BY:
Kushen Ramessur
School of Biosciences
University of Westminster
UK. kush@servihoo.com
Blood has a vital role in the human body and blood
transfusion can be life saving in patients with either massive blood loss like
in disseminated intravascular coagulation cases and accidents or in those
unable to produce blood due defective haemopoesis (Hoffbrand et al.,
2001). Nowadays, with modern separation techniques blood can be fractionated
into many useful products like fresh frozen plasma (FFP), platelets
concentrate, red cells concentrate and cryoprecipitate. They are used as
replacement or therapeutic products (Overfield, Dawson & Hamer, 1999).
However, all these three blood components have the
potential to carry pathogens like viruses, bacteria and parasites (Goldman
& Blajchman, 1991) and significant number of morbidity and mortality cases
were noted in immunocompromised individuals (Lin et al., 1994).
Today, blood components transfusion are safer than in
the last few decades due to the introduction of more sensitive screening tests
like enzyme linked immunosorbent assay (ELISA). More recently, with the use of
nucleic acid testing the `window period' was reduced from 70 days to 13 days in
hepatitis C screening test (Regan & Taylor, 2002). The introduction of
safeguard systems like detailed donor education, selection and deferral
procedures, post donation product quarantine, donor tracing and notification
when any infectious agents is detected occurs also helped in making blood a
safer product for transfusion (Klein, 2000).
Currently, the risk of transmitting a lethal virus is
very low. The table below summarised the risk of viral transmission through
transfusion (BCSH guidelines, 2001):
|
Risk Factor |
Estimated frequency per unit transfused |
Deaths per million units |
|
Hepatitis B |
1 in 100 000 to 1 in 400 000 |
< 0.5 |
|
Hepatitis C |
1 in 300 000 |
<0.5 |
|
HIV |
1 in 4 000 000 |
< 0.5 |
However, even if the screening techniques are
reliable enough to detect many lethal viruses blood is still not a safe product
for the following reasons:
1.
Most of the screening
techniques cannot detect the pathogens in the blood sample during the “window
period”. The problem is worsening as pooling of blood fractions from many
asymptomatic infected blood donors, in order to raise product yield, can raise
the infection rates (Council of Europe expert committee in blood transfusion
study, 2001).
2.
There is also the
possibility of introducing a new emerging pathogen, for which no contemporary
test exists, into the blood supply. A very good example to illustrate this is
the transmission of the Human Immunodeficiency Virus (HIV) in the late 1970's
early 80's to thousands of haemophiliac patients (Corash, 1998).
Bacteria and parasites also,
represent infective risks to blood products. Bacteria may be present as silent
infections in the donor or more frequently enter blood by way of veni-puncture.
In platelets products stored for 5 days at 20- 24° c the pathogens can
multiply to high levels and can cause morbidity and mortality if transfused
(Blajchman et al., 1994). The risk of septic death per million of pooled
platelets transfusion is 60 (Ness et al., 2001). The estimated
transmission of bacteria in red cell concentrate per unit transfused is 1 in
500 000 and death can result in nearly 20% of these cases (Perez et al.,
2001). UK SHOT 2001 annual surveillance report cites 15 incidents between 1995
and 2000 due to bacterial contamination and four of them were fatal (McDonald et
al., 2002). In Britain, there is also, the theoretical possibility of
transmission of variant Creutzfeldt-Jakob disease (CJD) by blood and currently
no tests are available to detect the prion in blood or blood products (Regan
& Taylor, 2002).
Labile blood products can
also, transmit various parasitic diseases like malaria, chagas disease (Moor et
al., 1999) and they are not currently tested in the routine serological
screening tests in blood bank services.
To further reduce the risks
of pathogen transmission via blood transfusion pathogen inactivation steps have
been routinely applied to labile blood product like fresh frozen plasma (FFP)
and possibly could be applied to blood cellular components (Council of Europe
expert committee in blood transfusion study, 2001).
Several pathogen inactivation
methods are available (Council of Europe expert committee in blood transfusion
study, 2001):
1.
Solvent/ detergent
treatment of FFP
2.
Methylene treatment of
FFP
3.
Leukocytes depletion
4.
Ultraviolet B
irradiation
5.
Gamma Irradiation
Some procedures in clinical
trials are photoinactivation using Psoralens, cyanines and riboflavin. Two
processes are currently available for pathogen inactivation in the UK:
Methylene blue and solvent-detergent treatment for FFP (Gibson et al.,
2002).
Pathogen inactivation of
labile blood products has multiple advantages. It can inactivate many viruses
in the “window period” and pathogen inactivation methods like Psoralen-303
could inactivate all potential pathogens except prions. This treatment would
make it unnecessary to irradiate blood components to prevent transfusion
associated graft v/s host disease (Regan & Taylor, 2002).
However, all Pathogen
inactivation methods only inactivate labile plasma components and cannot be
applied to blood cellular components. Whereas, viruses like HIV can exist both
freely in the plasma and also, in the nucleus of leucocytes (Council of Europe
expert committee in blood transfusion study, 2001).
The other disadvantages are:
1.
Solvent-detergent (SD)
and methylene blue(MB) treatments kill enveloped viruses such as hepatitis B, C
and HIV but some non-enveloped viruses like hepatitis A, parvovirus and prions
are unaffected. The inactivating reagents can also, be toxic to the cellular
components of blood (Koenigbauer et al., 2000; Pamphilon, 2000).
2.
Pathogen inactivation
(Psoralens & UV method) does not inactivate spore-forming bacteria (eg
Bacillus Species) (Knitson et al., 2000)
3.
There is decreased
platelets recovery and in-vivo survival (Corash et al., 1997)
4.
An increased in the
incidence of hyperfibrinolysis has been noted in SD treated plasma (de Jonge et
al., 2002)
5.
Virus inactivation
significantly alter red blood cells properties during storage (Wagner SJ, 1998)
6.
Factor VIII, protein S
and α2-antiplasmin are partially removed or damaged and high
molecular multimers of von Willebrand factor are absent and several plasma
proteins are affected in MB treated FFP (Council of Europe expert committee in
blood transfusion study, 2001).
7.
Pathogen inactivation
of granulocytes, haematopoietic progenitor cells and donor lymphocytes are not
available (Council of Europe expert committee in blood transfusion study,
2001).
Caspri 2002, reviewed the different pathogen
inactivation methods and made the following observations:
1.
single step
inactivation cannot destroy all potential contamination unless the virus load
is reduced beyond detection limit by previous screening
2.
It is very difficult to
investigate and evaluate the clinical effect of inactivated cellular components
in either healthy, in thrombocytopenic or anaemic patients.
3.
All methods inactivate
pathogens by modifying their nucleic acids and these inactivated products when
transfused in a patient do have a residual mutagenicity and teragenicity. As
there is no threshold for mutagenicity and teragenicity therefore we cannot
assess the long term effect of these mutagens in the transfused patients and
the risk of them developing a cancer later.
4.
The safety of the
products used in inactivating pathogens has been demonstrated only in model
viruses and in vivo studies are yet to be done.
There are also factors other
than pathogen inactivation that need to be taken into consideration if we want
to ensure total safety in transfusion. Blood products are a very labile
commodity; FFP life span is 12 months at -30°c, Red blood cells is 35 days at
5°c and platelets is only 5 days at room temperature. Therefore blood
availability is increasingly becoming a safety issue (Klein, 2000). The quest
to eliminate the last potentially risky blood donor has caused the loss of
thousands of healthy donors. The possible exclusion of blood donors who
received blood transfusion between 1980-1996, to reduce the possible risk of
CJD prions transmission via blood, will result in a further loss of 10 % donors
in the UK (Regan & Taylor, 2002). In the United States, 8% of elective
surgery was postponed and 25 % of transfusions were delayed by 1 or more days
because of shortage in blood availability (Klein, 2000).
Blood leucocyte depletion:
Blood leucocyte depletion
should be considered as it improves the quality and safety of labile blood
products (Murphy, 1999). Brown (1997) & Wilson et al.(2000)
suggested the possibility of leukocytes being involved in transmission of
spongiform encephalopathies. So, in order to minimise a potential risk for the
public leuco-depleted blood is issued by all transfusion centres in the UK
(Council of Europe expert committee in blood transfusion study, 2001).
Conclusion:
Pathogen inactivation of
labile blood will reduce the risk of transfusion-transmitted infections
especially in the “window period” but several drawbacks were noted. There are
concerns about the cost effectiveness of the methods used and the inactivating
products seemed to have a detrimental effect on the blood products biological
activity. There is also the possibility of exposing the patients to additional
risks as the inactivating substance might affect the nucleic acid of the
transfusion recipient resulting in possible mutagenicity or carcinogenicity in
the long term. So, as the risk of dyeing from an infectious disease through
blood transfusion is very small pathogen inactivation should be done only if it
does not give rise to malignancies and other side effects that could lead to a
major catastrophe in the long term.
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