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Issues in transfusion safety
Alana R. Rushton, MS, PA-C; Patricia R. Jennings, MHS, PA-C
Ms. Rushton is part-time faculty for the physician assistant program at Arizona
School of Health Sciences in Mesa, Ariz, and works in the emergency departments
of several hospitals in the Phoenix area. Ms. Jennings is Associate Professor,
Surgical Physician Assistant Program, University of Alabama at Birmingham, and
a member of the editorial board of JAAPA. The authors have indicated
no relationships to disclose relating to the content of this article.
Predonation screening and deferral
procedures and postdonation testing of blood samples protect the safety of the
blood supply—but even with high safety and surveillance levels, transfusion-related
transmission of disease remains possible.
Transfusion of blood products is a lifesaving treatment integral to modern
medical practice. Both the clinician and patient expect that all available technology
has been utilized in the transfusion process, from collection to delivery, to
ensure safety. Public perception of blood supply reliability, once favorable,
has been tempered by the disasters of transfusion-transmitted HIV infection
and hepatitis C virus (HCV) infection. Because of the public's awareness of
the system's recent failures, as well as the nature of issues influencing public
policy, such as cost-benefit ratios, availability of blood, and evidence-based
medicine, blood supply discussions evoke emotion and controversy.
Stringent screening, donor deferrals, advances in serology sensitivity, and
the introduction of nucleic acid testing (NAT) for HIV and HCV have reduced
the risk of viral transmission during transfusion. The first cases of HIV transmission
since the 1999 introduction of NAT were reported by the Associated Press in
2002, with cases involving a young adult and an older adult in Florida and one
of a 51-year-old man in Texas who received infected blood during bypass surgery.
Cases have also been reported of post-NAT transfusion-transmitted HCV infection.1
Most recently, the transmission of West Nile virus has been linked to blood
transfusion and organ donation, emphasizing the need for constant vigilance
against the threat of emerging pathogens that endanger the safety of the blood
supply.2 Bacterial contamination that can lead to sepsis is an underreported
risk and is much more prevalent than viral transmission.3 The public's
expectation of a safe blood supply demands a zero risk policy, rather than one
based on relative risk ratios.
For more than 50 years, those involved in blood safety have focused their
efforts on predonation screening and on developing and expanding postdonation
pathogen testing. We are reaching the financial and logistic limits of that
focus, while leaving the blood supply still vulnerable to emerging pathogens.
Emphasis seems to be shifting from screening and testing technology to processing
technology designed to cleanse blood components of pathogens and reactants.
This article reviews the tiers of safeguards now in place, as well as the current
risk status of blood products, new technological developments for inactivating
pathogens in blood products, and leukoreduction.
Donor screening and deferral
The first layer of blood supply safeguards requires an all-volunteer donor
pool, thus eliminating monetary gain that might color donor motivation and response
during screening. Prospective volunteer donors are screened using questionnaires
and interviews. A call-back system provides a confidential way for donors to
reveal that they have risk factors they were unable to report during the donation
process because of peer pressure to donate, privacy issues, or other factors.4
Screening and call back may result in temporary or permanent deferral, depending
on risk factors.
Screening is history based, specifically targeting medical and behavioral
risk factors and travel patterns. Donors must complete a written questionnaire
and deny specific risk factors during an oral interview.4 Donor screening
questions, format, and procedures have been evaluated for validity, specificity,
and sensitivity.5 The FDA continues to examine and invite comment
on the interview's written and oral formats. Detailed donor education is combined
with opportunities for self-deferral in an attempt to eliminate those with risk
factors for HIV/AIDS and hepatitis.4
Recent studies on HIV and HCV prevalence in first-time donors show a decrease
in rate, indicating that behavioral risk screening paired with donor education
reduces the number of infected donors.6 However, an anonymous survey
of 10,000 donors found 39 with at least one risk factor that would have resulted
in deferral. Several of the donations from those 39 donors were not released
because of positive antibody testing, and a few were withheld because of call-back
risk factor reporting. When overlap between the two deferred groups was accounted
for, donations from 37 deferrable risk factor donors had been released for transfusion.4
Donor failure to self-defer may result from denial, knowledge that all blood
is tested for HIV anyway, failure to comprehend questions or instructions, or
the desire to obtain free HIV testing without understanding or concern for the
consequences to blood donation recipients.4
Deferral is based on medical or behavioral factors and exposure due to locale
or travel. Initially, deferral criteria identified only injection drug users;
men who have had sex with men after 1977; women who have had sexual contact
with men with these risk factors; anyone who either paid for or was paid for
sex; and anyone with a history of syphilis or gonorrhea, needlestick, or transfusion
in the past year.4 Deferral criteria have now expanded to include
anyone who resided or traveled within the United Kingdom for more than 6 months;
anyone who lived on a military base in Europe for more than 6 months; Gulf War
veterans; soldiers and reservists on maneuvers in the southern United States
who were exposed to tick bites; people who resided or traveled in endemic malaria
areas; donors taking certain prescribed medications with teratogenic properties
at low plasma levels; and anyone taking antibiotics.7 The FDA's most
recent guidelines for industry outline smallpox-related deferral periods for
anyone who has received a vaccination and/or, in some cases, their close associates.
Under discussion are geographic deferrals addressing emerging pathogen transmission
(see Table 1).
TABLE 1
Donor deferral criteria
|
| CRITERION |
RISK FACTORS |
| Traditional |
|
| Anyone who paid for or was paid for sex |
HIV, hepatitis B and C |
| History of needlestick in past year |
HIV, hepatitis B and C |
| History of STD in past year |
HIV, hepatitis B and C |
| Injection drug users |
HIV, hepatitis B and C |
| Men having sex with men after 1977 |
HIV, hepatitis B and C |
| Transfusion in past year |
HIV, hepatitis B and C |
| Women having sex with men with these risk factors |
HIV, hepatitis B and C |
| Recent expansion |
| Anyone taking antibiotics |
Bacterial contamination |
| Anyone taking certain teratogenic medications |
Retained potential teratogenic effect at low plasma levels |
| Anyone taking human growth hormone |
TSE |
| Anyone who lived on a military base in Europe for more than 6 mo |
TSE |
| Close associates of someone with a recent smallpox vaccination |
Smallpox |
| Gulf War veterans |
Leishmania donovani |
| Recent smallpox vaccination |
Smallpox |
| Resided or traveled within the United Kingdom for more than 6 mo |
TSE |
| Soldiers and reservists exposed to tick bites in the southern United States |
Babesia microti |
| Travel or residence in endemic areas for malaria and other emerging pathogens |
Plasmodium falciparum, Trypanosoma cruzi, Borrellia burgdorferi |
| Currently under discussion |
| Further geographic deferrals |
Emerging pathogens |
| Key: STD, sexually transmitted disease;
TSE, transmissible spongiform encephalopathy. |
| Data from Brittenham et al7 and
Snyder and Dodd.10 |
The limitations of donor screening and deferral become apparent when the adequacy
of the blood supply is examined. While many factors are involved in the quantity
of the available blood supply and the medical system's demands on that supply,
shrinking donor pools resulting from more stringent screening and deferral clearly
will not support the continually increasing demand for blood products. Current
blood shortages have been called critical; in one survey of 2,500 hospitals,
6.6% had cancelled elective surgeries on one or more days during the survey
year because of blood shortages, and 16.2% reported at least one day in the
year when nonsurgical transfusion requirements could not be met.7
Postdonation testing
Prevention of adverse events following transfusion has progressed significantly
in the past 100 years. The initial concern was to reduce the occurrence of incompatible
transfusions that resulted in acute hemolysis. This had become a rare occurrence
by the early 1980s; and with the advent of the HIV/AIDS crisis, blood safety
focused on detection and prevention of viral transmission. Substantial reductions
in viral transmission risk resulted from characterization of the HIV and HCV
viruses, knowledge of modes of transmission, and advances in testing capabilities.
Only hepatitis B virus (HBV) and syphilis were routinely tested for before 1980.
Since then, nine other tests have been added to reduce pathogen transmission
risk.8 Controversy and policy-making concerns revolve around the
call to develop new serologic testing to screen for emerging pathogens, the
addition of new processing and testing technology to further reduce risk, and
the costs to achieve what are now small gains.9-11
Testing is routinely performed for antibodies to HBV, HCV, HIV-1, HIV-2, human
T-lymphotropic viruses (HTLV-1, HTLV-2), and syphilis (see Table 2). Antigen
testing is done for HBV surface antigen and HIV p24 antigen. Donor alanine aminotransferase
(ALT) levels are still measured as indicators of hepatitis infection. In certain
patient populations, such as neonates and immunocompromised patients, blood
is also screened for cytomegalovirus (CMV) infection.
TABLE 2
Routine screening tests now in use
|
| Test |
Agent identified |
Residual risk |
| ALT |
Liver enzymes that may indicate early liver disease |
NA |
| HBsAg |
Hepatitis B surface antigen |
NA |
| HBV |
Antibodies to HBV |
1:137,000 |
| HCV |
Antibodies to HCV |
1:237,000 |
| HCV (NAT) |
Nucleic acids indicating HCV antigen |
<1:1,000,000 |
| HIV-1, HIV-2 |
Antibodies to HIV-1 and 2 |
1:1,326,300 |
| HIV p24 (NAT) |
Nucleic acids indicating HIV antigen |
1:1,930,000 |
| HTLV-1, HTLV-2 |
Antibodies to HTLV |
1:641,000 |
| Syphilis |
Antibodies to Treponema pallidum |
Unknown |
| Key: HBsAg, hepatitis B surface antigen; HBV,
hepatitis B virus; HCV, hepatitis C virus; HTLV, human T- lymphotropic virus;
NA, not applicable; NAT, nucleic acid testing. |
| Data from Strong3
and Snyder and Dodd.10 |
NAT for HIV and HCV has been concurrently added to the testing menu since
1999. To overcome cost and delay in the release of blood products, NAT is typically
conducted using mini-pools of 12 to 16 samples of blood that have been centrifuged
to concentrate viral particles, treated to amplify RNA and DNA, and then tested
with target-specific DNA probes.12 The sensitivity of mini-pool NAT
as compared with single-sample NAT has been a matter of debate, with one case
study showing transmission of HIV from a sample consistently detected by single-sample
NAT and inconsistently detected by mini-pool NAT, while other studies were unable
to identify any seroconversions missed by NAT.12,13 Three years of
mini-pool NAT in the United States yielded one sample that was positive for
HCV in 250,000 samples not detected by serologic testing and one otherwise undetected
sample positive for HIV in 3 million samples.12
Residual risk remains in the window period before seroconversion. During this
phase, the donor may be asymptomatic but viremic without detectable antibody
or antigen markers. Increased sensitivity of serologic antibody and antigen
testing, as well as the use of NAT for HIV and HCV, have reduced the HIV window
from 22 to 12 days and for HCV from 70 days to 10 to 14 days.14
More than 20 million units of blood or blood products are estimated to be
transfused annually in the United States.15 Each transfusion event
involves between four and six units of blood, with the average number of donors
each patient is exposed to at five per event.16 When estimates are
studied, the aggregate risk of viral pathogen transmission is much higher than
when each pathogen is considered individually, and that risk must then be multiplied
by number of exposures. Pre-NAT aggregate risk estimates were 1 in 34,000 per
unit of blood and as high as 1 in 6,800 per transfusion event.17
While risk estimates will be lower post-NAT, aggregate risk must be considered
when weighing the pros and cons of cost-benefit issues and future residual risk
reduction.
The effect of NAT on blood product shortages, outdating, and safety has been
reviewed by FDA-mandated surveys of blood centers and hospitals during the phase-in
of NAT. The additional time that blood products need to be quarantined resulted
in shortages of red cells in 13% of blood centers and 11% of the hospitals surveyed.18
Platelets, which are stored at room temperature and outdate in 5 days, were
short in 29% of the blood centers and 23% of the hospitals, and had an increased
frequency of outdating in 13% of blood centers and 11% of hospitals.18
An unexpected outcome of the study showed that implementation of NAT and quarantine
of blood products was not uniform nationwide, possibly masking the extent of
potential shortages created by introducing new testing or processing requirements.18
As NAT becomes more commonplace, testing times are expected to decrease while
availability increases, leading to reduced quarantine time, shortages, and outdating.
The significant post-NAT difference in risk rates already described shows
clear benefit from NAT. A study of data from blood donations to the American
Red Cross, which represents about half of US blood donations, confirmed that
despite a two-fold increase in cases of HCV and HIV infection in first-time
donors since 1999, NAT effected an expected decrease in residual risk of transfusion-transmitted
viral infection.19
The disadvantages of postdonation testing include delays in the release of
blood products and the costs of postdonation testing. When compared to drug
industry standards, cost-effectiveness is only within the economically accepted
limits for antibody testing for HIV and HCV and leukoreduction for certain frequently
transfused patient populations.9 Cost-effectiveness is decreased
as technology such as NAT is added. Higher cost is acceptable because less risk
is tolerated from blood transfusion than from other treatments; however, continued
investment and reliance on testing-focused technology returns diminishing gains—while
leaving the blood supply open to emerging pathogens and threat of bacterial
contamination.
Emerging pathogens
Emerging threats to the US blood supply include both known and newly discovered
pathogens. Known pathogens may qualify as emerging threats because of increased
human travel to endemic areas, and endemic areas may grow larger because of
changes in environment and habitat. Diseases may be insect-borne, such as malaria,
caused by several Plasmodium species, or Chagas' disease, caused by the
protozoan parasite Trypanosoma cruzi via the reduviid bug. Tick-borne
pathogens include Rickettsia rickettsii, which causes Rocky Mountain
spotted fever; Ehrlichia species; Borrelia burgdorferi, which
causes Lyme disease; and Babesia microti, carried by the tick genus Ixodes
and responsible for babesiosis. Several new hepatitis agents have recently been
identified that are transmitted by transfusion, but not all have been shown
to cause disease. New human herpes viruses (HHVs) and herpes simplex viruses
(HSVs) include HHV-6, HHV-7, and HSV-8. The first two viruses show a prevalence
of greater than 95% in donor populations in surveillance studies and are important
in transplant patients. Bacterial contamination of blood products is estimated
to be 50 to 250 times more likely than viral contamination.3 The
most common agent is Staphylococcus epidermis, but gram-negative agents
have also been implicated.15 Autologous transfusion is as susceptible
to bacterial contamination as is donor transfusion. Bacterial contamination
of transfusion products may not always be included in the differential diagnosis,
but it is worth pursuing because prompt diagnosis and treatment of transfusion-related
sepsis might improve outcomes.20
New technology: Leukoreduction and pathogen inactivation
The leukocyte component in blood products is associated with febrile nonhemolytic
transfusion reactions (FNHTR), graft-versus-host (GVH) disease, alloimmunization,
and platelet refractoriness.8,21 Leukocytes are also involved in
the transmission of bacteria and viral pathogens such as CMV, HTLV-1 and HTLV-2,
Epstein-Barr virus, and HHV-6, -7, and -8. B lymphocytes are identified as a
vector for the new variant of Creutzfeldt-Jacob disease (nvCJD).8,21,22
Removing leukocytes from red cells and platelets is an important processing
step to prevent adverse effects, pathogen transmission, and improve the shelf
life and quality of stored blood.21
Leukocyte depletion by either prestorage or poststorage filtration, which
is used for specific immunocompromised or multitransfused patient populations,
has recently been instituted for all blood components (universal leukoreduction
[ULR]) by the United Kingdom, France, Spain, Portugal, and Ireland.21,23
ULR is recommended in the United States but not yet FDA mandated,24
and debate about it is ongoing. In January 2001, the Department of Health and
Human Services Advisory Committee on Blood Safety and Availability concluded
that ULR should be instituted as soon as possible, arguing that even a small
reduction in morbidity and mortality related to adverse transfusion effects
would have a significant public health impact because of the quantity of blood
transfused annually.24 Also in 2001, however, the University Health
System Consortium formed an expert panel to study the same question, concluding
that clinical evidence was insufficient to mandate ULR although it was useful
in select patient groups.25
The benefits of ULR include reducing adverse effects and viral transmission.
The filtration process binds to T cruzi, possibly reducing the transmission
of Chagas' disease.24 One study showed 50% less mortality in cardiac
surgery patients who received leukoreduced blood components.24 Another
showed mean hospital costs lowered by $1,700 for cardiac patients receiving
leukoreduced blood. The increased cost of $25 to $35 per unit was offset by
decreased patient morbidity rates and hospital stays.26
Leukoreduction is not perfect since the current technology cannot remove sufficient
quantities of WBCs to assure total protection against viral transmission and
adverse effects. European standards include reducing leukocytes to under 13106
per unit.21,22 A French study performed 6 months after ULR was introduced
in France showed a 2.5% to 10.4% frequency of failure to achieve the WBC reduction
standard in the groups studied.22 Concentrations required for transmission
of some viral pathogens are not known, nor are residual levels of cellular components
that cause GVH disease or FNHTR.
Acellular plasma can be treated with solvent/detergent agents for pathogen
inactivation. This measure is effective against lipid-enveloped viruses including
HBV, HCV, HIV, HTLV, CMV, and Epstein-Barr virus, although not against the nonlipid-enveloped
viruses such as hepatitis A and parvovirus B19. Solvent/detergent plasma is
available, but processing requires pooling of up to 250 donors and the risk
of pathogen transmission may actually increase over the risk for single-donor
untreated plasma.3
Platelets and red cells will not survive solvent and detergent treatments,
which dissolve cell membranes. Newer technology targets and binds DNA and RNA,
leading to viral, bacterial, and leukocyte inactivation.3 An ultraviolet
(UV)-activated psoralen compound, S-59, when added to platelet units, inactivates
both lipid- and nonlipid-enveloped viruses, gram-positive and gram-negative
bacteria, Plasmodium malariae, and T cruzi.3 Riboflavin
also binds to DNA and RNA under UV light and is being studied for platelet pathogen
inactivation. No toxicity or antibody reaction has been demonstrated, and platelet
potency was unaffected.3 Single-donor units of plasma can also be
treated with S-59.
Since hemoglobin absorbs light, red cells cannot be treated with UV light
for pathogen inactivation, but another agent, S-303, is in clinical trials for
this purpose. S-303 depends on pH changes to crosslink RNA and DNA using nucleic
acid anchors, effectively inactivating pathogens and leukocytes.3
A new substance being studied, Inactine, which is activated electrostatically,
results in nucleic acid modification leading to the disruption of transcription
and replication.3,17,27 Processing technology that targets nucleic
acids enables inactivation of many viral pathogens, bacteria, leukocytes, cell-free
infectious particles, and provirus or latent forms of retroviruses.27
Known and unknown pathogens are neutralized by these new methods, and GVH disease,
FNHTR, and other immune-modulated adverse effects of transfusion are decreased
by the inactivation of leukocytes.16
Conclusion
Blood product screening and postdonation testing have been described as reactive
strategies to insure blood supply safety.16 The disadvantages of
current screening and testing methods include cost, vulnerability to emerging
pathogens, delay in blood release, testing method sensitivity, testing method
volume capabilities, and loss of the donor pool. While screening and testing
have reduced known risk factors to exceedingly small possibilities, immune-modulated
adverse effects of transfusion, bacterial contamination, and emerging pathogens
remain as unaddressed risks. Patient and provider perceptions of the safety
of the blood supply have been colored by earlier transfusion-related transmission
of HIV/AIDS and HCV. Current expectations are that every possible safeguard
be utilized—no matter how small the gains or how high the cost—in
order to approach a zero risk status.
The literature calls for a switch from the current screening and testing technology
to a processing technology that can achieve a safe blood supply while containing
the escalating costs of developing more sensitive and specific testing and reducing
losses from donor deferral. Leukoreduction and pathogen inactivation are the
newest risk-reduction processes to treat blood and blood products. When NAT
pathogen inactivation processes are used, both transmissible infectious agents
and leukocytes are neutralized. Risks from emerging pathogens, variant strains
of known pathogens, viremic but seronegative window donations, dilution of mini-pool
testing, and testing errors are virtually eliminated. Immune cell-modulated
adverse effects are also reduced. Clinical trials are under way for pathogen
inactivation agents. We must decide in the near future how to utilize these
advances and whether they should either be used concurrently with existing safeguards
or replace current screening and testing strategies. We must view benefits and
related costs relative to overall aggregate savings in morbidity reduction and
donor-pool maintenance.
Public debate related to the blood supply occurs and policy is set in an emotionally
charged atmosphere. Policies tolerate less favorable cost-benefit ratios and
call for increasingly stringent screening and deferral in reaction to emerging
threats. Sound public policy must consider financial, logistical, and public
health issues. Transfusion safety is a complex problem. The better we understand
its specifics, the more rational the debate and the more effective the ensuing
policy decisions. When considering the issues, we must remember that the object
of transfusion therapy is to save lives. If almost perfect suppression of pathogen
transmission is achieved by screening and deferral instead of by more costly
processing technology, but adequacy and availability of the blood supply are
sacrificed by loss of the donor pool, then the cost is too high. As health care
providers, we need an expanded understanding of blood safety issues to enable
us to make clinically sound treatment choices, to provide appropriate patient
education, and to attain truly informed consent.
KEY POINTS in this article
- For more than 50 years, those involved in blood safety have
focused their efforts on predonation screening and on developing and
expanding postdonation pathogen testing.
- We are reaching the financial and logistic limits of that focus
while leaving the blood supply still vulnerable to emerging pathogens.
- Emphasis seems to be shifting from screening and testing technology
to processing technology, such as leukoreduction and pathogen inactivation,
designed to cleanse blood components of pathogens and reactants.
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Alana Rushton. Issues in transfusion safety. JAAPA May 2004;17:39-46.
Copyright © 2004, Advanstar Medical Economics Healthcare Communications at Montvale, NJ 07645-1742. All rights reserved.
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