The US Food and Drug Administration (FDA) deploys a five-layer system to safeguard the volunteer-driven blood system: (1) Donor screening (upfront information about donor eligibility and specific and direct questions), (2) Donor deferral lists (all donors checked against the registry), (3) Extensive donation testing, (4) Quarantine of all collected blood until tested, and (5) Problem and deficiency investigation/ process improvement.
In December, 2014, the FDA added a sixth layer: Pathogen Reduction (PR), i.e. photochemical treatment to achieve at least a 4 log reduction of viral and bacterial infectivity, and T-lymphocyte inactivation in single donor apheresis platelets and plasma. Additionally, PR protects against emerging or novel threats to the blood supply such as Dengue, Chikungunya, Babesia, and so forth.
The PR process approved by the FDA uses a psoralen compound, amotosalen, in the presence of UV-A light exposure to form DNA and RNA monoadducts and cross-links in pathogens contaminating platelets and plasma rendering them incapable of causing disease (photochemical process).
Another process, in clinical trials for platelets and plasma and expected to achieve FDA approval, uses Riboflavin (vitamin B2) and UV light exposure that causes direct DNA and RNA damage and guanine modification (photodynamic reaction involving reactive oxygen species). Riboflavin/UV treatment of whole blood, now in clinical trials, applies a higher UV dose than used with platelets and plasma, and expands PR treated products to include red cells.
Another process, FDA approved previously for reducing pathogen infectivity in pooled volunteer or paid plasma donations, uses a solvent, tri-n-butyl phosphate, and a detergent, octoxynol, to disrupt lipid membranes of enveloped viruses. Since the solvent/detergent process affects lipid membranes, it is not applicable to cellular blood components.
Recognizing hemoglobin absorbs UVA light, an additional process in clinical trials for red cell PR, involves a frangible anchor-linker effector (S 303) and a quencher glutathione. In a pH-dependent reaction and taking advantage of its amphipathic character, the chemical compound passes through membranes and intercalates helical regions of pathogen nucleic acids. Previously, this approach resulted in red cell neo-antigen formation and antibody response now mitigated by a revised process.
Reported PR studies demonstrate inactivation of enveloped viruses such as HIV (cell free and cell associated), hepatitis B and C, HTLV-I/II, West Nile Virus, and CMV effectively eliminating infectivity of existing or new infections such as those in the “window period” between exposure and test detection. PR also reduces transmission risks associated with protozoa: Trypanosoma cruzi, plasmodia, leishmania, and babesia.
Non-enveloped viruses such as hepatitis A and E and Parvovirus B19 are resistant as are prions.
PR inactivates Gram positive, Gram negative, and Gram positive anerobic bacteria in platelets. An important intervention since clinical sepsis occurs after 1 per 100,000 platelet transfusions and 1 per 3000 platelet components contain bacteria. FDA addressed this hazard in a December, 2014 Draft Guidance document advising hospital transfusion services to perform rapid testing (point-of-care testing) on day 4 or day 5 platelets. Although not addressed in the Draft Guidance, PR treatment of platelets would obviate the need for such testing by hospital transfusion services.
Some spore-forming bacteria escape inactivation by current PR techniques.
Toxicity studies involving toxicology, genotoxicity, and carcinogenicity demonstrate adequate safety margins. No novel (neo-) antigens occurred in plasma or platelet testing.
The results of multiple clinical trials seeking efficacy endpoints show PR treated platelets have reduced post-transfusion corrected count increments (CCI), days to next platelet transfusion, and increased number of platelet transfusions compared to non-treated platelets. Notably, the non-inferiority designed SPRINT trial involving 645 patients and powered to detect clinical bleeding rather than surrogate post-transfusion platelet count increments, found no differences in incidence of WHO Grade 2 bleeding or time to onset of WHO Grade 2 bleeding in those receiving PR treated or control platelets.
PR treated plasma provides similar results to non-treated plasma although there is a 20%-30% loss of Factor VIII.
Chemical and UV light exposure of lymphocytes in PR treated blood components reduces the risk of transfusion-associated Graft-versus-Host Disease (T-A GvHD), thereby avoiding gamma or x-ray irradiation of platelets for T-A GvHD prevention.
Additional benefits of PR include: elimination of bacterial testing including point-of-care testing for platelets, extension of platelet shelf life to 7 days, avoidance of blood donor travel deferrals to malaria endemic areas, and prophylactic inactivation of novel pathogens and those not discovered currently.
Barriers to PR implementation include: cost/affordability, availability at this time only for platelets and plasma, perceived safety of the blood supply, success of emerging pathogen surveillance, and decreased platelet recovery despite no difference in bleeding incidence.
Predictions: Universal PR adaption will occur via implementation by early adapters followed by others or via FDA regulation. Some currently performed procedures (platelet bacterial testing and irradiation to prevent T-A GvHD) will be eliminated resulting in cost savings. Some currently performed blood donation tests (i.e. use of both serology and nucleic acid tests) will be eliminated resulting in cost savings. Emerging or novel infectious agents will be interdicted at an early stage enhancing blood safety without the need for additional tests. The paradigm change of transitioning the focus on product safety to transfusion (recipient) safety will accelerate with greater emphasis on patient blood management and prevention of blood specimen and patient misidentification errors.
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- FDA, CBER. Bacterial detection testing by blood and blood collection establishments and transfusion services to enhance the safety and availability of platelets for transfusion. Draft guidance for industry. December, 2014
- Okoye OT, Reddy H, Wong MD, et al. Large animal evaluation of riboflavin and ultraviolet light- treated whole blood transfusion in a diffuse, nonsurgical bleeding porcine model. Transfusion 2015;55:532-43
- Snyder EL, Stramer SL, Benjamin RJ. The safety of the blood supply-time to raise the bar. N Engl J Med 2015;372:1882-5