Advances in Pathogen Reduction Technologies to Improve Global Transfusion Safety

Over the past several decades, many developments in the field of transfusion medicine have improved the safety of blood transfusions. Along with advances in nucleic acid testing of transfusion-transmitted pathogens and improved screening programs for blood donors, implementing pathogen reduction technology (PRT) in blood products has also played a key role in improving transfusion safety practices. 

While the main purpose of PRT is reducing transfusion-transmitted pathogens within the blood supply, an added benefit is that it inactivates white blood cells (such as T lymphocytes) in blood products, which reduces the incidence of transfusion associated-graft versus host disease.^1,2,3 PRTs are currently used in various blood products, including platelets, plasma, and fractionated plasma products.¹ 

Early pathogen reduction technologies

The earliest adoption of PRT was in the production of fractionated plasma products. One of the first PRT methods used in albumin and globulin fractions required multiple steps of precipitation and centrifugation of precipitant and effluent. This was achieved using changes in pH, temperature ionic strength, and ethanol gradients. 

Another historical method of pathogen inactivation in albumin fractions was using heat treatment. Depending on the temperature, both lipid-enveloped and non-enveloped viruses could be inactivated. 

With further development of PRTs, various compounds, such as organic solvents and detergents, started being used in the pathogen reduction of single-donor plasma and pooled plasma protein concentrates. Many of these PRTs were used in combination with nanofiltration to further remove non-enveloped viruses in addition to viruses smaller than the filter’s pore size. 

Toward the end of the 20th century, methylene blue became a common PRT used for plasma, as the photoactive dye inactivated lipid-enveloped viruses when exposed to ultraviolet light.⁵

Current pathogen reduction technologies

Over the past two decades, there have been several developments in pathogen reduction systems, including the INTERCEPT^TM Blood System, Mirasol® Pathogen Reduction Technology, and THERAFLEX UV-Platelet System. 

INTERCEPT^TM Blood System

The INTERCEPT^TM Blood System uses amotosalen (a psoralen compound) in combination with UVA light. Amotosalen works by intercalating any DNA or RNA present in the blood product, and UVA light (320–400 nm wavelength) adducts and crosslinks adenine and thymidine bases, inactivating pathogens and leukocytes.^2,6 After treatment, residual amotosalen is filtered out using a Compound Adsorption Device.⁷ The INTERCEPT^TM Blood System is in use in more than 30 countries around the world, having received its CE mark as a class III medical device for platelets in 2002 and for plasma in 2006.^2,6,8 

Mirasol® Pathogen Reduction Technology

The Mirasol® Pathogen Reduction Technology is another photoactive technology that uses riboflavin in addition to broad wavelength UV light (280–400 nm).² When activated by UV light, riboflavin interacts with guanine residues in nucleic acids, inactivating DNA and RNA.⁷ The Mirasol® Pathogen Reduction Technology is in use in more than 20 countries around the world, having received its class IIb CE mark for platelets in 2007 plasma in 2008, and whole blood in 2015.^1,2,9 

THERAFLEX UV-Platelet System

The THERAFLEX UV-Platelet System is one of the newest approved PRTs for platelets. This technology does not contain a photoactive compound, and instead, only uses UVC light (200–280 nm wavelength) to induce the formation of cyclobutene pyrimidine and pyrimidine-pyrimidone dimers, inactivating DNA and RNA.⁶ Specially designed ethylene vinyl acetate bags are used with this technology to allow the UVC light to fully penetrate blood products.⁷ Although this PRT received its class IIb CE mark for platelets in 2009, it is currently not in routine use as it has only recently been evaluated in the clinical setting.^6,10

Advances in pathogen reduction technologies

Further development of novel PRTs are currently under investigation. Violet-blue light has been shown to be efficient against a broad spectrum of bacteria in platelets and plasma, while optimized ultrasound has been shown to inactivate various viruses in plasma.^11,12 

Other developments in PRT are addressing the need for pathogen inactivation in whole blood and red blood cells. The Mirasol® Pathogen Reduction Technology has been effective in whole blood, with studies demonstrating its application in improved transfusion safety practices.⁷ 

In addition, the INTERCEPT^TM Blood System has created a PRT for red blood cells using the compound amustaline. Amustaline contains three important components that contribute to the inactivation of genetic material in cells. The first component is an acridine anchor that intercalates and binds to nucleic acids; the second component is an effector that reacts with DNA or RNA bases; and the third is a linker that contains a labile ester bond that hydrolyzes at a neutral pH. Amustaline works in combination with a quenching agent, glutathione, that reacts with any residual amustaline present in the blood.²

Toward equitable access to PRTs

Pathogen reduction has been adopted across the globe with approximately 49 countries employing at least one type of PRT in the production of either platelets and/or plasma components. The geographical distribution of these countries varies, with most located within Europe and Asia.¹³ 

While it’s not surprising that PRTs have been adopted in countries that have the funding and infrastructure to develop and implement these technologies, resource-poor countries have limited access to PRTs.¹⁴ With novel pathogens emerging across the globe, the world must prepare for the event that a novel pathogen could affect the global blood supply. However, until resource-poor countries are granted equitable access to PRTs, global transfusion safety and hemovigilance practices cannot shift from the current reactionary system to a more precautionary system that would better protect patients worldwide.

To achieve global transfusion safety, every country needs equitable access to PRTs to improve the safety of blood products, including international collaborative efforts to fund PRT research and implement PRTs in resource-poor countries.

Improving blood product safety

Pathogen reduction has been increasingly used over the years to improve blood product safety against transfusion-transmitted infections and transfusion-associated graft-versus-host disease. Various PRTs have been developed to assist in the reduction and inactivation of pathogens and leukocytes in blood. However, to achieve universal blood transfusion safety, resource-poor countries need funding and support to implement and use PRTs in their blood supply.

References:

1. Wasiluk T et al. Maintaining plasma quality and safety in the state of ongoing epidemic – the role of pathogen reduction. Transfus Apher Sci 2021;60(1):102953. doi: 10.1016/j.transci.2020.102953
2. Li M et al. Is pathogen reduction an acceptable alternative to irradiation for risk mitigation of transfusion-associated graft versus host disease?Transfus Apher Sci 2022;61(2):103404. doi: 10.1016/j.transci.2022.103404
3. Castro G et al. UVA treatment inactivates T cells more effectively than the recommended gamma dose for prevention of transfusion-associated graft-versus-host disease. Transfusion 2018;58(6):1506–15. doi: 10.1111/trf.14589
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8. CERUS Intercept Blood System. Resources. 2022 [cited 2022 Jun 9]; Available from: https://www.interceptbloodsystem.com/en/resources/category/ce-mark-iso
9. Terumo. Health Canada approves Mirasol pathogen reduction technology system to treat platelets in plasma: Mirasol designed to add a later of safety to blood supply. 2021 [cited 2022 Jun 9].
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11. Stewart CF et al. Violet-blue 405-nm light-based photoinactivation for pathogen reduction of human plasma provides broad antibacterial efficacy without visible degradation of plasma proteins. Photochem Photobiol. 2022;98(2):504-12. doi: 10.1111/php.13584
12. Pförringer D et al. Novel method for reduction of virus load in blood plasma by sonification.Eur J Med Res 2020;25(1):1-8. https://doi.org/10.1186/s40001-020-00410-9
13. AABB. Listing of countries in which pathogen reduction technology systems and products are in use. 2015 [cited 2022 Jun 9].
14. Fong IW. Current trends and concerns in infectious diseases, emerging infectious diseases of the 21st century. 1st ed. Cham: Springer Nature Switzerland AG; 2020. Chapter 8, Blood transfusion-associated infections in the twenty-first century: new challenges; p. 191-215.