Anaesthesia 2015, 70, 511–527
Editorial
Limitations of component therapy for massive haemorrhage: is
whole blood the whole solution?
Death from uncontrolled haemor-
rhage remains a significant cause of
mortality among trauma patients
[1]. Provision of blood products for
patients with massive haemorrhage
following trauma is a key issue for
transfusion services, although only
4.8% of total red cell issues in Eng-
land were issued to trauma patients
in 2014 (Tinegate et al., Survey of
red cell use in England and North
Wales, unpublished observations).
There have been significant changes
in the approach to blood trans-
fusion in patients with massive
haemorrhage in recent years, as
understanding of the underlying
pathophysiology of the associated
coagulopathy has improved. Histor-
ically, coagulopathy was thought to
be dilutional following loss of coag-
ulation factors and platelets after
the transfusion of stored red cells.
Administration of components was
guided by laboratory tests; replace-
ment of coagulation factors with
plasma or cryoprecipitate, and
transfusion of platelets, were only
recommended when specific labora-
tory thresholds were met. More
recently, trauma coagulopathy has
been demonstrated to be driven by
cytokine release in response to the
initial injury, leading to endothelial
cell activation and release of tissue
plasminogen activator (tPA), causing
© 2015 The Association of Anaesthetists of Great Britain and Ireland
fibrinolysis. This is compounded by
increased protein C activity which,
together with acidosis and hypo-
thermia, reduces the functional
activity of coagulation proteases
[2, 3].
Alongside improvements in the
understanding of trauma coagulopa-
thy, an increasing body of evidence
(largely from observational studies
in military settings) has been sug-
gestive of improved outcomes with
major haemorrhage protocols [4, 5],
whereby plasma and platelets are
transfused even before any labora-
tory testing demonstrates evidence
of abnormal haemostasis. In addi-
tion, there is high-quality evidence
of the clinical benefit of the admin-
istration of tranexamic acid to
inhibit fibrinolysis [6]. The rationale
for the use of major haemorrhage
protocols is the anticipation of the
impending haemostatic problems
that occur as a pathological res-
ponse to the initial injury. Transfu-
sions of multiple blood components
in fixed ratios are used to address
the inevitability of abnormal hae-
mostasis, rather than waiting until
its effects are demonstrable in the
laboratory, at which point valuable
time has been lost.
The widespread adoption of
early transfusion of plasma and
platelets in trauma haemorrhage
has again raised the question of the
utility of transfusing whole blood
rather than individual components.
The history of the use of whole
blood goes back to James Blundell,
who is said to have performed the
first successful human-to-human
blood transfusion in 1818 [7]. Even
when Landsteiner discovered the
ABO blood group system in 1900,
and crossmatching techniques were
developed by Ottensteiner in 1912,
use of blood transfusion was limited
because of the rapid coagulation of
blood outside the body, and trans-
fusions largely had to be under-
taken directly from vein to vein [8].
Richard Lewisohn was the first to
use citrate as a storage solution in
1914, and later, during the First
World War, Peyton Rous and J.R.
Turner Jr. developed Locke’s solu-
tion which contained citrate as an
anticoagulant and dextrose as a pre-
servative of red cells [9]. This
allowed their colleague Oswald
Robertson to develop the world’s
first blood bank, transfusing Ameri-
can soldiers on the Belgian battle-
fields [10].
It wasn’t until the 1960s and
’70s that blood began to be sepa-
rated into its constituent parts. This
was vital in improving allocation of
resources and allowing prolonged
storage for transport, both for mod-
511
Anaesthesia 2015, 70, 511–527
ern healthcare requirements and in
the military, specifically in the Viet-
nam war [11]. By separating
donated whole blood into its con-
stituent parts, blood suppliers can
produce the full range of blood
components and use optimal stor-
age conditions for each component.
One donated unit of whole blood
can be used to make one unit of
red cells, one quarter of an adult
dose of pooled platelets, and either
one unit of fresh frozen plasma
(FFP) or one fifth of a dose of cryo-
precipitate. An obvious advantage
of blood component therapy is that
potentially useful products are not
wasted by being transfused to those
who do not need them. Further,
each patient only receives the com-
ponent he/she requires, and is not
exposed to those he/she doesn’t,
thus reducing the associated risks.
Aside from the added volume of
unnecessary components, significant
complications of transfusion of red
cells and platelets include the risk
of alloimmunisation (development
of antibodies against red cell, leuco-
cyte, and platelet antigens not pos-
sessed by the patient), which may
cause adverse effects such as
haemolytic and febrile transfusion
reactions following subsequent
transfusions. Furthermore, compo-
nent transfusion will prevent a
patient with chronic anaemia who
requires repeated red cell transfu-
sion from being exposed to unnec-
essary plasma with its risks of
transfusion related acute lung injury
(TRALI), transfusion-associated cir-
culatory overload (TACO) and
acute transfusion reactions.
Each blood component has
optimal storage conditions, and the
512
lifespan, efficacy and safety of each
constituent can be optimised by
storing them separately. Fresh fro-
zen plasma is processed, stored at
30°C for up to three years [12],
thawed and administered so as to
preserve coagulation factors
required for haemostasis. Red cells
are stored at 4  2°C for up to
35 days [12], minimising the risk of
bacterial replication while maintain-
ing red cell viability. Platelets are
stored at 22  2°C for up to seven
days in the UK since the introduc-
tion of routine bacterial testing
[12]. This environment promotes
the longevity of transfused platelets,
as the majority are given for pro-
phylaxis in thrombocytopenic
patients [13]. Interestingly, there are
in-vitro data to suggest that refrig-
erated platelets are more haemostat-
ically active than platelets stored at
22  2°C [14]. Some believe that
cold-stored platelets should be used
in trauma haemorrhage to promote
immediate haemostasis; their persis-
tence in the circulation beyond a
few hours is less important. How-
ever, there is a paucity of clinical
trial data to support this practice.
Processing and storage of the
product issued as ‘whole blood’ pri-
oritises viability of red cells at the
expense of coagulation factors, par-
ticularly factors V and VIII [15].
Many countries have introduced
universal leucocyte reduction of
blood components, and the passage
of whole blood through in-line
leucocyte filters effectively removes
viable platelets [15]. Hence, ‘whole
blood’ contains red cells but is lack-
ing in functional platelets; the con-
centration of coagulation factors
depends on the duration of storage
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Editorial
but the product can be considered
to contain approximately 50% less
factor VIII after seven days [16]. In
the modern era of blood compo-
nent usage, transfusion of whole
blood is almost entirely restricted to
the military and to developing
countries, where resources for sepa-
ration and processing of blood are
not available. The US military
transfuses fresh warm blood for
life-threatening injuries with bleed-
ing where any required individual
component is not available, or
when there is ongoing life-threaten-
ing bleeding despite transfusion in a
1:1:1 ratio of plasma, platelets and
red cells [11]. Under these circum-
stances, blood is neither leucocyte-
reduced nor stored, and therefore
contains near-physiological levels of
factor VIII and viable platelets.
However, as has been known for
more than a century, even fresh
warm blood requires anticoagula-
tion and in this issue of Anaesthesia
Ponschab et al. demonstrate that a
13% dilution of whole blood occurs
immediately the donation is added
to storage solution [17].
Blood component therapy
therefore has significant advantages
over the use of whole blood and in
the context of major haemorrhage,
clinical studies continue to address
how to use blood components most
effectively. Evidence to support
fixed ratios is largely from retro-
spective observational studies and
there is no internationally agreed
consensus, even with respect to the
initial ratio of plasma:platelets:red
cells [18–22]. The recently pub-
lished PROPPR trial, in which 680
severely injured trauma patients
were randomly assigned to receive
Editorial
plasma, platelets and red cells in a
1:1:1 or 1:1:2 ratio, found no differ-
ence in mortality and equivalent
rates of adverse events [23].
Few studies have modelled the
relative quantities of coagulation fac-
tors and platelets that are given with
differing component ratios, how
these relate to in-vivo levels in the
bleeding patient, and what effect
they may be expected to achieve.
Ponschab et al. present a characteri-
sation of the haemostatic profile of
reconstituted whole blood as deliv-
ered by a 1:1:1 ratio of plasma and
platelets to red cells [17]. Their find-
ings suggest that this ratio provides a
product inherently deficient in
fibrinogen. Recent studies suggest
that fibrinogen deficiency in massive
haemorrhage predicts survival [24,
25], and current practice is moving
towards more aggressive replace-
ment of fibrinogen, either with cryo-
precipitate or fibrinogen concentrate.
The outcome of the CRYOSTAT fea-
sibility trial, in which patients with
severe traumatic haemorrhage were
randomly assigned to receive or not
receive fibrinogen as first-line ther-
apy, is currently awaited (ISRCTN
55509212).
The work conducted by Ponsc-
hab et al. also demonstrates that
the combined result of transfusing
in a 1:1:1 ratio will inevitably lead
to reduction in the platelet count
and haematocrit [17]. The study is
limited by its in-vitro nature, but
the results draw attention to the
dilution of red cells, platelets and
coagulation factors caused by the
addition of solutions required for
their viability and safe storage. This
poses the question whether coagula-
tion factors can be provided in a
© 2015 The Association of Anaesthetists of Great Britain and Ireland
more concentrated form and in
Europe, the focus has been on using
prothrombin complex and fibrino-
gen concentrates in place of plasma
and cryoprecipitate [26]. Further-
more, point-of-care tests such as
thromboelastography/thromboelas-
tometry are being increasingly used
to guide product replacement, using
more global measures of coagulabil-
ity that are available in real time
[27]. This approach supports indi-
vidualised decision-making about
blood component requirements
based on tests that are available
quickly and that provide a better
measure of in-vivo haemostasis
than standard laboratory tests.
These methods are becoming com-
monly used in circumstances such
as cardiac surgery [28].
In conclusion, the optimal
transfusion management of massive
haemorrhage associated with
trauma is yet to be established.
There are many recommended
schedules for massive transfusion
protocols but, as yet, there is no
consensus about the initial ratio of
red cells, plasma and platelets that
should be employed. The use of
fresh whole blood or replication of
fresh whole blood may appear
attractive as an answer to this
dilemma, but it is not the complete
answer, particularly if the coagul-
opathy is primarily due to con-
sumption of fibrinogen, which
requires other means for its
replacement. A potential solution is
more aggressive supplementation
with fibrinogen either in a fixed,
predetermined amount of cryopre-
cipitate or fibrinogen concentrate,
or as guided by point-of-care hae-
mostasis testing.
Anaesthesia 2015, 70, 511–527
Competing interests
No external funding and no com-
peting interests declared.
S. Hall
Specialty Registrar in Haematology
NHS Blood and Transplant John
Radcliffe Hospital
Oxford, UK
M. F. Murphy
Professor of Transfusion Medicine/
Consultant Haematologist
University of Oxford
Oxford, UK
NHS Blood and Transplant and
Oxford University Hospitals
Oxford, UK
Email: mike.murphy@nhsbt.nhs.uk
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Editorial
Was NAP5 ‘NICE’ enough; where next for depth of anaesthesia
monitors?
I do not fear computers. I fear the
lack of them
—Isaac Asimov
Since the publication of the fifth
National Audit Project (NAP5)
regarding accidental awareness dur-
ing general anaesthesia (AAGA)
[1], there have been a number of
514
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administration of sedation [4].
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became interested in awareness and
depth of anaesthesia monitoring
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Editorial
updated European guideline. Critical
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doi:10.1111/anae.13071
after being involved in some low-
level research as a senior registrar
in the last century! He was excited
when NAP5 was announced and
eagerly volunteered to be a local
coordinator. This enthusiasm was
tempered somewhat by the method-
ology of the ensuing study. The
NAP5 investigators reassured us