Opinion: Selecting a Pathogen Inactivation System

Transfusion-transmitted infectious disease are a continuing threat.  Despite donor infectious marker testing and new donor questioning, there are many threats which are not addressed by these measures.  Also new pathogens are being identified for which there are no tests or specific donor questions available.  How can we handle these new threats?

Pathogen inactivation can significantly reduce infectious agents in blood components, although the degree varies depends on the agent.  Theoretically any agent with nucleic acid—RNA or DNA is affected.  The only class of agents not affected at all are prions, which have NO nucleic acid at all.

In general, a photoactive agent is added to the blood component which binds to the nucleic acid.  Photoactive agents include riboflavin, psoralen dyes, and methylene blue.  Then the component is irradiated, the time proportional to the volume of the unit.

The component is then exposed to ultraviolet light to photoactivate it, which disrupts the DNA and RNA present, including in the white cells.  Thus, NO irradiation or bacterial culture is required.

Here are my questions to consider when selecting a pathogen inactivation system:

Targets?  Platelets vs plasma vs whole blood?

Methylene may be used for plasma, but riboflavin or psoralens may be used for platelets or plasma.  Whole blood inactivation with riboflavin is CE-approved.

Photoactive dye:  Is it riboflavin vs psoralen vs methylene based?

Riboflavin is vitamin B2—the amount used is small and does not need to be removed whereas the psoralen must be removed for clinical use.

Does the photoactive material need to be removed before transfusion?

You can immediately use the riboflavin-treated component but the psoralen must be removed before transfusion—this may take 6 or 20 hours depending on the licensing of the product.

What is the loss of platelets or coagulation factors after treatment?

With treatment by all methods, there is some loss of platelets and coagulation factors.  The platelet loss may be greater in psoralen-based methods and require additional components be added to the pool to reach the desired dose.  Likewise, plateletpheresis components treated with psoralen may require a recalibration of the donor apheresis equipment to collect more platelets per dose to compensate.  There may be some RBC loss additionally in whole blood pathogen inactivation.

What is the efficacy of pathogen reduction for the infectious agents, particularly the ones in your region?

Example:  How well does the treatment handle local agents like Hepatitis E?  Psoralen agents may be less effective than riboflavin for this agent.

Does it work with platelet additive solution PAS?

There are minimum and maximum volumes for pathogen inactivation set by the manufacturer.  Can you get sufficient yields within these volumes?

How good is the data management system?  Can it be integrated with your blood bank computer system?

Can the equipment be integrated with your system?  This is important to set rules and enforce good manufacturing processes GMP.

Does it work well with an automated blood component production system?

Such automated systems like the Reveos can free up personnel for pathogen inactivation.  Can the volumes produced be handled effectively by the pathogen-inactivation method?  Do the timings for separation of components work synergistically with the pathogen inactivation method?

Vendor issues:  how well will the local agent provide support?  Is someone else in your country or region using the system?

You need an experienced vendor to provide optimal support.

Automation and Synergism: Joint Use of Reveos and Mirasol

This is the virtual talk I gave at the Russian Transfusion Congress in Moscow on 13 May. It gives a brief description of automated component processing and riboflavin-based pathogen inactivation and then discusses the use of these technologies together to free up labor and enhance the quality of products, i.e. improved GMP, especially if a dedicated blood bank computer system is used to enforce production rules.

My Opinion: Issues in Transfusion Medicine Software and Component Production

I anticipate that there are several innovations coming or in the process of coming to mainstream blood component production and software.  Some of these I have already addressed in some of my previous posts:

Pathogen inactivation:  We have had this for over a decade.  However, with new emerging pathogens, this will become more important so I expect it will be adopted in many centers where it is not currently being used.  I expect we will close the loop and pathogen-inactivated RBCs will be available so all components will be treated.  Still, the first-generation pathogen-inactivated RBCs may have reduced shelf life compared to regular, untreated units.

Automated component production:  Although this is expensive, it does provide excellent GMP production.  It is fast and may provide higher yields, especially for platelets.  I expect more centers will adopt this technology, especially in combination with pathogen inactivation.

Blood bank computer software:  This software must be considered as dynamically changing, and considerable resources are needed to keep in compliance with ever-changing international regulations and the latest epidemiologic data.  Production rules can be strictly and mercilessly enforced by a dedicated blood bank computer software.  It can also ensure that the final ISBT label is not applied unless all the production rules (registration, collection, processing, and testing) are met.  Manual processing is extremely risky nowadays with all the parameters to be monitored.

Patient Blood Management:  Current blood bank software does not adequately address the need for prospective review of component orders.  I expect that collaboration will occur between laboratory and blood bank software vendors to fill this gap.

Refrigerated platelets:  The pendulum swings back to this component which was used over 40 years ago.  Refrigerated platelets suspended in additive solution may be effective up to 14 days for hemostasis in the trauma setting.  These platelets are activated so standard 20-24C stored platelets may be preferred for prophylactic transfusions.

Low-titer group A universal plasma:  This is already available, but its use will increase because of the low numbers of group AB units available and increased demand.  This includes its production for COVID convalescent plasma.  Your transfusion medical director must decide what “low titer” means.  Also you need a robust way of performing anti-B titers, this may require use of an immunohematology analyzer with titration built-in.

Low titer group O whole blood:  Use of this product may reduce the need for components in massive transfusion settings but it requires performing anti-A and anti-B titers on large numbers of units.  Your transfusion medical director must decide what “low titer” means.  Also you need a robust way of performing anti-A and anti-B titers, this may require use of an immunohematology analyzer with titration built-in.  Also, you must decide whether to leukodeplete the whole blood units:  few whole blood filters are platelet-sparing.

Reveos Interface to Medinfo Hematos IIG

The Medinfo HIIG interface to the Reveos is a bidirectional interface, which was first developed by the Medinfo team for HMC in Qatar.  It is similar to the Atreus interface but there are 4 units processed simultaneously in each cycle of operation whereas the Atreus only processed 1 unit each cycle.  In Qatar it was used in conjunction with Mirasol riboflavin-based pathogen inactivation.

The process is:

  1. Medinfo controls registration, donor screening, and donor collection of whole blood and apheresis-derived (Trima) components.
  2. Medinfo will assign ISBT specimen labels for the whole blood collected with the Reveos blood kit.
  3. Medinfo will not allow processing of whole blood units not meeting donor criteria (donor screening, volumes, collection time, donor deferral database, etc.)
  4. Reveos will read ISBT specimen labels generated by Medinfo.
  5. Upon processing, Medinfo will receive from the Reveos machine the packed red blood cell, plasma, platelet, and buffy coat volumes for each bucket in the Reveos machine.
  6. If the volumes are within the specified ranges, platelet pooling and Mirasol pathogen inactivation of platelets and plasma may proceed.

For each component, the following information will be collected:

  1. All timestamps in the process
  2. Which Reveos machine used
  3. Which bucket in each machine used
  4. Volumes collected (packed RBCs, buffy coat platelet, plasma volume)
  5. Reveos collection set details
  6. Processing technologist ID

The key point is the complete TRACEABILITY of each component throughout its production.  Should there be a failure in production, we can trace exactly where the problem is and then quarantine this and any other affected units simply in the system.  Additionally, this information is part of the permanent record of the unit so it can retrieved subsequently at any time.