Pathogen Inactivation of Blood Products
Fung, M.D., Ph.D., Transfusion Medicine Fellow
Darrell J. Triulzi, M.D., Medical Director, The Institute
for Transfusion Medicine
Significant progress has
been made in improving the safety of both cellular and acellular blood
components, such that the current estimated risk of transmission of HIV, HCV,
HTLV, and HBV ranges from 0.5 to 7 per million transfusions. These advances
include: better donor screening, viral nucleic acid testing (NAT) of donated
blood, purification of plasma and plasma-derived products (affinity-purified
coagulation factors, nanofiltration, solvent-detergent treatment), and
recombinant factor concentrate production technology.
With these improvements in
reducing viral transmission risk, the focus of blood product safety
improvement has shifted to reducing the rate of bacterial contamination.
Currently, one in 500 to 2,000 platelet concentrates is bacterially
contaminated.1 In addition, the growing list of blood-borne
pathogens is outpacing our ability to devise and implement new screening
With these issues in mind,
the use of broadly active pathogen inactivation technologies is actively
being studied. Specifically, compounds are being developed that have a high
affinity for nucleic acids and, upon entering the nucleic acid strand,
permanently damage it, preventing further replication. These compounds
include psoralen-derivatives, riboflavin, ethylene imines, and methylene
blue. For psoralen-derivatives and riboflavin, some form of
photo-activation (UV irradiation or visible light) is required.
Light-independent compounds that target nucleic acids have also been
developed for red cell concentrates. These include S-303 and PEN110,
proprietary compounds developed by Cerus Inc. and Vitex Inc., respectively.
Both of these products are in phase II/III clinical trials.
For a more detailed history
and description of pathogen inactivation methods, the review article by Bopp
et al.2 is recommended.
CONCENTRATES AND IMMUNOGLOBULINS
Recombinant factors VIII and
IX are available for treatment of hemophilia A and B, but patients with von
Willebrand factor deficiencies still require plasma-derived concentrates.
Intravenous immunoglobulins (IVIG), anti-Rh immunoglobulin (RhIg), and
albumin are widely used blood-derived products that routinely undergo
Pasteurization is perhaps
the oldest of the pathogen inactivation techniques. With pasteurization as
the sole method of pathogen inactivation, no cases of transmission of HBV,
HAV, HIV, HCV, or HGV (hepatitis G) have been documented.3
Another currently used method is solvent-detergent treatment, which is
effective against lipid-encapsulated viruses (HBV, HCV, HIV), but not
against HAV and parvovirus, which are not lipid encapsulated. For these
reasons, a multi-tier system of virus decontamination has been adopted which
includes plasma fractionation steps, affinity chromatography, and
nanofiltration. No cases of viral transmission have been reported where two
or more decontamination steps have been used.
Recent concerns for
transmissible spongiform encephalopathies (e.g. “Mad Cow disease”) have led
to modifications in donor criteria, as well as, a re-examination of the
efficacy of current pathogen inactivation methods. Currently, there is no
human evidence of transmission by exposure to blood-products, only a
theoretical risk based on animal studies.4,5,6 Some evidence suggests that
plasma fractionation and nanofiltration, may reduce this risk.7,8,9 Gamma irradiation studies with
human albumin preparations have found only a modest reduction (1.5 log) in
Solvent detergent treatment
of FFP is used in Europe, but is no longer available in the US due to
concerns over pooling during manufacture (2,500donors/batch) and thrombotic
complication. Currently, there are no approved pathogen inactivation
systems for FFP. The only method available to further reduce the low risk of
donor-associated disease transmission is quarantine of FFP units until the
donor returns for a subsequent donation and standard viral screening tests
are negative (donor re-tested plasma). While this is theoretically possible
due to the one-year shelf life of FFP, it is impractical because it would
only be applicable to units from frequent donors.
The use of a psoralen-based
compound (S-59) to photoinactivate bacteria and viruses in FFP is in
clinical trials. In vitro experiments with S-59 show elimination of
bacteria, viruses, and parasites on the order of 5 logs. Studies in healthy
volunteers show no change in vivo recovery of coagulation factors with S-59
treated FFP.11 Similarly, patients with
end-stage liver disease showed equivalent effectiveness of treated and
untreated FFP.12 Other methods using nucleic
acid-targeted pathogen inactivation are in pre-clinical trials, including
PLATELET AND RED
There are currently no
approved methods for pathogen inactivation of platelet or red cell
concentrates in the US. A European trial of S-59 treated whole
blood-derived platelets showed comparable efficacy to control platelet
concentrates in thrombocytopenic patients.15 Similar results were
found in the corresponding American study using single donor platelets.16
In both studies, however, more treated platelet units were required to
achieve the same clinical endpoint due to platelet loss during treatment.
Due to the photoabsorptive
effects of hemoglobin in red cells, S-59 treatment and photoactivation with
UV-A is not effective, though riboflavin treatment with visible light
activation is apparently not impaired.17 Phase I and II studies
with PEN110, and S-303, light-independent inactivating compounds with high
affinity to nucleic acids, showed efficacy with no adverse effects.18
Phase III studies have recently begun.
The nucleic acid-based
pathogen inactivation methods that are currently in clinical trials are
quite promising. These new methods would provide a broad pathogen
inactivation process and do not appear to affect the clinical efficacy of
blood products. The long history of minimal toxicities associated with
psoralen-based compounds and riboflavin is also encouraging, but further
investigation is needed before implementation as a standard process.
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Bopp et al.,
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Miekka et al.,
Vox Sang 84:36-44, 2003.
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Mintz et al.,
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Goodrich et al.,
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Reddy et al.,
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AuBuchon et al.,
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©2003, Institute For
Editor: Donald L. Kelley, M.D., MBA: