Apheresis frozen plasma, psoralen-treated

To provide an additional layer of product safety, Canadian Blood Services aims to introduce pathogen-reduced components and products, wherever possible. This publication provides information on apheresis frozen plasma, psoralen-treated, a blood group specific, pathogen-reduced human plasma for transfusion.  

The INTERCEPT Blood System (Cerus Corporation) for pathogen inactivation reduces the risk of transfusion-transmitted infections and was approved by Health Canada in 2016. This technology inactivates a broad spectrum of enveloped and nonenveloped viruses, Gram-positive and -negative bacteria, spirochetes, and parasites, in addition to potentially harmful residual donor white blood cells in whole blood-derived or apheresis plasma. Treating blood components with Cerus’ INTERCEPT technology enhances their safety profile and was previously implemented in platelet processing at Canadian Blood Services in 2022.  

Apheresis frozen plasma, psoralen-treated is collected in anticoagulant citrate dextrose solution A (ACD-A; contains sodium citrate 22.0 g/L, citric acid 8.0 g/L, dextrose 24.5 g/L) using automated apheresis techniques, which includes leukoreduction. The component may be collected from a donor with a history of pregnancy.  

After collection, the component is transported to a Canadian Blood Services production centre for further processing. Please see Figure 1 for a detailed illustration of processing steps. 

Image

Figure 1. Illustration of the pathogen reduction process used by Canadian Blood Services in the production of apheresis frozen plasma, psoralen-treated. 

Compound absorption device (CAD). 

Pathogen reduction is achieved with the Cerus INTERCEPT Blood System for Plasma, which includes the addition of 15 mL of 6 mM amotosalen solution (a synthetic psoralen), illumination with 3 Joules/cm² of UVA light (wavelength 320 to 400 nm), exposure to a compound adsorption device for the removal of residual amotosalen and free photoproducts and splitting of the pathogen-reduced component into three single transfusion units.

Table 1. Typical unit content is based on the number of units (n) tested during validation from July 2024 to Aug 2024, inclusive.  

†Volume includes approximately 35 mL of ACD-A anticoagulant. 
Standard deviation (SD) 

Prior to making blood components available for transfusion, blood samples collected from the donor at the time of donation are tested for ABO group, RhD type, anti-A and anti-B titres, and clinically significant antibodies against red cell antigens. The sample must test non-reactive for: 

• human immunodeficiency virus (HIV-1 and HIV-2): anti-HIV-1 and anti-HIV-2 antibodies, HIV-1 and HIV-2 RNA  
• hepatitis C virus (HCV): anti-HCV antibodies, HCV viral RNA  
• hepatitis B (HBV): Hepatitis B core antigen (HBcore), hepatitis B surface antigen (HBsAg), presence of HBV viral DNA 
• human T-cell lymphotropic virus, type I and II (HTLV-I/II): anti-HTLV-I/II antibodies 
• syphilis 

In some cases, a donor sample is tested for the presence of IgA, antibodies to Trypanosoma cruzi (T. cruzi or Chagas Disease) and West Nile Virus RNA. For more information on donor testing, read Chapter 6 of the Clinical Guide to Transfusion. 

In addition to viral testing, pathogen inactivation treatment is used to inactivate a broad range of pathogens, including viruses, bacteria, and protozoan parasites, thus reducing the risk of transfusion-transmitted infections.  

In some emergency situations, with the approval of both Canadian Blood Services and recipient’s physician, partially tested or untested blood may be released for transfusion. 

Apheresis frozen plasma, psoralen-treated is stored in bags using a plastic film that is made of a copolymer of ethylene and vinyl acetate (EVA).¹  

Apheresis Frozen Plasma, Psoralen Treated has been in contact with DEHP plasticizer during their collection and manufacturing.^1-4 

Apheresis frozen plasma, psoralen-treated components are stored at -18°C or colder for a maximum period of 12 months. The component should be thawed in a watertight protective plastic overwrap using gentle agitation in a water bath at 30–37°C (thawing may take up to 30 minutes) or in a microwave specifically manufactured for this use. Once thawed, plasma components should not be refrozen. If stored at 1–6°C, the component should be transfused within 5 days. 

A visual inspection of the component should be performed according to the individual facility’s policies. For more information on variability in blood components, please see the Visual Inspection Tool (VIT).  

Apheresis frozen plasma, psoralen-treated shares the same indications as fresh plasma and may be useful in the management of: 

• Bleeding patients or patients undergoing invasive procedures with high bleeding risk who require replacement of multiple plasma coagulation factors. 
• Patients receiving massive transfusion with clinically significant coagulation abnormalities. 
• Patients on warfarin who are bleeding or need to undergo a high bleeding risk invasive procedure before vitamin K could reverse the warfarin effect, and where prothrombin complex concentrate is not available or is contraindicated.^5-7 
• Patients with selected coagulation factor or with rare specific plasma protein deficiencies for which a more appropriate alternative therapy is not available. 
• Preparation of reconstituted whole blood for exchange transfusion in neonates. 
• Patients with thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome undergoing plasma exchange. 

Patients with known anaphylaxis to plasma components should only receive plasma components under appropriate medical supervision. Recipients with known anti-IgA should receive IgA deficient plasma.   

Plasma components should not be used to treat hypovolemia. 

Do not use apheresis frozen plasma, psoralen-treated for: 

• Patients with a history of hypersensitivity reaction to amotosalen or other psoralens. 
• Neonatal patients treated with phototherapy devices that emit a peak energy wavelength less than 425 nm, and/or have a lower bound of the emission bandwidth <375 nm, due to the potential for erythema resulting from interaction between ultraviolet light and amotosalen. 

Apheresis frozen plasma, psoralen-treated must be ABO-compatible, or as defined by individual facility’s policies. RhD need not be considered. The intended recipient must be properly identified before the transfusion is started. 

DEHP plasticizer can leach from DEHP-plasticized medical devices into blood and blood components. Currently, there is no conclusive scientific evidence that DEHP exposure via medical treatments has harmful effects in humans. However, it is recognized that the potentially high-risk exposure during medical treatment may raise a concern for harmful effects in humans. Reducing DEHP exposure in neonatal patients has been recommended.^{4, 8}  

Some clotting factor activity in thawed plasma components may be significantly lost during storage for up to 5-days.^9-13 

Careful donor selection, laboratory tests, and the use of pathogen inactivation technology do not eliminate the hazard of transmitting infectious disease agents or pathogens. While laboratory studies of amotosalen processing with UVA light have shown a reduction in levels of certain viruses, bacteria, and parasites, there is no pathogen inactivation process that has been shown to eliminate all pathogens.¹ 

Apheresis frozen plasma, psoralen-treated should not be used when coagulopathy can be more appropriately corrected with specific therapy, such as vitamin K or specific factor replacement. For example, replacement of the vitamin K-dependent coagulation factors (i.e., factors II, VII, IX and X) can be achieved with prothrombin complex concentrates. 

Hemophilia A and B and von Willebrand disease (VWD) are more appropriately treated with recombinant or virally inactivated fractionation products or 1-deamino-8-D-arginine vasopressin as initial treatment. For replacement of fibrinogen and factor XIII, commercial virally inactivated concentrates are also available. Some products are only available through the Special Access Programme of Health Canada. 

Solvent detergent plasma is also available as an alternative to apheresis frozen plasma, psoralen-treated. 

Potential adverse events related to a blood transfusion range in severity from minor with no sequelae to life-threatening. All adverse events occurring during a transfusion should be evaluated to determine whether the transfusion can be safely continued/restarted. All adverse events suspected to be related to a transfusion (whether during or after a transfusion) should be reported to your local transfusion service and, when required, the hospital/regional hemovigilance network. Health Canada’s Blood Regulations requires reporting of adverse events that may be attributed to the manufacturing process (e.g., associated with blood component quality) to Canadian Blood Services.^14-17 For more information on reporting adverse transfusion reactions, see the publication, A guide to reporting adverse transfusion reactions. 

Reporting of suspected cases of transfusion-related infections such as HIV, HCV, HTLV, HBV, WNV and other transfusion-related infections is described in Chapter 1 of the Clinical Guide to Transfusion and in the publication, A guide to reporting adverse transfusion reactions. 

The transfused volume of apheresis frozen plasma, psoralen-treated depends on the clinical situation and the size of the recipient. The most common dosing is 10–15 mL per kg of body weight.   

Serial laboratory assays of coagulation function may be of assistance in planning the dose. A standard blood administration set containing a 170–260 micron filter or a filter of equivalent efficacy, approved by Health Canada, must be used for infusion. 

No medications or solutions may be added to or infused through the same tubing simultaneously with blood or blood components, unless the solution has been approved for this use by Health Canada or there is documentation available to show that addition of the solution to the blood component involved is safe. Please refer to the Circular of Information  for component for further information. 

The transfusion rate is dependent on clinical factors. For more information, refer to the Clinical Guide to Transfusion. All transfusions should be completed within 4 hours of removal from storage. Recipients should be under observation during transfusion with close observation during the first 15 minutes and in accordance with institutional guidelines. 

Hemostatic efficacy 

See Table 2 for a comparison of factor levels across standard frozen plasma, INTERCEPT treated plasma, and solvent detergent plasma. All coagulation factors fall within normal laboratory clinical reference ranges.  

Table 2. Comparison of day 0 post-thaw plasma in vitro quality across plasma types 

^†Alpha-2 antiplasmin and ADAMTS-13 were determined using kits designed for research purposes. The other parameters were tested on Stago Coagulation Analyzer. All methods are designed for clinical diagnostic samples; however, we are using them “off label” to measure coagulation related parameters in plasma components (n = 33 for all the parameters). 
^‡Data were gathered from development data at Canadian Blood Services. 
^§All parameters taken from product monograph (n = 12),¹⁸ except for ADAMTS-13 (n =18) taken from https://www.octaplasma.ca/standardization-of-plasma-protein-levels-in-octaplasma/  
^||There are currently no defined acceptance criteria listed by CSAZ902-2514 specifically for pathogen reduced plasma. 
^¶Reference ranges were taken from Erickson et al.¹⁹ and were established on fresh frozen, normal donor plasma samples by Machaon Diagnostic Laboratory 
^#The percentage of activity and the IU/mL unit are directly proportional (i.e., if the activity is 50%, it would be 0.5 IU/mL). 
**Data from Heger et al.²⁰   

The safety and efficacy of INTERCEPT treated plasma has been evaluated in a number of clinical trials that included patients with congenital coagulopathies, acquired coagulopathies, as well as those undergoing therapeutic plasma exchange for TTP. Findings showed no differences observed in achieving clinical hemostasis, or safety. These results suggest that psoralen-treated plasma was able to effectively support hemostasis similar to conventional plasma.^21-23 

A randomized, controlled, double-blinded study was conducted at 5 sites in the United States that included 121 patients aged 2 years or older, with an acquired coagulopathy requiring therapeutic or prophylactic plasma transfusion that were indicated for an invasive procedure or reversal of warfarin therapy.²¹ Patients with coagulopathy due to trauma were not eligible. Patients were randomized to receive standard plasma or plasma that had undergone photochemical treatment process using a synthetic psoralen. No differences were observed in use of blood components, clinical hemostasis, or safety.  

A retrospective study compared therapeutic efficacy and safety outcomes (i.e., acute hepatic artery thrombosis and mortality) in patients undergoing liver transplantation treated with conventional plasma compared to amotosalen-UVA pathogen inactivated plasma.²⁴ The study included 212 transplants supported with standard plasma and 215 transplants supported with amotosalen-UVA pathogen inactivated plasma. No significant differences were observed in blood component utilization or safety outcomes. 

Safety  

The number of adverse events reported by studies assessing the safety of psoralen-treated plasma is lower than the reported adverse transfusion event rate to untreated frozen plasma. The reaction rate in 2022 prior to increasing access to solvent detergent plasma in Ontario was 0.06% based on adverse transfusion reactions reported by 159 Ontario hospitals to the Transfusion Transmitted Injury Surveillance System out of 40,873 untreated frozen plasma transfusions.²⁵  

In a post-surveillance study the occurrence of adverse events following psoralen-treated plasma transfusion that were classified as adverse transfusion reactions was approximately 0.1% of transfusions or 0.04% of psoralen-treated plasma components. French hemovigilance data similarly reported a rate of 0.34 events per 1000 transfused plasma components (or 0.034%).²⁶ No transfusion-related acute lung injury (TRALI) episodes were reported in 7483 transfusions of 19,069 psoralen treated plasma units.  

Irsch and Seghatchian summarize active hemovigilance reporting performed in several centers in an update on INTERCEPT plasma in routine clinical use for all patients and showed dramatically lower adverse events reported per year in INTERCEPT treated plasma compared to other types of transfused plasma.²⁷ In 2009 there were 12 reported adverse transfusion reactions with INTERCEPT treated plasma (out of 22,933 components) compared to 191 in other types of plasma (348,725 components) with comparable results in 2010 and 2011.²⁷  

A trial by Mintz et al. on patients with TTP, reported increased cardiac events in patients who received psoralen-treated plasma compared to standard plasma. Five patients in the psoralen-treated plasma group and no patients in the control plasma group had events categorized as cardiac disorders, including angina pectoris (n = 3), cardiac arrest (n = 1), bradycardia (n = 1), tachycardia (n = 1), and sinus arrhythmia (n = 1). However, two of the three events of angina pectoris were misreported as “cardiac” by the study site during the data query process. Further review of primary medical records, including electrocardiograms, by an independent cardiologist blinded to treatment assignment, concluded that chest pain in all three of these patients was non cardiac in origin. The cardiac arrest was attributed to anaphylaxis due to psoralen-treated plasma. All three arrhythmias were mild or moderate in severity, transient, and asymptomatic and did not require therapy. Transfusion reactions were reported in only two patients, one in each treatment group. Urticaria was reported in 26% of patients, pruritus and nausea each in 20%, and pyrexia and rigors in 11% and 14%, respectively. No statistically or clinically significant differences were observed between groups. One event of TRALI was reported in a patient from the standard plasma group. Of note in this study, one or more adverse events were experienced by almost every patient included in the study which was not surprising because patients with TTP are often systemically unwell, complex and have multisystem disease. Transfusion reactions and thrombotic and hemorrhagic adverse events occurred with equal frequency in both treatment groups.^{22, 26} 

Neonatal, pediatrics, and intrauterine transfusions

There are limited data available for the use of pathogen-reduced plasma for transfusion among pediatric and neonatal patients. However, the available hemovigilance data suggests the product is safe and well tolerated in this population.  

Preliminary animal studies of pathogen-reduced plasma reported no adverse impacts with transfusion in neonatal rats. Specifically, there were no amotosalen-related adverse effects found in the neonatal rats despite the exposure to amotosalen concentrations being as high as 48 times the standard exposure in adult patients.²⁸ 

Human clinical trials have similarly reported no or low-grade adverse events among pediatric and neonatal populations. An open label clinical trial conducted in Belgium and France reported that pathogen-reduced plasma transfusion was well tolerated in routine clinical use for children and infants.²⁶ The study assessed 160 children (aged 1–18 years) and 188 infants (aged < 1 years) from 2007–2011, constituting 11% of the total mixed hematology, medical and surgical patients in the study (n=3,232). Results for pediatric patients were not reported separately from the adult patients, but overall adverse transfusion reactions were reported in 0.11% (8/7483) of transfusions, with five being of Grade 1 severity and three serious adverse events; all adverse events occurred in adult patients in this study. There were no reported TRALI events.  

Another hemovigilance study assessing the safety profile of pathogen-reduced platelets and pathogen-reduced plasma in 11 countries over an 8-year period reported infrequent transfusion reactions among patients (0.4% of transfusions). The study assessed 440 infants (aged < 1 years) and 355 children (aged 1–18 years); the pediatric data was not reported separately from adult patients. A subsequent post-marketing hemovigilance study of 3, 179 pathogen-reduced plasma and platelet transfusions in 11 countries found that these components were well tolerated by a pediatric population with only low-grade transfusion reactions reported. The sample included 540 children (aged 1–18 years) and 499 infants (aged < 1 year) with mixed clinical indications for transfusion, including medical (45%), hematology-oncology (34%) and surgical (20%). Three of the 795 pediatric patients experienced a transfusion reaction. Symptoms were characterized by rash (n=2), urticaria (n=1), and chills (n=1) without serious consequences, TRALI, or transfusion associated sepsis.²⁹    

From a hemostasis perspective, a single-arm open label study of pathogen-reduced plasma reported good clotting factor kinetics post-transfusion and hemostatic efficacy when used for both prophylactic and therapeutic indications. The study included 34 patients who received 107 transfusions; a portion of the participants were pediatric patients (ages ranged from 3 to 77 years) but data for pediatric patients were not reported separately from adult patients.²³

Currently, there is limited safety data for apheresis frozen plasma, psoralen-treated when used for intrauterine transfusion.²⁴  

Pregnant people 

There are no studies that have specifically addressed use of INTERCEPT-treated pathogen-reduced plasma in pregnant people. Nonclinical studies in reproductive animal models have been conducted. Administration of photochemically treated plasma did not cause maternal or fetal developmental toxicity in these studies. ³⁰ 

Pathogen inactivated plasma has an added layer of protection against bacterial contaminants (gram-positive and gram-negative), viruses (enveloped and non-enveloped), protozoa parasites, and white blood cells (leukocytes).  

In addition to a reduction in the risk of pathogen transmission, other adverse transfusion reactions also decrease with use of pathogen reduction technology such as solvent detergent plasma.³¹ These include a reduction in allergic reactions and febrile non hemolytic transfusion reactions; however, these reductions may reflect the pooling of plasma and subsequent dilution of potential allergens or reactants rather than the pathogen-reduction process.  

There is a lot of variation in plasma color between plasma units and this is not expected to change with the introduction of INTERCEPT treatment. See Figure 2 for a comparison of plasma components when frozen and Figure 3 for a comparison of the plasma components when thawed.  

Further information on visual inspection of blood components can be found in the Visual Inspection tool. 

Image

Figure 2. Comparison of apheresis frozen plasma, psoralen-treated, and apheresis plasma not treated when both components are frozen. a) Apheresis frozen plasma, psoralen-treated; b) Apheresis plasma

Image

Figure 3. Comparison of apheresis frozen plasma, psoralen-treated and apheresis plasma when both components are thawed. a) Front of apheresis frozen plasma, psoralen-treated unit; b) Front of apheresis plasma unit; c) Back of apheresis frozen plasma, psoralen-treated unit; d) Back of apheresis plasma unit.

Zeller, M. P., Ning, S., Khandelwal, A., Howell, A., & Webert, K. (TBD). Apheresis frozen plasma psoralen-treated. Canadian Blood Services. https://profedu.blood.ca/en/transfusion  

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