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.

Investigation of Bacterial Infections Among Patients Treated With Umbilical Cord Blood-Derived Products Marketed as Stem Cell Therapies.

Importance: The number of clinics marketing stem cell products for joint diseases, chronic pain, and most recently, COVID-19, has increased despite warnings from the US Food and Drug Administration that stem cell products for these and other indications have not been proven safe or effective. Objective: To examine bacterial infections in 20 patients who received umbilical cord blood-derived products marketed as stem cell treatment. Design, Setting, and Participants: This case series is a national public health investigation including case-finding, medical record review and abstraction, and laboratory investigation, including sterility testing of products and whole-genome sequencing of patient and product isolates. Participants included patients who developed bacterial infections following administration of umbilical cord blood-derived products marketed as stem cell treatment during August 2017 to September 2018. Data analysis was performed from March 2019 to September 2021. Exposures: Umbilical cord blood-derived products marketed as stem cell treatment. Main Outcomes and Measures: Data were collected on patient infections and exposures. The Centers for Disease Control and Prevention performed sterility testing on undistributed and distributed vials of product marketed as stem cell treatment and performed whole-genome sequencing to compare patient and product bacterial isolates. Results: Culture-confirmed bacterial infections were identified in 20 patients (median [range] age, 63 [2-89] years; 13 male patients [65%]) from 8 US states who sought stem cell treatment for conditions including pain, osteoarthritis, rheumatoid arthritis, and injury; all but 1 required hospitalization. The most frequently isolated bacteria from patients with infections were common enteric species, including Escherichia coli (14 patients) and Enterobacter cloacae (7 patients). Of unopened, undistributed products sampled for testing, 65% (22 of 34 vials) were contaminated with at least 1 of 16 bacterial species, mostly enteric. A patient isolate from Arizona matched isolates obtained from products administered to patients in Florida, and patient isolates from Texas matched undistributed product sent from the company in California. Conclusions and Relevance: Unapproved stem cell products can expose patients to serious risks without proven benefit. Sequencing results suggest a common source of extensive contamination, likely occurring during the processing of cord blood into product. Patients and health care practitioners who are considering the use of unapproved products marketed as stem cell treatment should be aware of their unproven benefits and potential risks, including serious infections.

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.

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.

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.

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.

Thalassemia Patients from Baluchistan in Pakistan Are Infected with Multiple Hepatitis B or C Virus Strains.

There are an estimated 2,000 children with ß-thalassemia in the province Baluchistan of Pakistan. These children are at high risk of acquiring transfusion-transmitted infections (TTIs) due to their need of regular blood transfusions for survival. Therefore, we investigated the frequencies of TTIs among these multi-transfused patients in a region where the WHO guidelines for blood safety are not always followed. Sera from 400 children (mean age 7.7 ± 4.70 years) treated at two thalassemia centers in Baluchistan were investigated for TTIs. Eleven (2.8%) were hepatitis B surface antigen positive, and 72 (18.3%) had anti-hepatitis C virus (HCV), two of which were infected with both viruses. Only 22% of the children had been reached by the program for universal hepatitis B virus (HBV) vaccination which started in 2004. Half (51%) of the HCV infected had also been HBV infected. The HBV- and HCV-infected patients were older and had received more blood transfusions than the uninfected patients (P < 0.001). Molecular characterization of the viral strains revealed the presence of several genetically different strains in at least three HBV- and seven HCV-infected children. This is the first study to demonstrate infections with multiple HBV or HCV strains simultaneously infecting thalassemia patients. These may become the source for new emerging recombinant viruses of unknown virulence. The high prevalence of anti-HCV-positive children, and the presence of HBV infections among children who should have been vaccinated, highlights an urgent need for improvements of blood safety in this region of Pakistan.

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.

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.

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.

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.

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.

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 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.

Low retention rate of voluntary blood donors: contribution of an original method based on a composite classification (results of a monocentric study in the Democratic Republic of Congo).

INTRODUCTION: in order to improve the safety of blood transfusion, the retention of voluntary donors remains a major concern in the Democratic Republic of Congo. Nevertheless, retention is still difficult to assess because of the lack of local studies. The present study establishes the donors' profile and regularity, as well as regularity-associated factors, at the Provincial Blood Transfusion Centre in Bukavu. METHODS: this descriptive and analytical cross-sectional study included the records of 387 out of 773 blood donors during the period from 2015 to 2017. Donor retention and its associated factors were measured. The composite approach used here considered the number of blood donations, their frequency, the previous regularity of donors and the inter-donation interval. RESULTS: we bring to light an important loss of regular voluntary donors in the centre. Only 23.8% of them were still regular donors in 2017. The majority of donors registered in the centre are young males and have no income. On the contrary, factors associated with the profile of a regular donor in 2017 were: age at least 46 years old, being a woman and working in the formal sector. The composite classification highlighted that an important proportion of former regular donors, namely 72.8% (N=161/221), had not given blood in 2017. CONCLUSION: the use of a composite classification to assess the regularity of voluntary blood donors provides more accurate information that will enable the improvement of donors' awareness and retention as well as the possible reinstatement of former donors.

Estimation of mosquito-borne and sexual transmission of Zika virus in Australia: Risks to blood transfusion safety.

BACKGROUND: Since 2015, Zika virus (ZIKV) outbreaks have occurred in the Americas and the Pacific involving mosquito-borne and sexual transmission. ZIKV has also emerged as a risk to global blood transfusion safety. Aedes aegypti, a mosquito well established in north and some parts of central and southern Queensland, Australia, transmits ZIKV. Aedes albopictus, another potential ZIKV vector, is a threat to mainland Australia. Since these conditions create the potential for local transmission in Australia and a possible uncertainty in the effectiveness of blood donor risk-mitigation programs, we investigated the possible impact of mosquito-borne and sexual transmission of ZIKV in Australia on local blood transfusion safety. METHODOLOGY/PRINCIPAL FINDINGS: We estimated 'best-' and 'worst-' case scenarios of monthly reproduction number (R0) for both transmission pathways of ZIKV from 1996-2015 in 11 urban or regional population centres, by varying epidemiological and entomological estimates. We then estimated the attack rate and subsequent number of infectious people to quantify the ZIKV transfusion-transmission risk using the European Up-Front Risk Assessment Tool. For all scenarios and with both vector species R0 was lower than one for ZIKV transmission. However, a higher risk of a sustained outbreak was estimated for Cairns, Rockhampton, Thursday Island, and theoretically in Darwin during the warmest months of the year. The yearly estimation of the risk of transmitting ZIKV infection by blood transfusion remained low through the study period for all locations, with the highest potential risk estimated in Darwin. CONCLUSIONS/SIGNIFICANCE: Given the increasing demand for plasma products in Australia, the current strategy of restricting donors returning from infectious disease outbreak regions to source plasma collection provides a simple and effective risk management approach. However, if local transmission was suspected in the main urban centres of Australia, potentially facilitated by the geographic range expansion of Ae. aegypti or Ae. albopictus, this mitigation strategy would need urgent review.