INTRODUCTION — The possibility of transmitting infectious organisms via blood products and plasma derivatives is a major public health concern.
The paradigm for ensuring the safety of the blood supply using donor screening and laboratory testing is limited because it requires prior knowledge of the possible infectious agents, development of effective laboratory tests for each agent, and widespread testing of all collected blood. Screening donors and testing products is a reactive approach to preventing transfusion-transmitted infections that takes time to implement while transfusion transmissions from emerging infections continue to occur. It has been a long-sought goal to find an effective way to sterilize blood after collection using a pathogen inactivation technology.
This topic review discusses available methods for pathogen inactivation of blood products including plasma, platelets, red blood cells, and plasma derivatives, and it provides evidence for the effectiveness and potential limitations of these procedures.
Approaches to reducing infectious risk using blood donor screening and blood product testing to eliminate products at risk of carrying infectious organisms are discussed in separate topic reviews. (See "Blood donor screening: Medical history" and "Blood donor screening: Laboratory testing" and "Blood donor screening: Overview of recipient and donor protections".)
GENERAL PRINCIPLES OF PATHOGEN INACTIVATION
Terminology — The terms pathogen inactivation and pathogen reduction have been used interchangeably. Strictly speaking, pathogen inactivation refers to complete prevention of infectivity by a pathogen, whereas pathogen reduction refers to decreasing the amount of an infectious pathogen, either by physical removal (eg, nanofiltration) or by an inactivation technology (eg, methods that damage lipid envelopes or nucleic acids).
Some experts have proposed that the term "pathogen inactivation" be used to refer to the processing of the component, and "pathogen-reduced blood component" be used to refer to the transfusable product because no method can guarantee complete sterility of the component .
In the United States, the US Food and Drug Administration (FDA) approves specific products. Approval for use in European countries is by CE mark.
Technologies — Various technologies have been studied for pathogen inactivation. Early studies focused on developing methods that could be applied to transfusable plasma such as Fresh Frozen Plasma (FFP), which is especially amenable to inactivation treatments because it does not contain cells that might be destroyed or become functionally impaired by an inactivation procedure .
The two major approaches involve the following:
●Methods that damage lipids and thus target a large number of pathogenic lipid-enveloped viruses (solvent/detergent [S/D] treatment).
●Methods that damage nucleic acids (DNA, RNA) and prevent normal replication of a wide array of microorganisms. Examples include adding amotosalen or riboflavin to the blood component, both of which are then activated using ultraviolet (UV) light, or methylene blue, activated using visible light.
During the manufacture of plasma derivatives, there are multiple steps in the fractionation and purification processes that remove and/or destroy infectious agents. These include heat pasteurization (treatment at 60°C for 10 hours), which was first used in the manufacture of serum albumin and shown to kill hepatitis B virus (at the time called "serum hepatitis virus"), as well as chromatography, S/D treatment, and nanofiltration [3-5].
Methods that damage lipids — Methods that damage the lipid envelopes of viruses may target a broad range of viruses, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotropic virus (HTLV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). However, these methods do not target non-enveloped viruses such as hepatitis A virus (HAV), hepatitis E virus (HEV), and parvovirus B19. Methods that inactivate lipid-enveloped viruses have been available since the mid-1980s.
Solvent/detergent treatment — S/D treatment was first applied to the manufacture of plasma derivatives and subsequently has been adapted for the production of transfusable plasma units such as Fresh Frozen Plasma (FFP). The process involves pooling large numbers of individual units together prior to applying the S/D treatment. It uses the properties of organic solvents (eg, tri-n-butyl-phosphate) and non-ionic detergents such as triton X-100 to disrupt lipid-based membranes. This is highly effective in inactivating viruses with lipid envelopes [6,7]. S/D treatment does not inactivate non-enveloped viruses, but other plasma units in the pool are likely to contain antibodies to these viruses that may reduce the pathogenicity of the component to the recipient. With a few exceptions, S/D treatment does not affect the structure or function of plasma proteins [8,9].
Methods that damage nucleic acids — Methods that damage nucleic acids (DNA, RNA) are especially appealing because almost all pathogens (with the exception of prions) require nucleic acids to reproduce and to cause clinically significant infection, whereas red blood cells (RBCs) and platelets lack nuclei and do not require functional nucleic acids. These methods target all nucleic acids (regardless of the specific nucleotide sequence) and as a result are able to inactivate viruses (enveloped and some non-enveloped), bacteria, and parasites that use nucleic acids to replicate. The relative resistance of some non-enveloped viruses to inactivation is thought to be due to the inability of the added chemical to fully penetrate the viral capsid.
Amotosalen+UVA light — The psoralen compound amotosalen (previously called S-59) intercalates into DNA and RNA and can be photoactivated by long wavelength ultraviolet light (UVA) to crosslink the base pairs together, preventing replication . Plasma proteins and coagulation factors are not adversely affected by this treatment, and significant adverse effects have not been reported [11-15]. Amotosalen is removed from the blood product after treatment, before the blood product is transfused, to provide further protection against adverse reactions or toxicity in the recipient. This method is used in the INTERCEPT systems, which are available for pathogen-reduced plasma, Cryoprecipitate, and platelets. (See 'Plasma/FFP' below and 'Platelets' below and 'Cryoprecipitate' below.)
Riboflavin+UV light — UV light breaks nucleic acid bonds, and a portion of the riboflavin (vitamin B2) molecule binds to nucleic acids; UV light activation of riboflavin leads to oxidization of guanine (G) [16,17]. The altered nucleic acids prevent DNA replication. In this case, the UV light is mostly UVB, but light in the UVA and UVC spectrum are also included.
Riboflavin is a water-soluble vitamin that has a well-characterized safety profile and thus does not need to be removed from the blood product (see "Overview of water-soluble vitamins", section on 'Vitamin B2 (riboflavin)'). Plasma proteins and coagulation factors are not adversely affected by this treatment, and significant adverse effects have not been reported [18-20]. This method is used in the Mirasol systems, which are used for pathogen inactivation of plasma, platelets, and RBCs or whole blood. (See 'Plasma/FFP' below and 'Platelets' below and 'RBCs and whole blood' below and 'Cryoprecipitate' below.)
Methylene blue+visible light — Methylene blue (MB) treatment coupled with visible (white or red) light treatment prevents viral replication by damaging the DNA of lipid-enveloped viruses including HIV, HBV, HCV, HTLV, EBV, and CMV . Certain arboviruses such as chikungunya and dengue are also inactivated . However, this system works only with products that have been leukocyte depleted prior to MB treatment as it appears that MB cannot penetrate cell membranes and inactivate intracellular viruses.
During initial development of the MB technology, MB-treated plasma had a faint blue tinge; transfusion of large numbers of units could cause a slight, temporary discoloration of the skin and mucous membranes in recipients. However, the technology was modified to include filters that remove the MB prior to transfusion. Such products have reduced concentrations of some coagulation factors (eg, fibrinogen, factor V, factor VIII) and thus may be less effective for certain patients who require high levels of these factors [23-26].
UV light alone — Certain wavelengths of ultraviolet (UV) light also can cause DNA damage independent of chemical crosslinking compounds . An example is short-wavelength UV light (UVC). This method is used in the THERAFLEX system for pathogen inactivation of platelets. (See 'Platelets' below.)
Reducing or eliminating infectious organisms — In principle, pathogen inactivation technologies have the potential to make the blood supply safer by broadly reducing or eliminating infectious organisms without the need to screen or test for specific pathogens. The paradigm being advocated by federal regulators in the United States, however, is that pathogen inactivation technologies would be used in addition to standard screening for the majority of transfusion-transmitted infections.
Pathogen inactivation is especially appealing for pathogens with the following characteristics:
●Those that cause asymptomatic infection among blood donors
●Those with a long window period during which serologic testing would be ineffective
●Emerging bloodborne infectious organisms such as dengue virus, Zika virus, chikungunya virus, and as yet unknown emerging pathogens for which donated blood is not screened
Pathogen inactivation is more effective at reducing the risk of an emerging pathogen than available screening methods, since the inactivation processes work against entire classes of pathogens rather than requiring knowledge of a specific organism's characteristics and the specific host response (whether the host will be symptomatic and/or develop a serologic response).
Malaria and other parasites — The benefit of pathogen inactivation in reducing transfusion-transmitted malaria was demonstrated in a trial conducted in Ghana, where malaria is endemic and testing of donated blood for malaria is not routinely available. In this trial, 226 adults who required blood transfusion were randomly assigned to receive whole blood that had been treated with riboflavin plus UV light (see 'Riboflavin+UV light' above) or whole blood that had not been treated with pathogen inactivation . Among all whole blood units transfused in the trial, approximately one-fourth had detectable parasitemia. Transfusion-transmitted malaria was distinguished from other routes of infection (eg, de novo infection) using parasite DNA sequencing. The rate of transfusion-transmitted malaria was significantly lower with the riboflavin plus UV-treated units (1 of 28 versus 8 of 37 [4 versus 22 percent, respectively]). The increase in hemoglobin and the incidence of adverse events were similar between the two arms of the trial.
In vitro and animal model studies have demonstrated that riboflavin plus UV light can also inactivate Trypanosoma cruzi, Babesia microti, Babesia divergens, and Leishmania donovani in whole blood [29-31]. These studies revealed a 3.3 to 7.0 log reduction in parasite load. The amotosalen plus UVA light method has also been shown to inactivate parasites in platelet and plasma products .
Viruses — The use of pathogen inactivation in reducing transfusion-transmitted Zika virus infection has been tested by in vitro studies in which Zika virus was added to platelet or plasma components that were then treated with amotosalen plus UVA light (see 'Amotosalen+UVA light' above), followed by testing for titer and infectivity using polymerase chain reaction (PCR)-based assays and viral culture, respectively [33,34]. These assays demonstrated no Zika infectivity or replicative virus following the pathogen inactivation treatment of plasma or platelets. A US Food and Drug Administration (FDA)-approved pathogen-reduction device may be used for plasma and apheresis platelet donations as an alternative to a blood screening test for Zika.
Similar inactivation has been reported for other common arborviruses including West Nile virus, chikungunya virus, and dengue virus. Japanese encephalitis virus (JEV, a mosquito-borne flavivirus) was effectively inactivated by methylene blue plus visible light in plasma products and by UVC light in platelet concentrates .
In addition to emerging infections, both the riboflavin plus UV light and the amotosalen plus UVA light methods have demonstrated pathogen inactivation of established transfusion-transmitted viruses, including both enveloped and non-enveloped viruses such as HIV, HBV, HCV, CMV, and parvovirus [32,36-38].
Pathogen inactivation has been demonstrated to be effective against SARS-CoV-2 [39-41]. However, data demonstrate that SARS-CoV-2 does not appear to be transmitted via transfusion . (See "Blood donor screening: Laboratory testing", section on 'SARS-CoV-2/COVID-19 blood safety policies'.)
Bacteria — Bacterial contamination of blood products now leads to the most common transfusion-transmitted infection in countries with developed transfusion services, with a bacterial contamination incidence of approximately 1 in 2000 for platelets and 1 in 30,000 for RBCs [43-47]. (See "Transfusion-transmitted bacterial infection".)
Platelet transfusions are the most susceptible since the units are stored at room temperature. In the United States, FDA guidance from September 2019 requires transfusion services to include additional measures to address bacterial contamination of platelet units . Pathogen inactivation is one of the options permitted by this guidance. While both riboflavin plus UV light and amotosalen plus UVA light methods have demonstrated pathogen inactivation of primary bacterial contaminants by at least four to five logs, only amotosalen plus UVA light is approved by the FDA in the United States [18,49]. Pathogen-reduced platelets are more expensive than the alternatives to meet the FDA guidance [50-52], but many blood centers and hospitals have selected use of pathogen-reduced platelets to meet the FDA guidance . (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Strategies for reducing bacteria and other pathogens'.)
Preventing transfusion-associated graft-versus-host disease — Another potential benefit of the pathogen inactivation technologies that damage nucleic acids is their role in reducing the need to irradiate products to prevent transfusion-associated graft-versus-host disease (ta-GVHD) [54-56]. Ta-GVHD is a life-threatening complication of transfusion in which donor white blood cells (WBCs) attack the bone marrow and other tissues of the transfusion recipient [57-60]. Damage to the DNA of donor WBCs renders them unable to mount an immune attack against the recipient [54,55,61,62]. (See 'Methods that damage nucleic acids' above.)
If universal pathogen inactivation were instituted for all components, this would eliminate the need for irradiation to prevent ta-GVHD.
Pathogen inactivation methods do not eliminate the need for leukoreduction, because inactivated WBCs may still leak cytokines that can cause febrile nonhemolytic transfusion reactions (FNHTRs). (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction' and "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)
Other potential benefits — Pathogen inactivation of platelets also has the potential to extend the shelf-life of platelet units to seven days. Storage is generally limited to five days in most countries, due to the need for room temperature storage and the associated risk of bacterial infection. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Storage' and "Transfusion-transmitted bacterial infection".)
In addition, since pathogen inactivation is effective against CMV, it limits the need for CMV testing to maintain CMV-negative inventories. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'CMV'.)
Potential limitations — Pathogen inactivation technologies have several potential limitations related to efficacy, possible toxicity, possible reduction in component quality, and cost.
●Incompleteness of inactivation – Even with robust inactivation, there is a possibility that some pathogens can evade inactivation or that the pathogen load is too high for complete inactivation. As an example, inactivation technologies have been demonstrated to reduce a target virus by six logs (to 0.0001 percent of the starting concentration); however, some pathogens can be present at even higher concentrations . (See 'Plasma/FFP' below.)
The possibility of transfusion-transmitted viral infection despite pathogen inactivation was illustrated in a case report of HIV transmission in Spain . The whole blood donation responsible for transmitting HIV tested negative for HIV antibody and for HIV RNA by minipool nucleic acid testing; the latter test was negative because of the low HIV viral load in the donation (see "Blood donor screening: Laboratory testing", section on 'Minipool testing'). The unit was used to prepare RBCs, buffy coat-containing platelets, and plasma. The plasma was treated with methylene blue (MB) plus visible light (see 'Methylene blue+visible light' above). Recipients of the platelets and plasma each became infected with a strain of HIV that was matched to that of the blood donor by viral RNA sequencing and phylogenetic analysis. Given the low viral load in the donation, it is unclear why the MB treatment failed to prevent the HIV transmission from the plasma transfusion.
As noted above, methods that only target enveloped viruses (see 'Methods that damage lipids' above) have allowed transmission of non-enveloped viruses including hepatitis A virus (HAV) and parvovirus B19. Of these, parvovirus transmission has been documented more commonly; hepatitis A and hepatitis E transmission have occurred less frequently due to viremia being lower grade and less frequent [65-67]. Patients may also be at least partially protected from becoming infected with these viruses by antibodies to hepatitis A and parvovirus in the pooled, S/D-treated plasma. An additional protection required by regulatory authorities is screening of the final product to ensure that hepatitis A and parvovirus B19 concentrations are below defined acceptable limits. Usually, plasma input units are screened for these viruses before they are allowed to be included in the plasma pool.
The FDA also highlighted that there were three septic transfusion reactions with pathogen-reduced platelets between 2019 and 2021, even though the units adhered to the updated guidance . The platelet units were contaminated with Acinetobacter species, Staphylococcus saprophyticus, Lecleria adecaboxylata, or a combination of these species despite undergoing amotosalen plus UVA light pathogen reduction.
●Inability to inactivate prions – No known procedure that can be used with human blood or plasma has been shown to inactivate prions, the abnormally folded proteins that are associated with Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).
Governmental regulators in the United States and other countries have adopted a conservative position with regard to vCJD transmission in which individuals with potential exposure to prion diseases are not included as donors. (See "Blood donor screening: Medical history", section on 'Prion disorders' and "Variant Creutzfeldt-Jakob disease", section on 'Transfusion-related vCJD'.)
●Potential for lack of efficacy against new or unrecognized pathogens – While it is possible that new or previously unrecognized pathogens might not be inactivated by available methods, pathogen inactivation technologies are more likely to be effective in reducing the transmission of new or previously unrecognized pathogens than approaches involving identification of infected donors and/or products [69,70].
●Inability to prevent FNHTRs – Pathogen inactivation prevents WBCs from mounting an immune response, but it does not reduce febrile nonhemolytic transfusion reactions (FNHTRs) because inactivated WBCs may still leak cytokines.
●Potential for damaging or depleting plasma proteins or cellular components – Overall, pathogen inactivation of plasma units does not appear to significantly impact clinical efficacy. However, the potential for pathogen inactivation methods to affect the function of plasma proteins has been raised in certain settings.
As an example, in thrombotic thrombocytopenic purpura (TTP), the ADAMTS13 protein in the plasma used for therapeutic plasma exchange (PEX; also abbreviated TPE) is thought to contribute to PEX efficacy and thus a theoretical concern might be raised regarding decreased ADAMTS13 activity due to the pathogen inactivation process. However, as discussed separately, available evidence suggests that pathogen-inactivated plasma and standard plasma have similar clinical benefit in patients with acquired TTP. (See "Immune TTP: Initial treatment", section on 'Overview of procedure and plasma products' and 'Plasma/FFP' below.)
Pathogen inactivation methods likely reduce platelet function; this was addressed in a 2017 Cochrane review, which identified five randomized trials comparing pathogen-reduced platelets to untreated platelets, as well as a randomized trial from 2018 [71,72]. While there were no statistically significant differences in the rates of bleeding, mortality, complications, or other bleeding outcomes, several trials and observational studies have shown that pathogen inactivation of platelets leads to decreased corrected count increments and increased requirements for platelet transfusion [71,73,74]. (See 'Platelets' below.)
●Potential toxicities – Theoretical considerations have been raised about potential toxicities of pathogen inactivation methods, such as formation of potentially immunogenic neoantigens on RBCs, or causing direct damage to the recipient's cells [7,75]. Concerns have been raised about potential toxicity with the long-term effects of amotosalen (see 'Amotosalen+UVA light' above). There has not been evidence of significant adverse effects despite widespread use of some of these products.
●Cost – Pathogen-reduced products are generally more expensive to prepare than products that have not undergone pathogen inactivation. Cost effectiveness is a legitimate concern because of the large number of units transfused. It is especially challenging to demonstrate clinical benefit and related cost savings of pathogen inactivation procedures in resource-rich countries, in which numerous other donor screening and laboratory testing procedures have resulted in an extremely low (in the case of some pathogens, negligible) likelihood of pathogen transmission.
Cost effectiveness calculations also need to take into account the specific product costs, storage conditions, and shelf-life of existing blood products. As an example, plasma products can be frozen, which both reduces the survival of certain pathogens (eg, bacteria) and extends the shelf-life of the products. In contrast, platelets are stored at room temperature and have a very short shelf-life; pathogen inactivation procedures for platelets may allow the shelf-life to be extended and result in fewer units of platelets being discarded, which could produce cost savings.
In addition, some of the increased cost and time required for pathogen inactivation may be offset by the elimination of certain procedures such as irradiation of cellular products and the costs averted by preventing infections in recipients. (See 'Potential benefits' above.)
AVAILABLE PRODUCTS — Available blood products such as plasma derivatives, plasma, platelets, and red blood cells (RBCs), are pathogen reduced using the inactivation methods described above. Specific pathogen inactivation systems with commercial names are noted below, along with historical background and information about their availability in various jurisdictions.
Plasma derivatives including clotting factors and fibrinogen — Plasma derivatives include a variety of products containing proteins or combinations of proteins manufactured from human plasma. Examples include immune globulins, plasma-derived coagulation factors, fibrinogen, and albumin. (See "Plasma derivatives and recombinant DNA-produced coagulation factors".)
In most cases, manufacture of plasma derivatives involves pooling of 500 to up to 10,000 liters of plasma; each liter represents approximately four units from whole blood donation or 1.7 plasmapheresis donations. The pooled plasma undergoes one or more purification and fractionation steps, often followed by freezing and/or lyophilization (drying). All of these steps contribute to pathogen reduction by damaging proteins and membranes. As an example, freeze-drying used in lyophilization is highly effective in inactivating hepatitis A virus (HAV; by two to six logs) . The solvent/detergent (S/D) method has been used widely on plasma derivatives. (See 'Solvent/detergent treatment' above.)
Cryoprecipitate — Pathogen-reduced Cryoprecipitate is manufactured by blood centers from pathogen-reduced plasma (table 1).
A CE mark is available in European countries for pathogen-reduced plasma by amotosalen plus UVA light (INTERCEPT), methylene blue plus visible light (THERAFLEX), and riboflavin plus UV light (Mirasol) methods. Some of these products may not be easily accessible, and in many cases, fibrinogen concentrate is used rather than Cryoprecipitate, since the major indication is to provide fibrinogen. (See "Disorders of fibrinogen", section on 'Fibrinogen concentrate: Dosing and monitoring'.)
The US Food and Drug Administration (FDA) has approved Cryoprecipitate prepared from amotosalen plus UVA light-treated plasma.
●Amotosalen plus UVA light – Amotosalen plus UVA light (the INTERCEPT system) damages nucleic acids and thus inactivates numerous pathogens. (See 'Amotosalen+UVA light' above.)
Cryoprecipitate manufactured from amotosalen plus UVA light-treated plasma retains adequate levels of fibrinogen, factor VIII, factor XIII, and von Willebrand factor to meet European guidelines; in vitro it corrected dilutional coagulopathy as measured by thromboelastometry and thrombin generation [77-79]. Amotosalen plus UVA light Cryoprecipitate stored at room temperature for five days after thawing has also been demonstrated to contain sufficient fibrinogen and clotting factors to restore in vitro clot strength, as measure by thromboelastometry .
In addition to the CE mark in Europe for plasma, the FDA approved the amotosalen plus UVA light system for Pathogen Reduced Cryoprecipitated Fibrinogen Complex (PRCFC) in November 2020 for the treatment and control of bleeding, including massive hemorrhage, associated with fibrinogen deficiency .
Unlike standard Cryoprecipitate, the advantage of this product is that the FDA approved PRCFC for a five-day shelf-life after thawing compared with four to six hours for standard Cryoprecipitate. However, PRCFC costs more money than standard Cryoprecipitate.
●Methylene blue plus visible light – Treatment with methylene blue plus visible light (eg, THERAFLEX) damages DNA of lipid-enveloped viruses and thus inactivates numerous pathogens. (See 'Methylene blue+visible light' above and 'Riboflavin+UV light' above.)
Cryoprecipitate manufactured from methylene blue plus visible light PRT plasma retains sufficient levels of fibrinogen to meet European guidelines . The shelf-life and storage are similar to standard Cryoprecipitate.
This product is not available in the United States.
●Riboflavin plus UV light – Treatment with riboflavin (vitamin B2) and UV light (the Mirasol system) damages nucleic acids and thus inactivates numerous pathogens. (See 'Riboflavin+UV light' above.)
Cryoprecipitate manufactured from riboflavin plus UV light-treated plasma retains sufficient levels of fibrinogen, factor VIII, and von Willebrand factor to meet European guidelines . The shelf-life and storage are similar to standard Cryoprecipitate.
This product is not available in the United States.
Plasma/FFP — There are several methods for pathogen inactivation of plasma that will subsequently be stored as Fresh Frozen Plasma (FFP) or Plasma Frozen Within 24 Hours After Phlebotomy (PF24). All are available in Europe, but only amotosalen plus ultraviolet A (UVA) light and S/D treatment are available in the United States (table 1).
Pathogen-reduced plasma has not been demonstrated to cause any toxic or immunologic adverse reactions beyond what would be expected for any plasma product . In fact, a small series suggested that its use might reduce allergic transfusion reactions . (See "Clinical use of plasma components", section on 'Plasma products'.)
●Amotosalen plus UVA light – Treatment with amotosalen (S-59; a psoralen) and UVA light (eg, the INTERCEPT system) damages nucleic acids and thus inactivates numerous pathogens (see 'Amotosalen+UVA light' above). It can be used on any unit of plasma prior to freezing. Amotosalen and UVA light treatment of plasma does not alter levels of procoagulant and anticoagulant factors, including protein S and protein C; factors V, VIII, IX, X, thrombin, fibrinogen, and von Willebrand factor; and ADAMTS13 .
The INTERCEPT Pathogen Inactivation System has been approved for use in European countries ("CE marked") since 2006 and was approved by the US Food and Drug Administration (FDA) in 2014 . This technology is also available for Cryoprecipitate and platelets. (See 'Cryoprecipitate' above and 'Platelets' below.)
●Methylene blue plus visible light – Treatment with methylene blue and visible light (eg, THERAFLEX MB-Plasma system) prevents viral replication by damaging DNA of lipid-enveloped viruses, as noted above. Thus, lipid-enveloped viruses, including HIV, hepatitis C virus (HCV), hepatitis B virus (HBV), human T-lymphotropic virus (HTLV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), chikungunya virus, and dengue virus are more susceptible than non-enveloped viruses, although there is some effect on non-enveloped viruses such as hepatitis A and hepatitis E viruses and parvovirus B19 [22,88,89]. (See 'Methylene blue+visible light' above.)
Methylene blue treatment also depletes some clotting factors, including fibrinogen, factor V, and factor VIII. The clinical implications have not been well studied.
THERAFLEX MB-Plasma was CE marked in 2011, although an MB-based pathogen reduction system has been used widely in many European countries (in some countries with the filter to remove the MB and in others without the filter) since 1992. This technology is also available for Cryoprecipitate (see 'Cryoprecipitate' above). This technology is not licensed in the United States.
●Riboflavin plus UV light – Treatment with riboflavin (vitamin B2) and UV light (eg, the Mirasol PRT system) damages nucleic acids and thus inactivates numerous pathogens (see 'Riboflavin+UV light' above). It can be applied to any unit of plasma prior to freezing.
The Mirasol PRT system was CE marked in 2008, and while there has been less world-wide experience with this technology than with INTERCEPT, performance has been similar [18-20,90-94]. This technology is also available for Cryoprecipitate (see 'Cryoprecipitate' above), platelets (see 'Platelets' below), and whole blood. (See 'RBCs and whole blood' below.)
●Solvent/detergent treatment – S/D treatment destroys the lipid envelope of lipid-enveloped viruses including HIV, HBV, HCV, HTLV, EBV, and CMV [6,7]. In the history of more than two million units of S/D Plasma that have been transfused worldwide, there have been no reports of transmission of the major viral pathogens (HIV, HCV, HBV). This method is applied to pools of plasma prior to freezing rather than to individual units [69,95]. (See 'Solvent/detergent treatment' above.)
S/D treatment results in the loss of approximately 30 percent of selected clotting factors in plasma, including protein S, alpha-2 antiplasmin, and alpha-1 antitrypsin [96-100]. Clinical trials in which patients were randomly assigned to treatment with standard FFP or S/D FFP have failed to show any difference in efficacy in various clinical settings including open heart surgery, liver disease, or liver transplantation [9,99,101,102]. However, most trials have been underpowered to detect a small difference, and in many cases the evidence for clinical value of standard FFP is itself weak .
S/D Plasma was licensed in Europe in 1991 (as Octaplas) and in the United States in 1998 (as PLAS+SD) . PLAS+SD subsequently was withdrawn in the United States during the early 2000s, but a product (Octaplas) similar to the one available in Europe was approved by the US FDA in 2013 .
S/D Plasma has some unique properties of which to be aware, although these do not appear to affect clinical practice dramatically:
•PLAS+SD (only available in the United States in the 1990s) was deemed contraindicated in liver transplantation after serious thrombotic events or excessive bleeding occurred in a small number of patients undergoing orthotopic liver transplantation. In contrast, Octaplas, licensed in the United States in 2013, does not have this restriction and is in fact specifically licensed for use in liver transplantation.
•S/D treatment removes ultralarge multimers of von Willebrand factor, and S/D Plasma thus was theorized to have a potential advantage over standard FFP in patients receiving plasma exchange (PEX) therapy for thrombotic thrombocytopenic purpura (TTP) . However, in the absence of clinical data to support this practice, all plasma products are considered equivalent for this indication. (See "Immune TTP: Initial treatment", section on 'Overview of procedure and plasma products'.)
•S/D Plasma carries a lower risk of transfusion-related acute lung injury (TRALI), likely because it uses pooled plasma and thus dilutes out antibodies or other TRALI-causing substances from individual plasma units . This issue has receded in importance as practice has evolved to obtain non-S/D Plasma units almost exclusively from male donors, resulting in a diminished risk of TRALI. This issue is discussed in more detail separately. (See "Transfusion-related acute lung injury (TRALI)", section on 'Use of solvent/detergent-treated plasma'.)
Platelets — Technologies developed for pathogen inactivation of platelets during the 2000s include amotosalen plus UVA light (INTERCEPT), riboflavin plus UV light (Mirasol), and UVC light (THERAFLEX). Amotosalen plus UVA and riboflavin plus UV are available in Europe (table 1). UVC is in development. Only amotosalen plus UVA light is licensed in the United States.
These technologies can only be applied to specific types of platelet collections as authorized by regulatory authorities in a given country. In the United States, amotosalen plus UVA can be applied to apheresis platelets and not to whole blood-derived platelets. The apheresis platelet collection must have a platelet count in a predesignated range and the media in which the platelets are suspended is specific to the apheresis platform used (100 percent plasma or platelet additive solution [PAS]). In Europe, amotosalen plus UVA and riboflavin plus UV can be used for apheresis platelets and whole blood-derived platelets.
●Amotosalen plus UVA light – Amotosalen plus UVA light (eg, the INTERCEPT system) damages nucleic acids and thus inactivates numerous pathogens. (See 'Amotosalen+UVA light' above.)
The INTERCEPT system for platelets was CE marked in Europe in 2002 and was approved by the US FDA in 2014 . A similar system is available for plasma and Cryoprecipitate. (See 'Plasma/FFP' above and 'Cryoprecipitate' above.)
●Riboflavin plus UV light – Treatment with riboflavin (vitamin B2) and UV light (eg, the Mirasol system) damages nucleic acids and thus inactivates numerous pathogens. (See 'Riboflavin+UV light' above.)
The Mirasol system for platelets was CE marked in 2007 . It is not available in the United States.
●Short wave UV light (UVC) – Short wavelength UV light treatment (UVC; eg, THERAFLEX system) damages nucleic acids and inactivates a variety of types of viruses and other organisms. The THERAFLEX system for pathogen inactivation of platelets was CE marked in 2009. It is not available in the United States. (See 'UV light alone' above.)
Numerous hemovigilance studies have documented that there are no increased adverse events in recipients who were transfused with amotosalen plus UVA light-treated platelet products [107-110]. As an example, in a retrospective analysis from Belgium involving transfusion records from 795 patients who received INTERCEPT platelets compared with 688 patients who received standard platelets over a three-year period, there were no adverse events of the pathogen inactivation and no difference in the number of units of platelets or red blood cells transfused . Similar safety and efficacy data are available for the riboflavin plus UV light pathogen inactivation technology [72,73].
Clinical outcomes with pathogen-reduced platelets compared with standard (untreated) platelets have been compared in at least 10 randomized clinical trials of prophylactic platelet transfusion in patients receiving chemotherapy and hematopoietic cell transplant (HCT). The results have been further analyzed in several systematic reviews and meta-analyses [111,112]. A 2017 Cochrane review comparing pathogen-reduced platelets with standard platelets among more than 2000 patients did not find evidence of differences in clinically significant bleeding (risk ratio [RR] 1.1, 95% CI 1.0-1.3), mortality, or serious adverse events . However, compared with standard platelets, pathogen-reduced platelets were associated with increased rates of platelet refractoriness (RR 2.9, 95% CI 2.1-4.2). A 2018 trial also did not find a difference in bleeding outcomes between pathogen-reduced and standard platelets . There have been no trials comparing different pathogen-reduced platelet products with each other, and cost analyses were not performed.
Despite these findings, concerns about pathogen-reduced platelets remain in some settings due to the well documented decreased platelet count increments (eg, corrected count increments at 1 and 24 hours) with pathogen-reduced platelets compared with standard platelets .
RBCs and whole blood — Pathogen inactivation of red blood cells (RBCs) is more challenging than platelets or plasma for the following reasons:
●UV light does not penetrate the cells as well.
●There is concern for cellular damage as these blood products are stored longer.
●Historically, these technologies have raised concerns with extra antigens adhering to the RBCs after treatment.
The only technology available for inactivation of whole blood or RBCs is riboflavin plus UV light (Mirasol), which is available in Europe, Middle East, and Africa (table 1).
●Riboflavin plus UV light – Treatment with riboflavin (vitamin B2) plus UV light (eg, the Mirasol system) damages nucleic acids and thus inactivates numerous pathogens. (See 'Riboflavin+UV light' above.)
The Mirasol system for whole blood was CE marked in 2015. It is not available in the United States.
Studies of radiolabeled RBCs in humans showed the riboflavin plus UV light pathogen inactivation system led to acceptable cell quality and recovery [114,115]. In addition, hemostatic efficacy, as measured by coagulation factors, platelet aggregation, and thromboelastography, is largely unaffected by the pathogen inactivation treatment . A study of 70 pediatric patients in Russia assigned to received standard RBCs or RBCs derived from pathogen reduced whole blood found similar hemoglobin increments and no difference in adverse events among the two groups . A hemovigilance study in Ghana involving >2000 whole blood transfusions demonstrated there were fewer transfusion-related adverse reactions among individuals who received pathogen-reduced whole blood compared with those who received conventional whole blood. As noted above, this approach was effective in reducing transfusion-transmitted malaria in Africa. (See 'Potential benefits' above.)
Other methods for pathogen inactivation of RBCs and whole blood are under development. (See 'Additional methods for RBCs and whole blood' below.)
METHODS AND PRODUCTS UNDER DEVELOPMENT — New blood products are being developed. Universally ABO-compatible solvent/detergent (S/D) Plasma, as well as pathogen inactivated red blood cells (RBCs) and whole blood, are under development.
Universally ABO-compatible S/D Plasma — A product is in development (Uniplas S/D), in which anti-A and anti-B isoagglutinin antibodies have been removed using resins coated with synthetic A and B antigens . Removal of isoagglutinins from plasma results in the creation of universally ABO-compatible, isoagglutinin free plasma that can be used in place of AB plasma. In addition to the S/D treatment, this product has the potential to eliminate reactions to plasma transfusion due to ABO incompatibility, reduce the need for large plasma inventories, and enhance the supply of plasma in emergency situations.
Additional methods for RBCs and whole blood — The following products are under development for whole blood or RBC units, in addition to riboflavin plus UV light mentioned above. (See 'RBCs and whole blood' above.)
●A compound that can intercalate into (and damage) DNA is under evaluation in clinical trials (amustaline, previously known as S-303 and referred to as a Frangible Anchor-Linker-Effector [FRALE] compound). The treated RBC unit does not require activation by light, but the pathogen inactivation process can take up to 18 hours. Preliminary trials using this agent have demonstrated similar efficacy to standard RBC transfusions without an increase in adverse events [119-121]. As an example, a randomized trial in 80 individuals with transfusion-dependent thalassemia that compared RBCs treated with amustaline plus glutathione (a quencher) versus conventional RBCs found similar increments in hemoglobin and no differences in adverse events . Additional clinical trials are underway.
●A short wavelength UV light treatment (THERAFLEX system), originally designed for platelets, is also being evaluated for RBCs. (See 'Platelets' above.)
OTHER MEANS OF REDUCING INFECTIOUS RISK — Pathogen inactivation procedures are not a substitute for adherence to strict standards of donor recruitment and donor screening. Additional measures to ensure the safety of blood products other than pathogen inactivation include:
●Medical history to identify individuals at increased risk of transmitting an infectious organism. (See "Blood donor screening: Medical history".)
●Laboratory testing of blood for infectious organisms. (See "Blood donor screening: Laboratory testing".)
●Reducing incentives (monetary payment or test seeking opportunities) for potential donors has been important and a long-standing policy by the vast majority of blood collection organizations to ensure a safe blood supply. However, a very small number of pathogen-reduced platelets in the United States are collected from donors who receive financial compensation. (See "Blood donor screening: Overview of recipient and donor protections", section on 'Protection of the recipient'.)
●Avoidance of unnecessary transfusion. (See "Indications and hemoglobin thresholds for RBC transfusion in adults" and "Red blood cell transfusion in infants and children: Indications" and "Platelet transfusion: Indications, ordering, and associated risks" and "Clinical use of plasma components".)
For plasma derivatives, the use of recombinant DNA techniques in which a specific protein (eg, coagulation factor) is produced in cultured cells or transgenic animals rather than from human plasma is an option for certain products such as factor VIII and factor IX concentrates for hemophilia A and B, respectively. (See "Plasma derivatives and recombinant DNA-produced coagulation factors".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management".)
●Definition – Strictly speaking, pathogen inactivation refers to complete prevention of infectivity by a pathogen, whereas pathogen reduction refers to decreasing the amount of a pathogen, either by physical removal (eg, nanofiltration) or by an inactivation technology. Some experts have proposed that the term "pathogen inactivation" be used for the processing method and "pathogen-reduced blood component" be used for the transfusable product. (See 'Terminology' above.)
●Methods – The two major approaches involve methods that inactivate lipids and thus target a large number of lipid-enveloped viruses (solvent/detergent [S/D] treatment); and methods that damage nucleic acids and prevent normal replication of an array of microorganisms (table 1) (amotosalen plus ultraviolet [UV]-A light, riboflavin plus UV light, methylene blue [MB] plus visible light, UV light alone). (See 'Technologies' above.)
●Benefits – Pathogen inactivation technologies may make the blood supply safer by broadly eliminating infectious organisms such as malaria or Zika virus without the need to screen for specific pathogens. Pathogen inactivation of platelets also may extend the shelf-life of each platelet unit and meets requirements of the US Food and Drug Administration (FDA) for additional bacterial mitigation. Another potential benefit is in reducing the need to irradiate blood products to prevent transfusion-associated graft-versus-host disease (ta-GVHD). (See 'Potential benefits' above.)
●Limitations – Potential limitations include incomplete inactivation, reduced increments, possible toxicity, and cost. (See 'Potential limitations' above.)
●Available products – These are summarized in the table (table 1) and include:
•Cryoprecipitate – Available pathogen-reduced Cryoprecipitate products include Cryoprecipitate made from plasma treated with riboflavin plus UV light (Mirasol), MB plus visible light (Theraflex) and amotosalen plus UVA light (INTERCEPT) in Europe. The FDA has approved the amotosalen plus UVA light system for Pathogen Reduced Cryoprecipitated Fibrinogen Complex (PRCFC) with a five-day shelf-life after thawing. (See 'Cryoprecipitate' above.)
•Plasma – Available pathogen-reduced plasma/Fresh Frozen Plasma (FFP) products include plasma treated with amotosalen and UVA light (the INTERCEPT system); MB and visible light (THERAFLEX MB-Plasma system); riboflavin and UV light (the Mirasol PRT system), and S/D plasma. Pathogen-inactivated plasma has not been demonstrated to cause any toxic or immunologic adverse reactions beyond what would be expected for any plasma product. An S/D-treated plasma product in which anti-A and anti-B isoagglutinins have been removed is under development as a universally ABO compatible plasma product. (See 'Plasma/FFP' above and 'Universally ABO-compatible S/D Plasma' above.)
•Platelets – Available pathogen inactivation technologies for platelets include amotosalen plus UVA light (INTERCEPT) in the United States and Europe and riboflavin plus UV light (Mirasol) and UVC light (THERAFLEX) in Europe. (See 'Platelets' above.)
•RBCs – A pathogen inactivation technology for whole blood or red blood cells (RBCs; not available in the United States) is riboflavin plus UV light (Mirasol) (table 1) (see 'RBCs and whole blood' above). Other technologies are under development. (See 'Additional methods for RBCs and whole blood' above.)
●Other approaches to reducing infectious risk – Pathogen inactivation procedures are not a substitute for adherence to strict standards of donor recruitment and donor screening. In some cases, avoidance of transfusion or use of a recombinant product may reduce the risk of transfusion-transmitted infections. (See "Blood donor screening: Medical history" and "Blood donor screening: Laboratory testing" and "Blood donor screening: Overview of recipient and donor protections", section on 'Protection of the recipient'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Arthur J Silvergleid, MD, to earlier versions of this and many other topic reviews.
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