications of the current deferral period, and examine the issue of noncompliance with donor deferral rules. We also propose an eligibility screening format that involves an individual risk-based screening protocol and, unlike current FDA guidelines, does not effectively exclude donors on the basis of gender identity or sexual orientation. Our policy proposal would allow historically marginalized community members to participate with dignity in the blood donation process without compromising blood donation and transfusion safety outcomes.

The 'rejuvenating factor' TIMP-2 is detectable in human blood components for transfusion.

BACKGROUND AND OBJECTIVES: Tissue inhibitor of metalloproteinases 2 (TIMP-2) is a protein suspected to be crucial in numerous physiological and pathological processes such as morphogenesis, tissue remodelling and metastasis suppression. In animal models, the administration of TIMP-2 to aged mice improved their cognitive functions. Therefore, one can hypothesize that differences in TIMP-2 levels between blood donors and recipients might influence cognitive functions also in humans. However, the stability of TIMP-2 during processing and storage of blood components for transfusion has not been intensively investigated so far. This study determined TIMP-2 concentrations in fresh-frozen plasma (FFP), erythrocyte concentrate (EC) and pathogen-inactivated platelet concentrate (PI-PC) depending on the donor's demographic factors age and gender. MATERIALS AND METHODS: Tissue inhibitor of metalloproteinases 2 was measured in FFP (n = 30), EC (n = 12) and PI-PC (n = 12) using a Q-Plex single-plex immunoassay for chemiluminescence-based detection. Absolute quantification of TIMP-2 was performed with Q-view software. Fresh umbilical cord plasma was used as a positive control. RESULTS: Tissue inhibitor of metalloproteinases 2 was detected in FFP (30/30 samples), EC (11/12 samples) and PI-PC (12/12 samples). The median TIMP-2 concentration in EC (17·2 ng/ml; range: 0-26·5 ng/ml) was significantly lower compared with FFP (63·4 ng/ml; range: 44·4-87·3 ng/ml) or PI-PC (69·9 ng/ml; range: 39·9-83·6 ng/ml). Across all blood components, TIMP-2 levels are comparable in male and female donors and independent of age. CONCLUSION: Tissue inhibitor of metalloproteinases 2 is detectable and stable in FFP, PI-PC and, in low concentration, EC. It can be hypothesized that TIMP-2 will be transmitted to recipients during transfusion.

Registration errors among patients receiving blood transfusions: a national analysis from 2008 to 2017.

BACKGROUND AND OBJECTIVES: The key first step for a safe blood transfusion is patient registration for identification and linking to past medical and transfusion history. In Canada, any deviation from standard operating procedures in transfusion is an error voluntarily reportable to a national database (Transfusion Error Surveillance System [TESS]). We used this database to characterize the subset of registration-related errors impacting transfusion care, including where, when and why the errors occurred, and to identify frequent high-risk errors. MATERIALS AND METHODS: A retrospective analysis was conducted on transfusion errors reported to TESS by sentinel reporting sites relating to patient registration and patient armbands, between 2008 and 2017. Free-text comments describing the error were coded to further categorize into common error types. The number of specimens received in the transfusion laboratory was used as the denominator for rates to allow for comparison between hospital sites. RESULTS: Five hundred and fifty-four registration errors were reported from 10 hospitals, for a global error rate of 5·4/10 000 samples (median 5·0 [interquartile range 3·7-7·0]). The potential severity was high in 85·7% of errors (n = 475). The patient experienced a consequence in 10·8% of errors (n = 60), but none resulted in patient harm. Rates varied widely and differed by nature across sites. Errors most commonly occurred in outpatient clinics or procedure units (n = 160, 28·8%) and in emergency departments (n = 130, 23·5%). CONCLUSION: Registration errors affect transfusion at every step and location in the hospital and are commonly high risk. Further research into common root causes is warranted to identify preventative strategies.

The immune potential of ex vivo stored platelets: a review.

Platelets are now acknowledged as key regulators of the immune system, as they are capable of mediating inflammation, leucocyte recruitment and activation. This activity is facilitated through platelet activation, which induces significant changes in the surface receptor profile and triggers the release of a range of soluble biological response modifiers (BRMs). In the field of transfusion medicine, the immune function of platelets has gained considerable attention as this may be linked to the development of adverse transfusion reactions. Further, component manufacturing and storage methodologies may impact the immunoregulatory role of platelets, and an understanding of this impact is crucial and should be considered alongside their haemostatic characteristics. This review highlights the key interactions between platelets and traditional immune modulators. Further, the potential impact of current and novel component storage methodologies, such as refrigeration and cryopreservation, on this functional capacity is examined, highlighting why further knowledge in this area would be of benefit.

Blood supply management in times of SARS-CoV-2 pandemic - challenges, strategies adopted, and the lessons learned from the experience of a hospital-based blood centre.

INTRODUCTION: Numerous concerns regarding maintenance of blood inventory have been raised after SARS-CoV-2 pandemic outbreak. These concerns were based on the experience of blood centres in previous pandemics where shortage of blood components was reported. The present study had tried to understand the impact of SARS-CoV-2 pandemic on blood collection and demand as well as the impact of disaster planning in maintaining an adequate inventory. METHODS: Data related to blood supply and demand were collected retrospectively using blood bank management software for pre-COVID-19 and COVID-19 time period and compared. Strategies adopted and effects of changes in existing disaster plans to maintain an adequate inventory were studied. RESULTS: A drastic fall in the red cell inventory was observed as compared to pre-COVID-19 time period was observed due to disproportionate decrease in blood collection (1/6 to 1/9 of the previous collection) and demand (1/2 of the previous demand). The buffer stock fell gradually over a period of three weeks with cancellation of planned blood donation drives. A buffer stock equivalent to 2-week inventory led to adequate inventory in the initial lockdown periods. Similar fall was observed in the platelet inventory with reduction in the blood collection but almost a proportionate reduction in the platelet demand led to adequate inventory. No increase in wastage was observed for both red cells and platelets during this period. DISCUSSION: A buffer stock of blood and blood components, strict adherence to the transfusion triggers, good coordination with the clinical staff and a prospective review of blood transfusion requests to ensure rational blood transfusion were some of the steps which helped us to successfully maintain transfusion requirements in the initial phases of the COVID-19 pandemic. Use of first-in-first-out policy prevented any wastage due to outdating of blood.

Transfusion Safety Officers in the United States: Survey of characteristics and approaches to implementation.

BACKGROUND: Transfusion safety officers (TSO) function as liaisons between the blood bank and clinical staff, utilizing audits, quality improvement, reviews, communication, education, and general vigilance to enhance transfusion safety. While hospitals in Europe and Canada have long employed TSOs, a majority of institutions in the United States (US) have yet to implement this resource, despite the mounting evidence to support their effectiveness. STUDY DESIGN AND METHODS: An anonymous 20-question survey was administered to 104 hospitals with valid email contact information. Survey questions addressed the presence of a TSO, characteristics, backgrounds, and education of TSOs, the reporting and funding structure of the position, and role responsibilities. RESULTS: 53 responses were received, with 52 surveys completed (51 % response rate). The majority of responding institutions have a patient blood management (PBM) program (n = 40, 77 %) and 33 (63 %) have at least 1 TSO. 61 % of TSOs report an educational background in nursing, with 11 additional unique training backgrounds identified. TSO responsibilities are varied and include quality improvement, education, transfusion safety event analysis, and participation in PBM initiatives. Barriers to implementing a TSO position include lack of resources, financial impediments, and a lack of understanding of the position and its value by administrators and clinicians. DISCUSSION: The results of this survey highlight how TSOs contribute to transfusion safety and PBM and may provide guidance to hospitals interested in implementing a TSO position. It also elucidates the range of TSO responsibilities and approaches that institutions utilize to advocate for, and implement, this position in the US.

Plasma pooling in combination with amotosalen/UVA pathogen inactivation to increase standardisation and safety of therapeutic plasma units.

OBJECTIVES: Assessment of the impact of pooling five single-donor plasma (SDP) units to obtain six pathogen-reduced therapeutic plasma (PTP) units on standardisation and the retention of labile coagulation factors. BACKGROUND: SDP shows a high inter-donor variability with potential implications for the clinical treatment outcome. Additionally, there is still an existing risk for window-period transmissions of blood borne pathogens including newly emerging pathogens. METHODS/MATERIALS: Five ABO-identical SDP units were pooled, treated with the INTERTCEPT™ Blood System (Cerus Corporation, U.S.A.) and split into six PTP units which were frozen and thawed after 30 days. The variability in volume, labile coagulation factor retention and activity was assessed. RESULTS: The variability of volumes between the PTP units was reduced by 46% compared to SDP units. The variability in coagulation factor content between the PTP units was reduced by 63% compared to SDP units. Moderate, but significant losses of coagulation factors (except for vWF) were observed in PTPs compared to SDPs. CONCLUSION: The pooling of five SDP units to obtain six PTP units significantly increases product standardisation with potential implications for safety, economics as well as transfusion-transmitted pathogen safety, making it an interesting alternative to quarantine SDP (qSDP) and pathogen-reduced SDP.

Financial analysis of large-volume delayed sampling to reduce bacterial contamination of platelets.

BACKGROUND: Effective and financially viable mitigation approaches are needed to reduce bacterial contamination of platelets in the US. Expected costs of large-volume delayed sampling (LVDS), which would be performed by a blood center prior to shipment to a hospital, were compared to those of pathogen reduction (PR), point-of-release testing (PORt), and secondary bacterial culture (SBC). METHODS: Using a Markov-based decision-tree model, the financial and clinical impact of implementing all variants of LVDS, PR, PORt, and SBC described in FDA guidance were evaluated from a hospital perspective. Hospitals were assumed to acquire leukoreduced apheresis platelets, with LVDS adding $30 per unit. Monte Carlo simulations were run to estimate the direct medical costs for platelet acquisition, testing, transfusion, and possible complications associated with each approach. Input parameters, including test sensitivity and specificity, were drawn from existing literature and costs (2018US$) were based on a hospital perspective. A one-way sensitivity analysis varied the assumed additional cost of LVDS. RESULTS: Under an approach of LVDS (7-day), the total cost per transfused unit is $735.78, which falls between estimates for SBC (7-day) and PORt. Assuming 20,000 transfusions each year, LVDS would cost $14.72 million annually. Per-unit LVDS costs would need to be less than $22.32 to be cheaper per transfusion than all other strategies, less than $32.02 to be cheaper than SBC (7-day), and less than $196.19 to be cheaper than PR (5-day). CONCLUSIONS: LVDS is an effective and cost-competitive approach, assuming additional costs to blood centers and associated charges to hospitals are modest.

Health economics of Patient Blood Management: a cost-benefit analysis based on a meta-analysis.

BACKGROUND AND OBJECTIVES: Patient Blood Management (PBM) is the timely application of evidence-based medical and surgical concepts designed to improve haemoglobin concentration, optimize haemostasis and minimize blood loss in an effort to improve patient outcomes. The focus of this cost-benefit analysis is to analyse the economic benefit of widespread implementation of a multimodal PBM programme. MATERIALS AND METHODS: Based on a recent meta-analysis including 17 studies (>235 000 patients) comparing PBM with control care and data from the University Hospital Frankfurt, a cost-benefit analysis was performed. Outcome data were red blood cell (RBC) transfusion rate, number of transfused RBC units, and length of hospital stay (LOS). Costs were considered for the following three PBM interventions as examples: anaemia management including therapy of iron deficiency, use of cell salvage and tranexamic acid. For sensitivity analysis, a Monte Carlo simulation was performed. RESULTS: Iron supplementation was applied in 3·1%, cell salvage in 65% and tranexamic acid in 89% of the PBM patients. In total, applying these three PBM interventions costs €129·04 per patient. However, PBM was associated with a reduction in transfusion rate, transfused RBC units per patient, and LOS which yielded to mean savings of €150·64 per patient. Thus, the overall benefit of PBM implementation was €21·60 per patient. In the Monte Carlo simulation, the cost savings on the outcome side exceeded the PBM costs in approximately 2/3 of all repetitions and the total benefit was €1 878 000 in 100·000 simulated patients. CONCLUSION: Resources to implement a multimodal PBM concept optimizing patient care and safety can be cost-effectively.

An animal model of transfusion-related acute lung injury and the role of soluble CD40 ligand.

BACKGROUND AND OBJECTIVES: Transfusion-related acute lung injury (TRALI) is a life-threatening complication of transfusion and is one of leading causes of transfusion-associated fatalities. However, the pathogenesis of TRALI is still unclear. Soluble CD40 ligand (sCD40L) is a proinflammatory cytokine that accumulates during blood component storage and is involved in transfusion reactions. The objective of this study was to establish a clinically relevant TRALI animal model and to evaluate the role of sCD40L in TRALI. MATERIALS AND METHODS: Rats' red-blood-cell (RBC) suspensions were prepared, and the quality of RBC was evaluated. A trauma-haemorrhage-transfusion strategy was applied to build the animal model. Lung oedema was evaluated by histopathology examination, total bronchoalveolar lavage fluid (BALF) protein concentration, Evans blue dye (EBD) leakage and inflammatory cytokines. The sCD40L concentrations were measured. RESULTS: Storage lesions of RBCs gradually increased over time. Obvious histological evidence of lung injury of rats transfused with a 35-day RBC was observed. The total BALF protein concentration, EBD leakage, inflammatory cytokines concentration were increased significantly in the Day 35 group. The sCD40L concentration increased significantly in the storage RBC suspension over time but was slightly elevated in rat plasma. CONCLUSIONS: These findings indicated successful establishment of a TRALI animal model with trauma-haemorrhage-transfusion, in which sCD40L may play a minor role in the development of TRALI.

Collecting and evaluating convalescent plasma for COVID-19 treatment: why and how?

Plasma provided by COVID-19 convalescent patients may provide therapeutic relief as the number of COVID-19 cases escalates steeply worldwide. Prior findings in various viral respiratory diseases including SARS-CoV-related pneumonia suggest that convalescent plasma can reduce mortality, although formal proof of efficacy is still lacking. By reducing viral spread early on, such an approach may possibly downplay subsequent immunopathology. Identifying, collecting, qualifying and preparing plasma from convalescent patients with adequate SARS-CoV-2-neutralizing Ab titres in an acute crisis setting may be challenging, although well within the remit of most blood establishments. Careful clinical evaluation should allow to quickly establish whether such passive immunotherapy, administered at early phases of the disease in patients at high risk of deleterious evolution, may reduce the frequency of patient deterioration, and thereby COVID-19 mortality.

Emergency preparedness, resilience and response guidance for UK hospital transfusion teams.

OBJECTIVES: To present Emergency Preparedness, Resilience and Response (EPRR) guidance for Hospital Transfusion Teams on behalf of the National Blood Transfusion Committee emergency planning working group. BACKGROUND: The Civil Contingencies Act 2004 requires healthcare organisations to demonstrate that they can deal with major incidents while maintaining critical services. Recent mass casualty events and the use of transfusion-based resuscitation have highlighted the evolving role of the Hospital Transfusion Team. METHODS: This multi-disciplinary advice is informed by recent global and national experience, the 2018 NHS England clinical guidelines for Major Incidents, and stakeholder workshops. GUIDANCE: Transfusion staff should be familiar with local EPRR plans including casualty type and numbers. Staff should be exercised as part of wider Trust preparation, with documented roles and responsibilities. Transfusion support should be proactive and include blood issue, regulatory compliance and sample handling. Robust LIMS-compatible emergency identification systems are essential to minimise errors. Emergency stock management requires rapid assessment of existing stock and estimated demand before re-ordering. Initial demand should be based on 2 to 4 red blood cells (RBC) per patient admitted. Patients with significant haemorrhage may require further red cells and early haemostatic support. Where "universal" components are demanded, they should be gender appropriate. Senior staff should lead the response, log and communicate key decisions, and prepare for post-incident recovery. CONCLUSIONS: Transfusion teams have an important role in ensuring continuity of transfusion support. Teams should develop their EPRR plans based on local plans and national guidance. Emergency preparedness should include post-incident debriefing for ongoing staff support and future service improvement.

Effective ways to retain first-time blood donors: a field-trial study.

BACKGROUND: Regular blood donors are the cornerstone of blood safety. Understanding the donors' behavior to donate blood improves blood donor retention programs. The purpose of this study is to evaluate the return rate of first-time blood donors following different interventions to identify effective ways to retain first-time donors. STUDY DESIGN AND METHODS: The study was conducted on 1356 first-time blood donors at four main blood centers in Iran. The donors were randomly assigned based on different interventions (phone calls, educational letter, emotional letter, incentive, motivational meeting, and no intervention) to six groups. The return rate of donors was defined as a second attempt to donate within 6 months after the first donation. Return rate and 95% confidence intervals (CIs) were calculated and compared among different groups. RESULTS: A total of 394 (29%) donors returned within 6 months for a second donation (95% CI, 0.26-0.31). The return rate in the emotional letter group, educational letter, phone reminder, incentives, motivational meeting, and control groups was 36% (95% CI, 0.31-0.42), 33.2% (95% CI, 0.27-0.38), 31.5% (95% CI, 0.25-0.37), 30% (95% CI, 0.22-0.38), 22% (95% CI, 0.17-0.27) and 22.1% (95% CI, 0.17-0.27), respectively. CONCLUSIONS: This study provides evidence supporting the fact that more first-time blood donors can be motivated to donate again by implementing targeted interventions. It demonstrates that emotional letters, educational letters, and phone reminders were effective in improving the return rate of first-time donors.

How do I get an emergency civilian walking blood bank running?

The shift toward using a transfusion strategy in a ratio to mimic whole blood (WB) functionality has revitalized WB as a viable option to replace severe blood loss in civilian health care. A military-civilian collaboration has contributed to the reintroduction of WB at Haukeland University Hospital in Bergen, Norway. WB has logistical and hemostatic advantages in both the pre- and in-hospital settings where the goal is a perfectly timed balanced transfusion strategy. In this paper, we describe an event leading to activation of our emergency WB collection strategy for the first time. We evaluate the feasibility of our civilian walking blood bank (WBB) to cover the need of a massive amount of blood in an emergency situation. The challenges are discussed in relation to the different stages of the event with the recommendations for improvement in practice. We conclude that the use of pre-screened donors as a WBB in a civilian setting is feasible. The WBB can provide platelet containing blood components for balanced blood resuscitation in a clinically relevant time frame.