Modeling the risk of an emerging pathogen entering the Canadian blood supply

BACKGROUND: As part of its risk management process, Canadian Blood Services (CBS) constructed mathematical models of how newly emerging pathogens might affect blood transfusion recipients. STUDY DESIGN AND METHODS: CBS convened an expert panel including medical, health economics, analytical, risk management, and insurance professionals to examine multiple data sources. The model for emerging pathogen risk included separate modules to calculate the frequency and severity of infections from transfusion‐transmitted agents that could cause either acute transient or chronic persistent infection. Important model input variables were annual number of components transfused, the presumed incidence and prevalence of a new agent, the time interval of recipient risk, recipient age and sex, projected recipient survival, rate of secondary infection, pathogen‐induced morbidity, and the associated medical costs of such morbidity. RESULTS: In the 5‐year time frame considered in the model, it was estimated that approximately 3500 recipient infections (two‐SD range of 0 to 11,370 infections) could occur from an emerging pathogen that establishes a chronic infection in donors, with 60% of these due to red blood cell transfusion. The medical costs associated with recipient outcomes due to a catastrophic emerging pathogen could be lowered by 20% if an effective pathogen reduction method for either platelets or plasma were in place. CONCLUSION: This modeling exercise offers a framework for other blood services to construct similar models. It also provides a useful way to model the implementation of new blood safety interventions (e.g., pathogen reduction) on emerging pathogen risk.     

Cost-effectiveness of pathogen inactivation for platelet transfusions in the Netherlands

The objective of this study is to estimate cost-effectiveness of pathogen inactivation for platelet transfusions in the Netherlands. We used decision tree analysis to evaluate the cost-effectiveness of the addition of pathogen inactivation of pooled platelets to standard procedures for platelet transfusion safety (such as, donor recruitment and screening). Data on transfusions were derived from the University Medical Centre Groningen (the Netherlands) for 1997. Characteristics of platelet recipients (patient group, age, gender and survival) and data/assumptions on viral and bacterial risks were linked to direct and indirect costs/benefits of pathogen inactivation. Post-transfusion survival was simulated with a Markov model. Standard methods for cost-effectiveness were used. Cost-effectiveness was expressed in net costs per life-year gained (LYG) and estimated in baseline- and sensitivity analysis. Sensitivity was analysed with respect to various assumptions including sepsis risk, reduction of the discard rate and discounting. Stochastic analysis to derive 90% simulation intervals (SIs) was performed on sepsis risk. Net costs per LYG for pathogen inactivation were estimated 554,000 euro in the baseline-weighted average over the three patient groups (90% SI: 354,000-1092,500 euro). Sensitivity analysis revealed that cost-effectiveness was insensitive to viral risks and indirect costing, but highly sensitive to the assumed excess transfusions required and discounting of LYG. Given relatively high net costs per LYG that are internationally accepted for blood transfusion safety interventions, our estimated cost-effectiveness figures for pathogen inactivation may reflect acceptable cost-effectiveness in this specific area. Two main assumptions of our model were that the pathogen inactivation was 100% effective in preventing transmission of the pathogens considered and was not associated with major and/or costly adverse reactions. Validation of several crucial parameters is required, in particular the Dutch risk for acquiring and dying of transfusion-related sepsis.     

Reengineering transfusion and cellular therapy processes hospitalwide: ensuring the safe utilization of blood products

Efforts to make blood transfusion as safe as possible have focused on making the blood in the bag as disease-free as possible. The results have been dramatic, and the costs have been correspondingly high. Although blood services will have to continue to deal with emerging pathogens, efforts to reduce the transfusion of infectious agents presently posing a risk will require high incremental costs and result in only improvements of a small magnitude.
The other aspect of safe blood transfusion, the actual transfusion process performed primarily in hospitals, has been accorded considerably less interest. We should turn our attention to enhancing overall blood safety by focusing on improving the process of blood transfusion. Errors involving patient, specimen, and blood product identification put transfused patients at risk, increasing the mortality risk for some. Solutions that could improve the transfusion process are discussed as a focus of this article.     

Cost-effectiveness of cardiac resynchronization therapy in combination with an implantable cardioverter defibrillator (CRT-D) for the treatment of chronic heart failure from a German health care systemperspective

Aim The aim of the study was to assess the incremental cost-effectiveness ratio (ICER) of Cardiac Resynchronization Therapy in combination with an Implantable Cardioverter Defibrillator (CRT-D) plus Optimal Pharmacological Therapy (OPT) compared to OPT alone in patients with chronic heart failure. Methods and results A decision analytic model was used to estimate the ICER from a German Health Care System perspective. Effectiveness data were used as reported in the COMPANION study. Direct medical costs were considered for inpatient and outpatient treatments. Resource utilization was valued by the prices charged in 2005. Costs and effects were discounted by a discount rate of 3% per year. Oneway and two-way sensitivity analyses were performed. The basecase analysis resulted in accumulated discounted QALYs of 0.958 for OPT, respectively 1.261 for CRT-D + OPT. Accumulated discounted costs were 4618 Euro for OPT, and 31 292 Euro for CRT-D + OPT, respectively, thus resulting in incremental costs per QALY gained of 88 143 Euro after two years. Considering a device longevity of seven years, this resulted in incremental costs per QALY of 24 650 Euro. Conclusion CRT-D plus OPT may be a costeffective alternative for the treatment of patients with CHF in NYHA functional class III and IV depending on device longevity. From the Institute for Health Care Management University of Duisburg-Essen Germany     

Cost-effectiveness of transfusion of platelet components prepared with pathogen inactivation treatment in the United States

BACKGROUND: The Intercept Blood System (IBS) for platelets has been developed to reduce pathogen transmission risks during transfusions. OBJECTIVE: This study was a comprehensive economic analysis of the cost-effectiveness of using the IBS for single-donor apheresis platelets (AP) and random-donor pooled platelet concentrates (PC) versus AP and PC without the IBS in the United States in patient populations in which platelets are commonly transfused. METHODS: All data used in this analysis were summarized from existing published sources (primarily indexed in MEDLINE) and data on file at Baxter Healthcare Corporation (Chicago, Illinois) and Cerus Corporation (Concord, California). A literature-based decision-analytic model was developed to assess the economic costs and clinical outcomes associated with the use of AP and PC treated with the IBS for several conditions and procedures that account for a considerable proportion of the platelet usage in the United States: acute lymphocytic leukemia, non-Hodgkin's lymphoma, coronary artery bypass graft, and hip arthroplasty Risks of infection with HIV, hepatitis C virus (HCV), hepatitis B virus, human T-cell lymphotropic virus type 1, or bacterial agents were incorporated into the model. Possible benefits of reduction of the risk of emerging HCV like pathogens and elimination of the need for gamma irradiation were explored in sensitivity analyses. RESULTS: The incremental cost per quality-adjusted life-year gained by using AP + IBS versus untreated AP ranged from 1,308,833 dollars to 4,451,650 dollars (without bacterial testing) and 4,759,401 dollars to 22,968,066 dollars (with bacterial testing). Corresponding figures for PC + IBS versus untreated PC ranged from 457,586 dollars to 1,816,060 dollars. Inclusion of emerging HCV like virus and the elimination of the need for gamma irradiation improved the cost-effectiveness to a range of 177,695 dollars to 1,058,127 dollars for AP without bacterial testing, 176,572 dollars to 1,330,703 dollars for AP with bacterial testing, and 22,888 dollars to 153,564 dollars for PC. The model was most likely to be affected by mortality from bacterial contamination, IBS effect on platelet utilization, and the inclusion of potential benefits (ie, gamma irradiation and/or emergent HCV-like virus). The model was relatively insensitive to changes in the IBS price and viral transmission risks. CONCLUSIONS: The cost-effectiveness of pathogen inactivation via the IBS for platelets is comparable to that of other accepted blood safety interventions (eg, nucleic acid amplification technology). The IBS for platelets may be considered a desirable strategy to increase the safety of platelet transfusions and a potential insurance against the threat of emerging pathogens.     

Cost-effectiveness of additional hepatitis B virus nucleic acid testing of individual donations or minipools of six donations in the Netherlands

BACKGROUND: To further reduce the risk of hepatitis B virus (HBV) transmission by blood transfusion, nucleic acid testing (NAT) can be employed. The aim of this study is to estimate the incremental cost-effectiveness ratio (ICER) in the Netherlands of employing a triplex NAT assay aimed at HBV nucleic acid detection in individual donations (ID-NAT) or in minipools of 6 donations (MP-6-NAT), compared to a triplex NAT assay in minipools of 24 donations (MP-24-NAT).
STUDY DESIGN AND METHODS: A mathematical model was made of the whole transfusion chain from donors to recipients of blood in the Netherlands. The annual number of avoided HBV transmissions was estimated with the window-period incidence model. The natural history of a HBV infection in recipients is described by a Markov model.
RESULTS: The ICER of adding HBV MP-6-NAT or HBV ID-NAT in the Netherlands is €303,218 (95% confidence interval [CI], €233,001-€408,388) and €518,995 (95% CI, €399,359-€699,120) per quality-adjusted life-year, respectively. The ICER strongly correlates with the age of transfusion recipients.
CONCLUSION: The cost-effectiveness of additional HBV NAT is limited by the limited loss of life caused by HBV transmission. Despite a higher effectiveness, HBV ID-NAT is less cost-effective than MP-6-NAT due to higher costs. A future equivalent participation of immigrants from HBV-endemic countries in the donor base renders HBV NAT only slightly more cost-effective.     

Blood-Borne Pathogens: A Canadian Blood Services Centre for Innovation Symposium

Testing donations for pathogens and deferring selected blood donors have reduced the risk of transmission of known pathogens by transfusion to extremely low levels in most developed countries. Protecting the blood supply from emerging infectious threats remains a serious concern in the transfusion medicine community. Transfusion services can employ indirect measures such as surveillance, hemovigilance, and donor questioning (defense), protein-, or nucleic acid based direct testing (detection), or pathogen inactivation of blood products (destruction) as strategies to mitigate the risk of transmission-transmitted infection. In the North American context, emerging threats currently include dengue, chikungunya, and hepatitis E viruses, and Babesia protozoan parasites. The 2003 SARS and 2014 Ebola outbreaks illustrate the potential of epidemics unlikely to be transmitted by blood transfusion but disruptive to blood systems. Donor-free blood products such as ex vivo generated red blood cells offer a theoretical way to avoid transmission-transmitted infection risk, although biological, engineering, and manufacturing challenges must be overcome before this approach becomes practical. Similarly, next generation sequencing of all nucleic acid in a blood sample is currently possible but impractical for generalized screening. Pathogen inactivation systems are in use in different jurisdictions around the world, and are starting to gain regulatory approval in North America. Cost concerns make it likely that pathogen inactivation will be contemplated by blood operators through the lens of health economics and risk-based decision making, rather than in zero-risk paradigms previously embraced for transfusable products. Defense of the blood supply from infectious disease risk will continue to require innovative combinations of surveillance, detection, and pathogen avoidance or inactivation.     

Pathogen-reduction systems for blood components: the current position and future trends.

The current multi-layered interventional approaches to blood safety have dramatically reduced the risk of viral contamination of blood components. Nowadays most of the residual transfusion transmitted infections (TTI) occur as the result of the interval between the time the donor is infected and the moment at which tests are capable of detecting the agent, the so called "window period" which has been considerably reduced by the increased sensitivity of nucleic acid testing (NAT). However, the residual risk of bacterial contamination and the unexpected appearance of some other emerging pathogens, almost every five years, are still of major concern to the public, politicians, regulatory agencies and place immense pressures on the organisations responsible for the provision of safe blood and its components. In view of these bleak scenarios, the use of human blood as a raw biological source is inherently unsafe, and screening/testing alone cannot exclude all the potential human pathogens; hence we need to put in place some sort of safer alternatives and/or additional preventative safety measures. Recently, several substitutes (alternatives) to virtual blood components have been developed and tried. Moreover, various mechanical methods such as cell washing and leukofiltration have been implemented as additional preventative safety measures but with limited success in abrogating the risk of transfusion transmitted cell-associated agents. The most promising approaches, so far, are methods that target pathogen nucleic acids (Methylene blue; Psolaren and Riboflavin UV light treatment). These procedures have undergone considerable in vitro studies to ensure their extremely high safety margins in terms of toxicity to the cells or to the recipients. In essence, while the technology of targeting nucleic acid to stop viral proliferation is common to the above three strategies, in practice these procedures differ in terms of operational, physicochemical and biological characteristics; including the potential impacts of their metabolites and photo-adducts; their effects on the spectrum of pathogens affected and the log reductions in culture infective studies. Accordingly, any strategy that involves addition of an extraneous agent or physicochemical manipulation of blood must balance the benefits of pathogen reduction against the loss or alteration to the cells and plasma functional integrity, short and long term toxicity to the cells and to the recipients, as well as the risk to the personnel involved and the community at large. Moreover, it must be noted that each method will have a different profile of adverse reactions and may differ in terms of the risk to particularly vulnerable groups of patients, requiring in depth clinical trials, while taking into consideration the cost benefit of the final process. Newer diagnostic procedures must be in place to establish the storage stability of products that have undergone pathogen inactivation, in particular tests reflecting the release of platelet-derived cytokines, cellular apoptosis or microvesiculation and their role in immunosupressiveness. This overview aims to provide an update on the continual improvements in blood component safety, in particular using methods that target pathogen nucleic acid. Emphasis is placed on methylene blue light treatment (MBLT) and Intercept or Mirasol PRT systems for platelets and plasma. The status of pathogen reduction of whole blood and red cells is also highlighted, though the progress in this area has been virtually stopped after the finding of antibody development in the clinical trial.     

新发再发病原体与血液安全

乙肝病毒、丙肝病毒及人类免疫缺陷病毒等输血相关病原体经输血传播风险逐渐减低,目前维持在较低水平,新发再发病原体越来越多被认识到其对输血安全构成威胁,其中一些已知的,如疟原虫、人细小病毒B19、戊型肝炎病毒、登革热病毒、人类T淋巴细胞白血病病毒及西尼罗病毒等已经被证实可经输血传播。其中,登革病毒曾经在中国爆发或流行过,将来或可再次爆发流行,其对血液安全威胁不容忽视。目前,我国常规血液筛查的病原体筛查项目只有4种,由于新发再发病原体层出不穷,采供血系统尚未建立相应的筛查制度,我国的血液筛查系统面临很大的挑战。我们讨论了几种新发再发病原体在我国的流行情况,探讨其对血液安全的影响以及采供血机构个性化病原体筛查策略制订的可行性。     

Proceedings of a Consensus Conference: pathogen inactivation-making decisions about new technologies

Significant progress has been made in reducing the risk of pathogen transmission to transfusion recipients. Nonetheless, there remains a continuing risk of transmission of viruses, bacteria, protozoa, and prions to recipients. These include many of the viruses for which specific screening tests exist as well as pathogens for which testing is currently not being done, including various species of bacteria, babesiosis, variant Creutzfeld-Jacob disease, hepatitis A virus, human herpes virus 8, chikungunya virus, Chagas disease, and malaria. Pathogen inactivation (PI) technologies potentially provide an additional way to protect the blood supply from emerging agents and also provide additional protection against both known and as-yet-unidentified agents. However, the impact of PI on product quality and recipient safety remains to be determined. The purpose of this consensus conference was to bring together international experts in an effort to consider the following issues with respect to PI: implementation criteria; licensing requirements; blood service and clinical issues; risk management issues; cost-benefit impact; and research requirements. These proceedings are provided to make available to the transfusion medicine community the considerable amount of important information presented at this consensus conference.     

Protecting the blood supply from emerging pathogens: the role of pathogen inactivation

Although the risk of infection by blood transfusion is relatively low, breakthrough infections still occur, Transfusion-related fatalities caused by infections continue to be reported, and blood is not tested for many potentially dangerous pathogens. The current paradigm for increasing the safety of the blood supply is the development and implementation of laboratory screening methods and restrictive donor criteria. When considering the large number of known pathogens and the fact that pathogens continue to emerge, it is clear that the utility of new tests and donor restrictions will continue to be a challenge when considering the cost of developing and implementing new screening assays, the loss of potential donors, and the risk of testing errors. Despite improving the safety of blood components, testing remains a reactive approach to blood safety. The contaminating organisms must be identified before sensitive tests can be developed. In contrast, pathogen inactivation is a proactive strategy designed to inactivate a pathogen before it enters the blood supply. Almost all pathogen inactivation technologies target nucleic acids, allowing for the inactivation of a variety of nucleic acid-containing pathogens within plasma, platelets, or red blood cells thus providing the potential to reduce transfusion-transmitted diseases. However, widespread use of a pathogen inactivation technology can only be realized when proven safe and efficacious and not cost-prohibitive.     

Preclinical pharmacokinetic and toxicology assessment of red blood cells prepared with S-303 pathogen inactivation treatment

BACKGROUND: A system has been developed to inactivate a wide spectrum of blood‐borne pathogens in red blood cells (RBCs) before transfusion. The system utilizes S‐303 to target nucleic acids of pathogens and white blood cells. The safety of pathogen inactivated RBC was assessed using S‐303–treated RBCs (S‐303 RBCs) and S‐300, the primary degradation product of S‐303. STUDY DESIGN AND METHODS: As part of a preclinical safety evaluation program, intravenous toxicity, safety pharmacology, toxicokinetic, and pharmacokinetic studies were conducted in rats and dogs with S‐303 RBCs and S‐300. RESULTS: Single and repeated transfusions of S‐303 RBCs were well tolerated in rats and dogs at S‐303 concentrations up to five times higher than that used to prepare RBCs for clinical use. For S‐300, the doses ranged from the lowest level representative of a clinical exposure from transfusion of 1 unit (0.052 mg/kg/day) to up to the amount of S‐300 that would result from exposure to more than 1900 units of RBCs (100 mg/kg/day). There were no related effects of S‐303 RBCs or S‐300 on mortality, clinical status, body weight, or clinical laboratory assessments and no evidence of organ toxicity. S‐300 did not accumulate in the plasma of rats and dogs after repeated transfusions. For all the studies, plasma S‐303 was consistently below the limit of quantitation. CONCLUSION: The level of residual S‐303 and S‐300 in the treated blood component is well below that at which no adverse effects were observed. These results support further clinical development of S‐303 RBCs for prevention of transfusion‐transmitted infections.     

The role of photochemical treatment with amotosalen and UV-A light in the prevention of transfusion-transmitted cytomegalovirus infections

Primary cytomegalovirus (CMV) infection is usually asymptomatic in immunocompetent patients but can cause serious life-threatening complications in immunocompromised CMV-seronegative patients, including patients receiving a bone marrow or peripheral blood stem cell transplant, recipients of some solid-organ transplants, and low-birth-weight neonates. Current recommendations for preventing transfusion-transmitted CMV (TT-CMV) infection in these patients include exclusive use of CMV-seronegative and/or leukoreduced cellular blood components (red blood cells and platelets) for transfusion. However, breakthrough cases of TT-CMV still occur. Despite improving the safety of blood components, testing remains a reactive approach to blood safety. In contrast, pathogen inactivation technologies offer a proactive approach with the potential to further improve blood safety. To reduce the risks associated with platelet transfusions, a photochemical treatment (PCT) process using a combination of the psoralen amotosalen HCl and long-wavelength UV light has been developed and introduced into clinical practice in Europe. PCT has been shown to result in greater than 5.9-log reductions in infectivity of human CMV in platelet concentrates and to prevent the transfusion transmission of murine CMV in a mouse transfusion model. Thus, PCT pathogen inactivation may play a role in further reducing the incidence of TT-CMV infection in patients who are at risk for serious CMV disease. Because PCT is a technology that targets nucleic acids, it also offers a proactive process for the inactivation of a broad range of viral, bacterial, and protozoan pathogens in addition to CMV.     

Costs associated with blood transfusions in Sweden--the societal cost of autologous, allogeneic and perioperative RBC transfusion

Anaemia is characterised by an insufficient number of red blood cells (RBCs) and might occur for different reasons, e.g. surgical procedures are often with associated blood loss. Patients who suffer from anaemia have the option of treatment with blood transfusion or medical treatment. In this study, the societal cost, for the case of Sweden, of RBC transfusion using three different techniques, i.e. allogeneic, autologous and intraoperative transfusion, was estimated. The analysis was based on information from interviews with hospital staff at large Swedish hospitals and from published data. The average cost for a 2 units transfusion was found to be Swedish kronor (SEK) 6330 (702 Euro) for filtered allogeneic RBCs and SEK 5394 (598 Euro) for autologous RBCs for surgery patients. Transfusion reactions accounted for almost 35 per cent of the costs of allogeneic RBC transfusions. The administration cost was found to be much higher for autologous transfusions compared with allogeneic transfusions. The cost of intraoperative erythrocyte salvage was calculated to be SEK 2567 (285 Euro) per transfusion (>4 units).     

Transfusion medicine in the era of genomics and proteomics

Viewing recent trends in transfusion medicine (TM), the authors make predictions about possible future developments within this specialty including greater cost-effectiveness and blood safety resulting from increased automation; techniques in genetics replacing serological typing in many standard assays; and TM service playing a major R&D role together with clinical services in the emerging cell-based therapeutics. To achieve this, the TM laboratory of the future will need to have available extensive skills in immunogenetics and database expertise; emerging techniques in genomics and proteomics will need to be integrated with classic immunohematology approaches; and collaborative networks of TM laboratories will need to raise their profiles as a competent partner in the ongoing clinical biotechnology revolution. Blood product safety is profiled to highlight some of these developments. Until recently, avoiding pathogen transmission has focused primarily on excluding at-risk donors and testing donor blood for pathogen markers. Newer trends in pathogen-inactivation procedures could alter the protein composition of the blood product, potentially causing unintended immune reactions that could outweigh their benefits in further reducing a very low current risk of pathogen transmission. By combining proteomics and immunohematology, those manufacturing processes least likely to generate posttranslational protein modifications will need to be identified.     

Is pathogen reduction an acceptable alternative to irradiation for risk mitigation of transfusion-associated graft versus host disease?

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

Expensive blood safety initiatives may offer less benefit than we think

BACKGROUND: Various blood safety initiatives have ensured a historically low risk of infection transmission through blood transfusion. Although further prevention of infection transmission is possible through, for example, nucleic acid testing and future introduction of pathogen inactivation, such initiatives are very costly in relation to the benefit they offer. Although estimation of the cost-effectiveness requires detailed information about the survival of transfusion recipients, previous cost-effectiveness analyses have relied on incorrect survival assumptions.
STUDY DESIGN AND METHODS: Based on empirical data of more than 1 million Scandinavian transfusion recipients followed for up to 20 years, we present two new survival functions. In a fictitious example we assessed the impact of survival assumptions on the estimated costs per quality-adjusted life-year (QALY) gained, by using the survival functions of three previous cost-effectiveness analyses along with the two new survival functions.
CONCLUSIONS: We conclude that despite considerable costs, previous cost-effectiveness studies may have underestimated the costs per QALY gained by as much as 44%.     

Clinical trials for pathogen reduction in transfusion medicine: A review

Despite the implementation of highly sensitive methods for the detection of pathogens in donor blood products, the risk of transmission of infectious disease to transfusion recipients remains. Of greatest concern, and accounting for most of the risk, are newly-emerging pathogens for which screening assays do not yet exist or well-known pathogens for which testing regimens are not routinely employed. Furthermore, passive donor screening programs are unlikely to capture all potentially infective donors. A promising strategy to overcome these limitations is the proactive incapacitation of pathogens residing in donor units. Several unique pathogen reduction/inactivation (PR/PI) platforms have been developed and implemented in clinical settings. The aims of this article are to review: (1) the basic methodology underlying PR/PI platforms, (2) the potential toxicities associated with PR/PI treatment of blood products, and (3) the data and outcomes from clinical trials involving currently available PR/PI platforms.