1. Transfusion and Apheresis Science 45 (2011) 287–290
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Transfusion and Apheresis Science
journal homepage: www.elsevier.com/ locate/ transci
Massive bleeding: Are we doing our best?
Marco Marietta a,⇑, Paola Pedrazzi a, Massimo Girardis b, Mario Luppi a
a Dipartimento Integrato di Oncologia, Ematologia e Patologie dell’Apparto Respiratorio, U.O.C. di Ematologia, Azienda Ospedaliero-Universitaria di Modena, Italy
b Dipartimento Integrato di Chirurgia Generale e Specialità Chirurgiche, U.O.C. di Anestesia e Rianimazione I, Azienda Ospedaliero-Universitaria di Modena, Italy
a r t i c l e i n f o
Keywords:
Massive bleeding
Coagulopathy
Trauma
Massive transfusion
Fresh frozen plasma
a b s t r a c t
Massive bleeding accounts for more than 50% of all trauma-related deaths within the first
48 h following hospital admission and it can significantly raise the mortality rate of any
kind of surgery. Despite this great clinical relevance, evidence on the management of mas-sive
bleeding is surprisingly scarce, and its treatment is often based on empirical grounds.
Successful treatment of massive haemorrhage depends on better understanding of the
associated physiological changes as well as on good team work among the different spe-cialists
involved in the management of such a complex condition.
2011 Elsevier Ltd. All rights reserved.
1. Introduction
Massive bleeding (MB) is a major healthcare problem,
since it is responsible for more than 50% of all trauma-re-lated
deaths within the first 48 h following hospital admis-sion
and it can significantly raise the mortality rate of any
kind of surgery [1,2].
In the last years, the knowledge of the pathophysiology
of MB has substantially improved, due to several studies
mainly focused on trauma-associated bleeding [3–5].
These studies led to an evolution of the notion of post in-jury
coagulopathy, which is now recognized to depend
on many contributing factors, as tissue injury with result-ing
hemorrhage, tissue hypoperfusion, clotting factor
dilution, hypothermia, acidosis and inflammation [3–6].
Moreover, the existence of the Acute Coagulopathy of
Trauma (ACoT) has recently been recognized, being a pri-mary
disorder, secondarily amplified by consumption, loss
and dilution, which significantly impairs survival and
increases mortality [1]. Although the exact mechanism of
ACoT is still unclear, Brohi and colleagues demonstrated
that ACoT is due not only to an insufficient amount of
coagulation factors, but also to an activation of thrombo-modulin-
protein C pathway, leading to a systemic antico-agulation
[7]. It has been postulated that in low flow
conditions the need for protecting the vascular bed leads
to an increased thrombomodulin presentation in order to
generate a local anticoagulant milieu. This appropriate
and protective response can turn bad when systemic
low-flow and widespread activated protein C generation
do occur, determining a systemic anticoagulation, even in
the presence of almost normal levels of coagulation factors.
This carries significant implications for the management of
traumatic hemorrhage, by suggesting that hypoperfusion
must be corrected before restoring the coagulation sys-tem’s
haemostatic balance.
Other relevant contributions to the knowledge of the
pathophysiology of MB have been provided by the use of
thromboelastography/thromboelastometry (TEG/ROTEM),
which allows to measure all the parts of the coagulation
process, including fibrinolysis [8,9]. Recently, by using
TEG, hyperfibrinolysis (HF) has been demonstrated to
occur in 6–8% of patients with major trauma, thus contrib-uting
to the development of coagulopathy and resulting in
a poorer outcome [10,11]. The implementation of TEG or
ROTEM for trauma coagulation management is promising,
particularly with regard to HF treatment [2], and it is
suggested by the recently published European trauma
guidelines [12]. However, TEG standardization needs
improvement [13], and an evidence-based determination
⇑ Corresponding author. Address: Dipartimento Integrato di Oncologia,
Ematologia e Patologie dell’Apparto Respiratorio, U.O.C. di Ematologia,
Ospedale Policlinico, via del Pozzo 71, 41124 Modena, Italy. Tel.: +39 059
4224640; fax: +39 059 4224429.
E-mail address: marietta@unimo.it (M. Marietta).
1473-0502/$ - see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.transci.2011.10.010

2. 288 M. Marietta et al. / Transfusion and Apheresis Science 45 (2011) 287–290
of the parameters’ cut-off levels to guide coagulation diag-nosis
and therapy is required [1].
Despite advances on the knowledge of basic mecha-nisms
of the coagulopathy associated with MB, the treat-ment
of this disease is largely empirical, because of the
lack of well-designed, high-level of evidence, trials. Hence,
only very weak recommendations can be given by current
Guidelines. However, patients continue to bleed, and every
day physicians have to give individualized answers to the
clinical requests that patients make them, despite the fact
that such answers cannot be found in randomized trials. In
the following section we’ll try to answer some of these
questions.
1.1. Is there a role for factor VIIa?
Since its introduction in March 1999 for the treatment
of bleeding in hemophilia patients with inhibitors to factor
VIII and IX, recombinant activated factor VII (rFVIIa) has
been regarded with great interest by physicians as a
‘‘pan-haemostatic’’ agent, able to control any kind of bleed-ing
[14]. This hope was initially confirmed by several case
reports and small case series, showing its effectiveness in a
wide range of acquired haemostatic disorders, including
traumatic or surgical bleeding [15]. However, all the pub-lished
randomized controlled trials on its use in non-hemophilia
patients failed to demonstrate a reduction in
mortality, reporting a limited efficacy only on reduction
of blood requirements [16]. Moreover, some concerns have
been raised about its safety in such patients [17]. Is there a
pathophysiological reason for this failure? An elegant pa-per
from Schols and colleagues can help us in addressing
this issue. These Authors demonstrated, by thromboelas-tography,
that fibrin clot formation is low in about half of
haemodiluted surgical patients with bleeding, but in only
13–20% of cases without or with stopped bleeding. How-ever,
in bleeding patients, the onset of the haemostatic
process (the lag-time) is not particularly impaired,
whereas capacity of the process is defective [18]. Indeed,
the peak thrombin level evaluated by thrombin generation
test (TG) decreases after dilution, because of a reduced
concentration of procoagulant clotting factor, but the start
of the process, i.e. the lag time, is not impaired [18]. This is
not surprising, if we consider that very small amounts of
factor VII are contained in normal plasma, as shown in
Table 1. In other words, the minimal haemostatic level
for FVII is much lower than that for prothrombin and
fibrinogen because the latter two are more rapidly con-sumed
towards the end of the cascade reaction. Consistent
with this, even if we force coagulation cascade by raising
FVIIa levels to supra-physiological values, the limiting
steps are downward, at prothrombin and fibrinogen level.
1.2. Do we need to improve thrombin generation?
The foregoing considerations suggest that an improve-ment
of thrombin generation is required to achieve a more
effective treatment of MB. That’s partly true, since it has
been demonstrated that in those patients in which thera-peutic
doses of fresh-frozen plasma (FFP) are unable to
stop bleeding, thrombin generation is unsatisfactory [19].
However, this vision is too simple and it does not represent
the complexity of the phenomenon. Indeed, it has also
been demonstrated that massively bleeding trauma pa-tients
show excessive systemic thrombin generation,
which however does not account for an increased ability
to respond to a wound [20]. In normal haemostasis, throm-bin
is generated primarily at the wound site only, but in
bleeding patients, useful thrombin wound-bound is re-duced,
because of lower levels of FII and other coagulation
factors, while non wound-bound thrombin is increased,
due to circulating procoagulants and reduced inhibitory
proteins. On this ground, it could be hypothesized that
FFP infusion would be able to replace coagulation factors,
thus accelerating haemostasis at the wound, as well as
inhibitor systems, by blocking non-wound-related throm-bin
generation. Therefore, it could be expected that the
more FFP is infused, the more effective the recovery of
the haemostatic system is. But it is true?
1.3. How much FFP is needed in massive bleeding?
Observational studies in trauma patients have sug-gested
that higher plasma: RBC ratios during massive
transfusion may improve patient outcome [21–23], and
these findings have led to changes in clinical practice in
some settings. However, this approach is not supported
by randomized trials, and it has been questioned by other
works that failed to demonstrate a survival advantage from
the use of 1:1 ratio resuscitation [24,25]. Moreover, it has
been demonstrated that there is a dose-dependent correla-tion
between blood product transfusion and adverse out-come
(increased mortality and infection) in trauma
patients [26]. This picture seems to be puzzling, but it sim-ply
reflects the lack of methodologically sound studies on
this field. Indeed, a recent meta-analysis confirmed that
in trauma patients receiving massive transfusion higher
PFC:RBC ratios were associated with a significantly de-creased
risk of death and multiorgan failure. However,
the evidence for this effect was derived from observational
studies subject to potentially important biases, mainly
including the so called ‘‘survivor bias’’ and is, therefore,
of very low quality [27]. In an attempt to control for survi-vor
bias and to provide insights into the time course of
massively bleeding civilian patients other Authors exam-ined
the effect of the deficit of plasma to RBC units, instead
of the ratio of plasma to RBC on survival [28]. They found
that the effects of plasma repletion play a major role in
Table 1
Plasma levels of coagulation factors.
Factor Plasma level (m)
Fibrinogen 7.6
Prothrombin 1.4
Factor V 0.03
Factor VII 0.01
Factor VIII 0.00003
Factor IX 0.09
Factor X 0.17
Factor XI 0.03
Factor XIII 0.03
Von Willebrand factor 0.03

3. M. Marietta et al. / Transfusion and Apheresis Science 45 (2011) 287–290 289
the first 2–3 h of care for massively bleeding individuals
and that plasma deficit rather than unit ratios may be a
more indicative measure [28]. In their conclusions, the
Authors highlighted the need for clinical predictors that
would allow clinicians to discriminate between patients
who are going to need early and massive plasma repletion
and those who are not. Relevant to this, a very recent paper
demonstrated that a high FFP:RBC ratio (around 1:1) may
improve survival for trauma patients who are at least at
a 40% risk of receiving a massive transfusion as assessed
by a Trauma Associated Severe Hemorrhage (TASH)-score
predictive model. Conversely, a high FFP:RBC ratio does
not improve mortality and may cause harm for those at
lower risk for a massive transfusion [29].
1.4. Is there something better than FFP?
Prothrombin complex concentrates (PCCs) are an
attractive way to ensure a faster and more reliable amount
of coagulation factors, and many animal models have been
developed, in order to assess the efficacy of PCCs to control
bleeding, associated with dilutional coagulopathy (Table
2). In all these models PCCs proved to be very effective,
both on clinical and laboratory end-points. A lively discus-sion
took place recently on JTH pages about pros and cons
of using PCCs for the treatment of massive bleeding in hu-mans
[30,31]. Both the authors, however, agreed that for
the present there are insufficient prospective data to sup-port
the efficacy and safety of PCCs in trauma and surgery
in humans, although some recently published data seem to
suggest the contrary [32–34].
However, should we decide to use PPCs for treating
massively bleeding patients, we have to be aware that they
are not enough. A recent paper has, indeed, questioned
the model in which fibrin clot formation is just a reflection
of the thrombin generation process [18]. Schols and
colleagues, demonstrated that generation and fibrin clot
formation are independently reduced, and that both
processes can become rate-limiting separately, each one
from the other. In addition, their data indicated factor
X as a main determinant of thrombin generation,
whereas fibrinogen is the key variable of fibrin clot
formation [18].
1.5. Is there a role for fibrinogen concentrates?
The effects of fibrinogen on clot firmness are already
well known, but, just in recent years, its crucial role for
ensuring sufficient and stable haemostasis during serious
bleeding has been disclosed. Recent findings suggest that
fibrinogen availability may have an important influence
on the survival of trauma patients [35]. Indeed, haemodilu-tion,
hyperfibrinolysis, acidosis, and hypothermia all de-plete
fibrinogen availability and consequently impair
coagulation process. Retrospective studies in trauma pa-tients
and animals suggest that fibrinogen supplementa-tion
may be beneficial [36,37]. Another interesting debate
took place on Journal of Thrombosis and Haemostasis
about the use of fibrinogen concentrates for the manage-ment
of MB [38,39]. While expressing opposite points of
view, the authors agreed that many questions need to be
answered by further trials, such as the definition of the
appropriate level of fibrinogen to trigger treatment, or they
way to supplement fibrinogen levels.
1.6. Which kind of laboratory monitoring is needed in massive
bleeding?
Coagulation monitoring in massively injured patients
by means of TEG or ROTEM has increasingly been analysed,
as both of them seem to overcome most of the drawbacks
of the traditional PT and APTT tests. TEG- or ROTEM-based
algorithms have been published for this setting and have
showed to be a more accurate indicator of blood product
requirements than conventional tests, thus resulting useful
tools for guiding blood transfusion requirements [40]. The
implementation of TEG or ROTEM for trauma coagulation
management is very promising and is suggested by the re-cently
published European trauma guidelines [12]. How-ever,
a better standardization of both tests [41] and an
evidence-based determination of the parameters’ cut-off
levels are needed.
Table 2
PCCs efficacy in animal models of massive bleeding.
Author (year) Model PCC vs. Efficacy
(In bold italic statistically
significant results)
Dickneite (2008) Dilutional coagulopathy in pigs, then femur or spleen injury 35 IU/kg vs. Saline ; time to haemostasis
; blood loss
Dickneite (2009) Dilutional coagulopathy in pigs, then femur or spleen injury 25 IU/kg vs. 15 ml/kg FFP or
40 ml/kg FFP
; time to haemostasis
; blood loss
Pragst (2009) Dilutional coagulopathy in rabbits, then kidney injury 25 IU/kg vs. Saline or
180 mg/kg rFVIIa
; time to haemostasis
; blood loss
Kaspereit (2010) Dilutional coagulopathy in pigs underwenting CPB with
hypothermia followed by normothermia
30 IU/kg vs. Saline ; suture hole bleeding
Normalization of SBT
peak thrombin generation
Dickneite (2010) Dilutional coagulopathy in pigs, then spleen injury 35 IU/kg vs. Saline or
180 mg/kg rFVIIa
; time to hemostasis
; blood loss
PCCs, prothrombin complex concentrates; FFP, fresh frozen plasma; rFVIIA, recombinant activated factor VII; CPB, cardio pulmonary by-pass; SBT, skin
bleeding time.

4. 290 M. Marietta et al. / Transfusion and Apheresis Science 45 (2011) 287–290
1.7. Conclusion: Are we doing the best, while treating
massively bleeding patients?
The answer is ‘‘yes’’ and ‘‘no’’ at the same time. On one
hand, there’s no doubt that every physician attending to a
massively bleeding patient is strongly committed to treat,
at its best, such a complex disease. However, it’s equally
undoubted that further efforts have to be made in order
to better understand basic pathophysiology of MB and to
collect much more evidence on the crucial issues related
to patient selection, timing and ratio of blood products
and possible choice of adjunct agents.
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