DEPARMENT OF SURGERY, DIVISION OF TRAUMATOLOGY, UNIVERSITY MEDICAL CENTER GRONINGEN
Fibrinogen level at admission is associated
with 24-hour mortality in polytraumatized
adults
Name: B. Gareb
Student number: S1870041
Supervisor: M. el Moumni, MD, trauma surgeon
Department: Department of Surgery, Division of Traumatology
Institution: University Medical Center Groningen
Period: September 2014 – February 2015
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
1
SUMMARY
BACKGROUND Trauma is one of the leading causes of death worldwide. Central
nervous system (CNS) injury and hemorrhage are the most common causes of mortality
within the first 24 hours after trauma. Hemorrhage is the leading cause of (potentially)
preventable death after injury, most often due to delay in treatment. Acute Traumatic
Coagulopathy (ATC) is a coagulopathy which results in a hypocoaguable and
hyperfibrinolytic state. Fibrinogen is the most vulnerable coagulation factor resulting in a
rapid fall in fibrinogen concentration after admission. The objective of this study was to
estimate the adjusted effect of fibrinogen level at admission on 24-hour mortality in
polytraumatized patients. Additionally, we tried to determine if this relationship is
different for sex, age, and traumatic brain injury.
MATERIAL AND METHODS Patients treated in 2004-2013 at the University Medical
Center Groningen with New Injury Severity Score (NISS) higher than 15 and age of 18-
80 years were included. Endpoint of this study was mortality within 24 hours after
admission. Patient’s characteristics consisted of demographics and initial shock-related
and coagulation parameters. For descriptive statistics, patients were divided into two
groups based on their outcome: survivors and non-survivors. Multivariable Cox
regression model was used to investigate the adjusted effect of fibrinogen level at
admission on 24-hour mortality in polytraumatized patients.
RESULTS Out of 1491 included patients, 1377 (92.4%) survived and 114 patients
(7.6%) died within the first 24 hours after admission. Median age of all subjects was 45
(25th-75th percentile [P25-P75] 28-60). The vast majority of patients were male (76.3%)
and had mainly blunt trauma (95.3%). Median Glasgow Coma Scale (GCS) was 13 (P25-
P75, 6-15). Median NISS (P25-P75) was 33 (25-43). Mean fibrinogen level (standard
deviation) of all patients was 2.0 (1.0). Of all characteristics, sex (P=0.819), cause of
injury (P=0.230), mechanism of injury (P=0.134), and pulse (P=0.878) were not
significantly different between both subgroups. Multivariable Cox regression analysis
showed a significant adjusted effect of fibrinogen level at admission on 24-hour mortality
(hazard ratio [HR] 0.475, 95% confidence interval [95% CI] 0.305-0.738; P=0.001). No
relevant effect modification was found.
CONCLUSION The present study demonstrates a significant adjusted association
between fibrinogen level at admission and 24-hour mortality in polytraumatized adults.
This effect of fibrinogen was not modified by sex, age, or traumatic brain injury.
Monitoring fibrinogen levels routinely at admission and actively supplementing
fibrinogen could reduce (potential) preventable deaths.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
2
SAMENVATTING
ACHTERGROND Trauma is één van de belangrijkste doodsoorzaken wereldwijd.
Schade aan het centraal zenuwstelsel en verbloedingen zijn de meest voorkomende
doodsoorzaken binnen 24 uur na trauma. Verbloeding is de belangrijkste (potentiaal)
vermijdbare doodsoorzaak, voornamelijk door een te laat ingezette behandeling. Acute
Traumatische Coagulopathie (ATC) is een coagulopathie wat resulteert in een
hypocoagulabele en hyperfibrinolytische toestand. Fibrinogeen is de meest kwetsbare
coagulatiefactor, wat resulteert in een snelle daling van fibrinogeenspiegel na opvang.
Het doel van deze studie was het schatten van het gecorrigeerde effect van fibrinogeen bij
opname op de 24-uurs mortaliteit bij polytrauma patiënten. Daarnaast wilden wij
vaststellen of deze relatie anders is voor geslacht, leeftijd en schedelhersenletsel.
MATERIAAL EN METHODES Patiënten die in de periode van 2004-2013 behandeld
zijn in het Universitair Medisch Centrum Groningen met een New Injury Severity Score
(NISS) hoger dan 15 en een leeftijd van 18-80 jaar werden geïncludeerd. Eindpunt van
deze studie was mortaliteit binnen 24 uur na opvang. Patiëntkarakteristieken bestonden
uit demografische gegevens, en shock gerelateerde en coagulatie parameters bij aanvang
van opname. Voor beschrijvende statistiek werden de patiënten opgedeeld in twee
subgroepen: overlevenden en niet-overlevenden. Multivariabele Cox regressie model
werd gebruikt om het gecorrigeerde effect van fibrinogeenspiegel bij opname op 24-uurs
mortaliteit bij polytrauma patiënten te onderzoeken.
RESULTATEN Van de 1491 geïncludeerde patiënten overleefden 1377 (92.4%) en
overleden 114 (7.6%) patiënten binnen 24 uur na opname. Mediane leeftijd van alle
geïncludeerde patiënten was 45 (25e-75e percentiel [P25-P75] 28-60). The meerderheid
van de patiënten was mannelijk (76.3%) en had voornamelijk stomp trauma (95.3%).
Mediane Glascow Come Scale (GCS) was 13 (P25-P75, 6-15). Mediane NISS (P25-P75)
was 33 (25-43). Gemiddelde fibrinogeenspiegel (standaard deviatie) van alle patiënten
was 2.0 (1.0). Van alle karakteristieken verschilden alleen geslacht (P=0.819), trauma-
oorzaak (P=0.230), traumamechanisme (P=0.134) en hartfrequentie (P=0.878) niet
significant tussen beide subgroepen. Multivariabele Cox regressie analyse toonde een
significante gecorrigeerde effect van fibrinogeenspiegel bij opvang op 24-uurs mortaliteit
(hazard ratio [HR] 0.475, 95% betrouwbaarheidsinterval [95% BI] 0.305-0.738;
P=0.001). Relevante effect modificatie werd niet gevonden.
CONCLUSIE De huidige studie toont een significante gecorrigeerde associatie tussen
fibrinogeenspiegel bij opvang en 24-uurs mortaliteit bij polytrauma patiënten. Dit effect
van fibrinogeen werd niet gemodificeerd door geslacht, leeftijd of schedelhersenletsel.
Het routinematig monitoren van fibrinogeenspiegels bij opvang en het actief
supplementeren van fibrinogeen zou (potentiaal) vermijdbare sterfgevallen kunnen
verlagen.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
3
TABLE OF CONTENTS
1. INTRODUCTION 5
1.1 Epidemiology 5
1.2 Haemostasis 5
1.2.1 Classical coagulation cascade 6
1.2.2 Cell-based model 7
1.2.3 The anticoagulant system 8
1.2.4 Fibrinolysis 9
1.3 Pathogenesis 9
1.3.1 Phenotypic variation of DIC 9
1.3.2 Overactive thrombomodulin-protein C pathway 10
1.3.3 The neurohormonal hypothesis 10
1.4 Risk factors 10
1.5 Diagnostics 11
1.6 Treatment 12
1.7 Prognosis 12
1.8 Fibrinogen level and prognosis 12
1.9 Aims 14
2. MATERIAL AND METHODS 16
2.1 Patients 16
2.2 Trauma protocol 16
2.3 Study parameters 16
2.4 Statistical analyses 17
2.4.1. Descriptive statistics 17
2.4.2 Association model 17
3. RESULTS 19
3.1 Patient’s characteristics 19
3.2 Survival analyses 19
4. DISCUSSION 24
4.1 Main findings 24
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
4
4.2 Strengths and limitations 28
4.3 Clinical message and recommendations 28
4.4 Conclusion 29
5. REFERENCES 30
APPENDIX 38
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
5
CHAPTER 1
INTRODUCTION
1.1 Epidemiology Trauma is one of the leading causes of death worldwide, with an
estimated mortality rate of 83.7 per 100.000 citizens per year. In 2000, these injuries
accounted for 5 million deaths worldwide, resulting in 9% of world’s deaths. Men are
affected twice as much compared to women. Furthermore, these injuries were responsible
for 12% of world’s burden of disease (1). Over 90% of the current injuries occur in low-
and middle-income nations. However, trauma also has a significant impact on morbidity
and mortality in industrialized nations. In 2003, 29 million people in the United States
(U.S.) were involved in injuries (i.e. more than 10% of the population). Among the
population aged 1 to 44 years, injury was the leading cause of death. In all age strata,
injury was the third leading cause of death. As a consequence, injury contributes to 30%
of potential life years lost which is the largest contribution of any cause of death and
about twice that of cancer, the second leading cause of death (2).
Central nervous system (CNS) injury and hemorrhage are currently the most
common causes of mortality within the first 24 hours after trauma, representing 40-50%
and 21-50% of deaths, respectively (3-6). Severe CNS injury often has devastating
outcomes, with few possible interventions for survivability and functional recovery
resulting in high pre-hospital mortality. Hemorrhage, however, is more susceptible to
intervention to decrease mortality, making it the leading cause of (potentially)
preventable death after injury, most often due to delay in treatment (3,7-9). In up to one
third of the patients arriving in hospital, abnormal coagulation is present (10). Compared
to mortality of patients without coagulopathy after trauma, patients with coagulopathy
have three- to eight-fold increased mortality (10).
Although CNS injury, particularly traumatic brain injury (TBI), is the primary
cause of death, hypotension due to bleeding doubles to triples mortality in this group (11-
13). This significant contribution to TBI deaths makes hemorrhage a major contributor to
overall mortality of trauma patients. Since the World Health Organization (WHO)
predicts that in 2020 traumatic injuries will rise dramatically, this traumatic injured
population will only have more impact on public health (1).
1.2 Haemostasis In 1964, the classical coagulation cascade was introduced by two
independent research groups (14,15). This model was called the cascade or waterfall
model because activation of one clotting factor resulted in activation of other clotting
factors. Eventually, this cascade leads to production of thrombin (factor IIa), which
converts fibrinogen (factor I) into fibrin (factor Ia). Fibrinogen is produced in the liver
and the norm value of fibrinogen in plasma level is 2.0 – 4.5 g/L (16). This model was
later divided into two pathways: an intrinsic and extrinsic pathway (17). This model was
a major discovery in understanding coagulation and provided an accurate prediction of
coagulation in vitro. However, it had several flaws when predicting coagulation in vivo.
Further research suggested a form of dependency between both pathways (18-22). As a
result, a new model of haemostasis was introduced in 1992 which was named the cell-
based model of haemostasis in 2001 (23,24). This model does not divide coagulation into
two pathways, but rather into three overlapping phases: the initiation, amplification and
propagation phase (19,23,25). Both models are described below.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
6
1.2.1 Classical coagulation cascade
The classical model of coagulation divides the coagulation sequence into two pathways:
the intrinsic and extrinsic pathway (figure 1). The intrinsic pathway consists of
components which are all present the blood. This pathway is measured using the
activated partial thromboplastin time (aPTT). The extrinsic pathway consists of factor
VIIa and a subendothelial cell membrane protein, tissue factor (TF). The latter is not in
contact with blood in healthy individuals, hence the name extrinsic pathway. The
prothrombin time (PT) is used to measure this pathway. Both pathways will eventually
assemble to the common pathway (19).
The intrinsic pathway starts with activation of factor XII (19,25,26). Factor XII is
produced in the liver and circulates in the bloodstream. It is activated by negatively
charged surfaces. During this conversion, it uses high-molecular-weight kininogen
(HMWK) as co-factor by using it as an anchor to negatively charged surfaces. Factor
XIIa, an endopeptidase, will cleave pre-kallikrein into kallikrein, which accelerates the
conversion of factor XII into factor XIIa (i.e. positive feedback). When a threshold of
factor XIIa is reached, it activates factor XI which activates factor IX. Factor IXa,
together with factor VIIIa, calcium, and phospholipid, activates factor X. All these
inactivated factors are zymogens (pro-enzyms) with the exception of factor V and VIII,
which are co-factors of the formed enzymes.
Figure 1. The classical coagulation model, divided into two pathways: the intrinsic and extrinsic pathway.
Solid lines imply activation pathways; interrupted lines imply inhibitory effects of anticoagulants. Ca:
calcium; PL: phospholipid; a: activated (19).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
7
Figure 2. Initiation phase of the cell-
based model of coagulation (26).
The extrinsic pathway consists only of TF and factor VII. TF is constantly
expressed by certain cells in vessel walls, like vascular smooth muscle cells, pericytes,
and adventitial fibroblasts (27-30). TF is also expressed in several other organs, like the
brain, lung, kidney, and heart (30,31). Upon vessel injury, TF binds circulating factor VII
and activates it. The activated TF/VIIa complex will activate factor IX from the intrinsic
pathway and factor X. The latter is activated using calcium (19,30).
The common pathway starts after activation of factor X. Factor Xa along with
factor Va, calcium, and phospholipids, converts prothrombin (factor II) to thrombin
(factor IIa). Thrombin converts fibrinogen into fibrin, which along with factor XIIIa will
form a stable fibrin clot (19,25,26,30).
As mentioned before, this model has several flaws. For example, deficiencies of
HMWK, pre-kallikrein, and factor XII prolong aPTT, but does not lead to a clinical
bleeding disorder, indicating that the intrinsic pathway is not essential (19,25,32).
However, patients with factor XI deficiency might have severe hemorrhage after surgery
or trauma, suggesting that factor XI is also activated through another mechanism (25). In
addition, deficiency of factor VIIIa (i.e. haemophilia A) or factor IXa (i.e. haemophilia B)
causes severe bleedings. This model can not explain why activation of factor X through
the extrinsic pathway can not compensate the deficiencies of the abovementioned factors
(19,26). Similar, factor VII deficiency also results in severe bleeding, although the
intrinsic pathway is intact. Thus, it seems improbable that these pathways operate
independently in vivo (19,26).
1.2.2 Cell-based model
The cell-based model strongly suggests that coagulation occurs in three overlapping
phases: the initiation, amplification, and propagation phase. In this model, two cells are
essential: a TF-bearing cell (extravascular) and platelets (intravascular). Activation of
coagulation is prevented until these two cells make contact with each other at the site of
injury. This model addresses the abovementioned flaws and questions (19,25,26).
The initiation phase (figure 2) starts when
TF is exposed to blood due to injury. Factor VII will
bind to TF, activating factor VII. The formed
TF/VIIa complex activates a low amount of factor
IX and X. Factor Xa, together with factor Va, binds
to the TF-bearing cell forming prothrombinase
complexes on the surface of the TF-bearing cell
(26,33). Factor V is activated by factor Xa or non-
coagulation enzymes (26,34,35). The produced
factor Xa generates a small amount of thrombin
(factor IIa) (25,26,36). However, antithrombin (AT)
neutralizes the produced factor Xa and thrombin.
Furthermore, tissue factor pathway inhibitor (TFPI)
inhibits the TF/VIIa/Xa-complex. As a result, the initiation phase only leads to a very
small amount of thrombin. Inhibition by AT and TFPI prevent overproduction of
thrombin. Thus, procoagulant triggering only continues if TF is exposed to high levels of
VIIa (i.e. massive injury) to overcome the inhibition by AT and TFPI (25,26).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
8
Figure 3. Amplification phase of the cell-
based model of coagulation (26).
Figure 4. Propagation phase of the cell-
based model of coagulation (26).
One of the major functions of the
amplification phase (figure 3) is activation of
platelets. Activation occurs by the small amount
of thrombin produced in the initiation phase.
Thrombin activates factor V on the activated
platelet. Furthermore, thrombin dissociates von
Willebrand factor (vWF) from factor VIII and
activating factor VIII. Factor VIIIa
subsequently binds to the surface of the
activated platelet. Free vWF allows additional
platelet adhesion and aggregation at the injured
tissue. These platelets express procoagulant
phospholipds on their surfaces, making
assembly of other coagulation factors possible
(25,26,37).
During the propagation phase (figure 4), large number of platelets are recruited.
This phase takes place at the surface of the
platelets. Factor IXa, activated during the
initiation phase, binds to factor VIIIa at the
platelet surface. Additionally, factor IXa can be
produced by factor XIa, which is bound to
platelets. The IXa/VIIIa-complex activates factor
X. Factor Xa binds to factor Va, forming the
prothrombinase complex on the surface of
platelets. This complex can form a burst of
thrombin, which will be sufficient to clot
fibrinogen into fibrin. At this moment, the platelet
is the only cell type known on which the
propagation phase could be carried out properly
due to the specialized coordination of the
VIIIa/IXa- and Va/Xa-complex (25,26).
1.2.3 The anticoagulant system
The major components of the anticoagulant system are protein C, protein S, and
antithrombin III. Their inhibitory effects are presented in figure 1. Its effects has not been
changed in the cell-based model (19,26).
Protein C is activated on the endothelial cell surface by thrombin and
thrombomodulin, an endothelial cell receptor. Activated protein C (APC) degrades factor
Va and VIIIa using protein S as co-factor. Protein S is mainly synthesized in the liver and
forms a complex with APC on negatively charged membranes, resulting in a ten-fold
higher affinity to these membranes compared to APC alone. Degradation of these factors
inhibits thrombin formation. As a result, thrombin is unable to convert fibrinogen into
fibrin, which is essential for clot formation (26).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
9
Antithrombin III binds to various glycosaminoglycans, which are expressed on
healthy endothelial cells. These glycosaminoglycans function as high affinity binding
sites for antithrombin III. Binding of these two components is crucial for rapid inhibition
of thrombin, factor IXa, and Xa.
1.2.4 Fibrinolysis
Fibrinolysis is crucial for clot dissolution. Plasminogen is synthesized by the liver and
released into the systemic circulation. Plasminogen activators convert plasminogen into
plasmin. The two physiological plasminogen activators are tissue plasminogen activator
(TPA) and urokinase plasminogen activator (UPA). TPA requires fibrin as co-factor,
whereas UPA can activate plasminogen without the presence of fibrin. Plasmin is a fibrin
degrading enzyme which results in dissolution of clots (25).
1.3 Pathogenesis Acute Traumatic Coagulopathy (ATC) is most commonly defined as a
prothrombin time ratio>1.2 (i.e. international normalized ratio, INR). However, other
definitions, like fibrinogen < 200 mg/dL, are also used (11). Traditionally, coagulopathy
associated with trauma was thought to be one of the three components of the ‘triad of
death’. Together with acidemia (pH<7.2) and hypothermia (< 33°C), it raises mortality
dramatically (38,39). Coagulopathy would occur due to loss, dilution or dysfunction of
coagulation factors. Loss of coagulation factors is caused by bleeding, whereas dilution
of these factors occurs after massive fluid and blood transfusion. Furthermore,
dysfunction of coagulation factors may occur due to hypothermia and acidemia resulting
in coagulation enzymes dysfunction (40-42). This description of ATC suggests that it
occurs late after injury and as a consequence of continuous hemorrhage and its treatment
(38,39).
However, recent studies suggest that ATC is a distinct coagulopathy (6,39,43-51).
These studies have shown that ATC developed before resuscitation of patients,
independent of loss, consumption, or dilution of coagulation factors or platelets.
Furthermore, ATC developed prior to development of acidosis or hypothermia. Also, the
median time from injury to the emergency department was short. These studies suggest
that ATC is a coagulopathy based on anticoagulation and hyperfibrinolysis rather than a
consumptive disorder. It must be noted that, although ATC can develop before these
factors are present, these factors exacerbate ATC.
At this moment, controversy about the underlying mechanism of ATC is still
present among researchers. The three main hypotheses are: a disseminated intravascular
coagulation (DIC) with fibrinolytic phenotype, an overactive thrombomodulin-protein C
pathway, and a neurohormonal hypothesis of cathecholamine-induced endothelial
damage (52).
1.3.1 Phenotypic variation of DIC
One of the three main hypotheses of ATC is a phenotypic variation of classical DIC.
Originally, DIC is described as a prothrombotic and hypercoaguable disorder. If the
underlying condition persists, it progresses into a consumptive, hypocoaguable disorder,
resulting in a hemorrhagic disorder (52). In the context of ATC, researchers describe DIC
with a fibronolytic phenotype. During the first 24-48 hours posttrauma, thrombin is
produced as a result of endothelial injury, hypoxia, and ischaemia. However, due to
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
10
massive release of plasminogen activators, plasminogen is converted in large amounts to
plasmin. These two events result in a hyperfibrinolytic and hypocoaguable state after
trauma. Furthermore, hyperfibrinogenolysis occurs, inhibiting conversion of fibrinogen to
fibrin due to lack of substrate (4,52-54).
1.3.2 Overactive thrombomodulin-protein C pathway
The second hypothesis contends that ATC occurs due to decreased thrombin degradation
and increased thrombomodulin activity. The underlying mechanism of these two events is
unknown. Thrombin itself is a prothrombotic agent. However, as presented in figure 1,
together with thrombomodulin and inactive protein C, this event leads to overactivation
of protein C. APC inhibits coagulation factors Va and VIIIa. Furthermore, it enhances
fibrinolysis through inhibition of plasminogen activator inhibitors, resulting in higher
intravascular concentrations of plasmin and thus in fibrinolysis (4,39,52,55-58).
1.3.3 The neurohormonal hypothesis
This final hypothesis describes catecholamine-induced endothelial damage as the initiator
of ATC. Tissue injury after trauma results in release of catecholamines (i.e. adrenalin and
noradrenalin) into the systemic circulation. These catecholamines change endothelial
cells from an antithrombotic to a prothrombotic state. This is beneficial and necessary at
the site of injury. A counterbalance system is also activated to prevent systemic
coagulation. This system counters the prothrombotic state of the endothelial cells,
inhibiting coagulation in blood. Major components of this system are thrombomodulin
and TPA, which results in anticoagulation and fibrinolysis, respectively. However, this
counterbalance system is poorly adapted as the degree of tissue injury increases. As a
result, the counter-regulatory response is overactive, leading to hypocoagulation and
hyperfibrinolysis (59-61).
These different hypotheses have lead to controversy about the underlying mechanism of
ATC. Although the initiator and mechanism of these hypotheses differ vastly, all three
hypotheses achieve a hypocoaguable and hyperfibrinolytic state. Several studies have
reported an association between low fibrinogen levels and increased morbidity and
mortality (5,62-64). Also, fibrinogen is the most vulnerable coagulation factor resulting
in a rapid fall in fibrinogen concentration after admission (62,65,66). Thus, researchers
and clinicians have focused mainly on fibrinogen to identify, treat and estimate prognosis
of ATC (5,52,57,58,63,67-76).
1.4 Risk factors Factors associated with low fibrinogen levels are high injury severity
score (ISS), time from injury, young age, male gender, injuries to extremities and pelvic
girdle, hypothermia, shock, and a low base excess due to hypoperfusion (5,39). Also,
massive fluid and blood transfusions are associated with low fibrinogen levels (67).
Risk factors in combination with low fibrinogen concentration for mortality are
high ISS, low base excess, high INR, and low Glasgow coma scale (GCS) (5,47,63).
However, controversy regarding gender, age, and platelet count exists as risk factors for
mortality (5,47,63).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
11
1.5 Diagnostics Early identification of ATC leads to early treatment and guidance of
treatment. This may lead to a reduction in mortality and morbidity. Various tests have
been used to identify ATC, which will be described below.
Traditionally, several tests were used to monitor coagulopathy, such as PT, aPTT,
INR, and platelet count. PT and aPTT, which are based on the classical coagulation
cascade, are measured using platelet-poor plasma at 37°C and normal pH. These tests
usually require 30-60 minutes (39). However, these tests only measure factor deficiencies
and do not take account possible hyperfibrinolysis. In addition, they often do not
represent in vivo coagulation of trauma patients, because they fail to account for
hypothermia and acidemia (52). Platelet count only provides quantitative information but
it does not reflect functional activity. Finally, trauma patients with ATC require acute
intervention. Tests that require 30-60 minutes to complete do not contribute to the
required acute intervention. Altogether, the abovementioned flaws of traditional
coagulation test result in poor early prediction of ATC (39,52,55,77,78).
Detection of these flaws and the conversion of the classical coagulation cascade to
the cell-based model of coagulation have led to interest in viscoelastic tests for trauma
patients. These tests (i.e. thromboelastography [TEG] and rotational thromboelastometry
[ROTEM]) are considered more global tests for coagulation (4,39,52,79,80). In contrast
to traditional coagulation tests, viscoelastic tests are able to monitor the entire
coagulation process from fibrin formation to fibrinolysis (81). This is an essential
advantage compared to traditional coagulation tests as hyperfibrinolysis plays a central
role in ATC. It has been used in clinical practice for several years, but recently it has
been available into the resuscitation room now that the technique is stable and rapid
enough for injured patients. These tests plot graphs which represent functional activity of
coagulation factors and platelet and fibrinogen function (39). Many variables could be
determined from the graph, which represent functional activity of the different phases of
coagulation (i.e. initiation, amplification and propagation phase) (52). The amplitude of
the graph, which represents the clot strength, appears to be essential in the context of
ATC. Woolley et al. have shown that amplitudes after 5 and 10 minutes (A5 and A10,
respectively) have sensitivities/specificities in predicting ATC of 0.96/0.58 and 1.00/0.70,
respectively (82). Other studies have compared the proportion of detection of ATC using
ROTEM and INR, defining ATC as A5 ≤ 35mm or INR > 1.2. The proportion of
individuals with ATC who tested positive was 71% versus 43%, respectively (4,79,83).
Although these results are promising, large studies validating these tests to
identify ATC are absent. Also, evidence of using ROTEM or TEG to improve morbidity
or mortality are lacking (52,80). Furthermore, viscoelastic tests could be less specific to
identify major deficiency of coagulation factors (<30% of norm values) compared to
traditional coagulation tests (84). Finally, these tests remain in vitro tests, which fail to
take physiological effects (e.g. endothelial effects) into account (52).
As a result of the abovementioned, no validated test is currently available that can
rapidly identify ATC (39). This deficiency makes timely and goal-directed therapy
difficult, contributing to high potentially preventable mortality due to hemorrhage (52).
Therefore, clinicians focus mainly on fibrinogen level to identify, treat, and estimate
prognosis of ATC (5,51,52,57,58,63,67-75,85,86).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
12
1.6 Treatment As mentioned before, fibrinogen plays a crucial role in coagulation as it is
converted to fibrin, which forms a stable blood clot with platelets (87,88). Low levels of
fibrinogen can be supplemented and different studies have reported that this is effective
(73,89). Fibrinogen can be supplemented using cryoprecipitate, fresh frozen plasma
(FFP) or fibrinogen concentrates (67,90). Concentrations of fibrinogen differ between
these three supplements. Cryoprecipitate contains 15 to 17 g/L while FFP contains 2.0 to
4.5 g/L fibrinogen. Fibrinogen concentrate is a pasteurized concentrate (i.e. powder) and
is available in vials containing 900 to 1300 mg fibrinogen. After reconstitution with
sterile water, it often contains 15-20 g/L (67,91). Using one of the three supplements, it is
believed that the environment of coagulation is improved due to sufficient substrate
concentration. This enhances speed and strength of clot forming, which can be analyzed
using ROTEM or TEG (67,92).
At this moment, strong evidence regarding the optimal source of
supplementation is absent (67,93). However, several studies suggest that fibrinogen
concentrate has the potential effect of reducing allogeinic blood products and may be the
most efficient way to correct fibrinogen deficiency (94). Avoiding transfusions with
allogeneic blood products have beneficial effects as it reduces morbidity and mortality
(67). Additionally, no increased risk of adverse effects have been reported (62,67,91).
Furthermore, it has some practical benefits compared to cryoprecipitate and FFP, for
example no need for defrosting and blood group matching, low administration volume,
virally inactivated as standard, and it can be delivered as a standard dose. The latter is
unlikely if cryoprecipitate or FFP is used due to the variable amount of fibrinogen
concentration (67,91). A counterargument to use fibrinogen concentrate is that is would
be more expensive than cryoprecipitate or FFP. However, no study have been performed
which prospectively compares the direct and indirect costs of these supplements.
Therefore, conclusions about cost-effectiveness may not be drawn (94-96).
Currently, European guidelines recommend fibrinogen supplementation if
fibrinogen concentration is less than 1.5-2.0 g/L (97). However, the evidence of these
guidelines is limited and it is based on data of elective surgery and postpartum
hemorrhage, rather than hemorrhage after trauma (5). Several authors suggest that early
and aggressive supplementation of fibrinogen can have beneficial effects (93,98-101).
Consequently, the optimal fibrinogen level as a trigger to initiate treatment is not clear.
Also, the fibrinogen level as treatment goal is unknown (63).
1.7 Prognosis Outcomes after ATC are devastating. ATC has a mortality approaching
50% (4,5). If death is not rapid (often due to hypovolemia), prolonged shock raises the
incidence of multi-organ failure (MOF) and late mortality. Late mortality is primarily
contributed to hypoxia, MOF, sepsis, ongoing internal hemorrhage or cardiovascular
failure (52). Furthermore, these patients have greater organ injury, more transfusion
requirements, and longer critical care stay (4).
1.8 Fibrinogen level and prognosis Researchers have focused mainly on fibrinogen to
estimate prognosis of ATC (5,57,58,63,67-75,85,86). The relationship between
fibrinogen and mortality is the most interesting relationship, as it can reduce potentially
preventable deaths.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
13
In 2014, Hagemo et al. built two regression models to determine the association
of fibrinogen level and mortality within 28 days after admission based on mainly
prospectively obtained data (5). The first model was a logistic regression model which
resulted in a significant association between fibrinogen level and mortality (odds ratio
[OR]: 0.46, 95% confidence interval [95% CI]: 0.31-0.67). The second model was a
piecewise logistic model divided into a lower and upper segment. The OR of the lower
and upper segment were 0.08 (95% CI 0.03-0.20) and 1.77 (95% CI 0.94-3.32),
respectively. Breakpoint of these two segments was a fibrinogen level of 2.29 g/L (95%
CI 1.93-2.64). Only the P-value of the lower segment was significant. The relationship of
fibrinogen level and mortality was adjusted for ISS, age, time from injury, mechanism of
injury, base excess, INR, platelet count, and gender in both models. The authors
mentioned a dramatic increase in mortality if fibrinogen level falls below their
breakpoint, and they suggest aggressive treatment if such fibrinogen level is found. The
CI of the OR of the upper segment is relatively wide and not significant and should
therefore be interpreted with caution.
Inaba et al. also built a regression model in 2013 containing fibrinogen level as
independent variable and 24-hour mortality as dependent variable (63). Fibrinogen level
was converted into a dichotomic variable: fibrinogen level≤100 mg/dL or >100 mg/L.
The authors found that low fibrinogen level (≤100 mg/dL) was associated with poorer
survival compared to a high fibrinogen level (OR: 3.97, 95% CI 1.34-11.74). This effect
was adjusted for GCS (≤8), laparotomy, ISS (>15), platelet count (<100*109/L), age,
systolic blood pressure, Abbreviated Injury Scale head, tracheostomy, units of
transfusion, aPTT and time from emergency department to intensive care unit. The
authors concluded that aggressive treatment is necessary if fibrinogen falls below 100
mg/dL, as this was a strong predictor of mortality. However, the CI is wide, this study
only consisted of patients who received massive transfusion, and patients were only
included if fibrinogen level was known. Also, patients who died in the emergency room
were excluded. This could have resulted in a biased conclusion (i.e. selection bias).
A study conducted by Rourke et al. in 2012 has associated fibrinogen level on
admission with 24-hour and 28-day mortality (both P<0.001) (62). However, only the OR
of 28-day mortality is given (OR 0.22; 95% CI 0.10-0.47). Other variables in this model
were ISS, aPTT, age, and gender. They suggest that there may be role for early and
aggressive supplementation for patients with hypofibrinogenemia.
Kimura et al. regressed fibrinogen on 7-day mortality in 2014 (64). Other
determinants in that model were New Injury Severity Score (NISS), Triage Revised
Trauma Score (T-RTS), BE, and lactate, resulting in HR of 0.99 (95% CI 0.98-0.998;
P=0.01). The authors also concluded that repeated measurements of fibrinogen levels and
appropriate supplementation are recommended.
In 2011, Tauber et al. have also tried to identify the adjusted effect of fibrinogen
level on mortality (75). They found a non-significant association between fibrinogen
level and 24-hour mortality (OR: 0.997, 95% CI 0.988-1.007). The authors found,
however, a significant relationship between fibrinogen level and red blood cell
requirements during the first 6h after admission (OR: 0.994, 95% CI 0.991-0.998).
Innerhofer et al. conducted a study in 2013. They found that the exclusive administration
of coagulation factor compared to fresh frozen plasma reduces transfusion requirement
after major trauma (73). The authors also monitored fibrinogen level over time during
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
14
critical care stay. However, no regression model was build, which could have resulted in
a misestimated conclusion (i.e. not adjusted for other patient’s characteristics).
Fibrinogen is also associated with morbidity and mortality in other clinical
settings. Karlsson et al. found the preoperative fibrinogen concentration was a significant
independent predictor of transfusion requirement after coronary artery bypass grafting
surgery (71). The authors found an OR of 2.0 (95% CI 1.1-3.7) per 1g/L decrease of
fibrinogen level. This OR was adjusted for sex, and aortic class-clamp time. Ucar et al.
and Blome et al. also suggested that preoperative fibrinogen level may be a potential risk
factor for postoperative bleeding after coronary artery bypass surgery (68,72). However,
the authors did not build a regression model. Finally, Charbit et al. found that fibrinogen
level could predict the risk of severe postpartum hemorrhage (PPH) (69). The authors
built a model of fibrinogen level and PPH at four moments. These four moments were
H0, H1, H2, and H4 which are defined as the intravenous administration of sulprostone
(i.e. start of partus) and 1, 2, and 4 hours afterwards, respectively. The corresponding
adjusted OR were 2.63 (95% CI 1.66-4.16), 2.70 (95% CI 1.75-4.16), 3.70 (95% CI 2.17-
6.25), and 5.00 (95% CI 2.63-9.09). These OR were calculated for each 1 g/L decrease of
fibrinogen level.
At this moment, the adjusted effect of fibrinogen on outcome, and especially
mortality, in trauma patients is not clear. The studies mentioned above have tried to
identify the association between fibrinogen level and mortality or transfusion
requirements. Hagemo et al., Inaba et al., Rourke et al., and Kimura et al. found an
association of fibrinogen and mortality. However, the conclusions of Hagemo et al. and
Inaba et al. differ. Hagemo et al. concludes that a fibrinogen level of 2.29 g/L or lower is
a trigger for aggressive treatment, while Inaba et al. defined 100 mg/dL (i.e. 1 g/L) as
crucial fibrinogen level. Also, the models lack important variables which could have
resulted in a misestimated conclusion. For example, the presence of TBI, pH of blood,
and temperature are not taken into account in the abovementioned models. Temperature
and pH of blood are two main contributors of the ‘triad of death’ and studies have shown
that mortality increases dramatically if hypothermia or acidemia are present (38,39).
Although Hagemo et al. did include base excess, pH blood gives extra information about
the nature of the alkalemia or acidemia. Base excess does not appropriately take the
metabolic responses into account and could lead to a misinterpreted conclusion (102).
Thus, these characteristics should have been included in these models. Furthermore, in
isolated TBI, approximately 35% of patients show acute traumatic coagulopathy, which
states that the presence of TBI may be important to identify the effect of fibrinogen (103).
Also, Tauber et al. have not found a significant relationship between fibrinogen level and
mortality at all. In other clinical settings, fibrinogen is associated with morbidity and
mortality. As a result, controversy is still present about the effect of fibrinogen level on
prognosis. Also, the adjusted effect of fibrinogen level on mortality after trauma is not
clear.
1.9 Aims Taking the devastating outcome of ATC and controversy of performed studies
into account, it is of paramount importance to clarify the effect of fibrinogen level on
mortality in these patients. The purpose of this study was to determine the adjusted effect
of fibrinogen level at admission on early mortality in trauma patients. Additionally, we
tried to determine if this relationship is different for sex, age, and traumatic brain injury.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
15
Our aim was to identify patients at increased risk of dying as a result of ATC using
fibrinogen concentrations. We hypothesized that lower levels of fibrinogen are associated
with higher mortality rates in trauma patients.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
16
CHAPTER 2
MATERIAL AND METHODS
2.1 Patients This was a retrospective study which included polytraumatized patients.
Trauma patients treated in the time period 2004-2013 at the University Medical Center
Groningen (UMCG) were eligible for inclusion. Inclusion criteria were New Injury
Severity Score (NISS) higher than 15 and age from 18 to 80 years. Exclusion criteria
were pregnant women and if time from injury to hospital was greater than 180 minutes.
Also, patients with known clotting disorders were excluded, but not patients using
anticoagulants for other reasons.
2.2 Trauma protocol Patients were initially assessed according the ATLS (104). This
protocol is based on the principle ‘treat first what kills first’ and follows a fixed order of
assessment of injuries. The most immediate life-threatening injuries are quickly identified
and treated in order of their risk potential. The next step of assessment was only
performed if the previous step of assessment was proven stable. If massive hemorrhage
was proven or expected (i.e. blood loss of 2 liters), massive transfusion protocol (MTP)
was followed (appendix, figure A1.1). MTP consisted of infusion of red blood cells, fresh
frozen plasma, and thrombocytes (ratio 4:4:1). Both ATLS protocol and MTP are
described in detail in the ATLS and UMCG trauma guidelines (104,105).
2.3 Study parameters Endpoint of this study was mortality within 24 hours after
admission. Patient’s characteristics were determined from electronic medical records.
Demographics consisted of gender, age, cause of injury, mechanism of injury, GCS, and
NISS. Shock-related parameters comprised pulse, systolic blood pressure, hemoglobin
level, arterial bicarbonate, and arterial pH. Finally, coagulation parameters used in this
study were INR, aPTT, PT, platelet count, and fibrinogen level. Shock-related and
coagulation parameters were obtained at the emergency department. For each parameter,
the first measured value within 3 hours after admission was used for analyses.
Cause of injury was divided into five categories: motor vehicle accidents, falls
from 3 meters and higher, falls from lower than 3 meters, violence, and other. Injury
mechanism was categorized into blunt or penetrating injury.
Injury severity was scored using the NISS. Severity of injuries was scored from 1
to 5: minor, moderate, serious (not life-threatening), severe (life-threatening, survival
probable), or critical (survival uncertain). The NISS is calculated by squaring and
summing up the highest grade of the three most severe injuries, regardless of the body
region in which they occur (106). The latter is an important difference compared to the
ISS, in which the highest grade of the three most severed body regions are squared and
summed up. Thus, NISS scores ranges from 1 to 75.
The GCS is measured by testing eye, motor, and verbal responses. Ranges of
scores of each test are 1 to 4, 1 to 6, and 1 to 5, respectively. The lowest possible total
score is 3 (deep coma) while the maximum score is 15 (fully awake person) (107). The
GCS of the emergency department was used in our analyses. However, missings were
supplemented with pre-hospital scores, which are highly correlated (108).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
17
PT and aPTT were determined using the regular method described in literature
(109,110). Norm values are 9-12 and 23-33 seconds (depending on laboratory),
respectively. INR was calculated by dividing the patient’s PT through the norm value of
PT, raised to the power of the international sensitivity index (ISI). ISI is a correction
factor to compare INRs between different laboratories with each other, making it an
international standard. Finally, hemodynamic instability was defined as systolic blood
pressure lower than 90 mmHg.
2.4 Statistical analyses
2.4.1. Descriptive statistics
Patients were divided into two subgroups based on their outcome 24 hours after
admission at the emergency department: survivors and non-survivors. Descriptive
statistics were used to describe the main characteristics of the patients. All normally
distributed variables were presented as means and standard deviations (SD). Mean values
of both groups (i.e. survivors and non-survivors) were compared using the independent-
samples t-test. Non-parametric continuous data were presented as medians and
interquartile range (25th-75th percentile, P25-P75). These data were compared between
both groups using the Mann-Whitney U test. All nominal or categorical variables were
described as frequencies and percentages. Comparison between both groups was
performed using the Fisher’s exact test.
2.4.2 Association model
An association model reveals the relationship between an independent variable A (i.e.
fibrinogen) and dependent variable B (i.e. mortality). This relationship is the crude effect
as confounders and effect modifiers can influence this relationship. A confounder
correlates with both the dependent and independent variable. Not taking into account
confounders leads to a misestimated effect of the independent variable on the dependent
variable. Effect modifiers also result in misestimating the relationship of the independent
and dependent variable. This happens due to a different relationship within independent
variable A on the dependent variable B. For example, different effects of variable A on
variable B for both sexes.
Survival was presented using a Kaplan-Meier curve. Only for this survival curve,
fibrinogen level was categorized into two groups based on European trauma guidelines:
normal (>1.5 g/L) and critical (≤1.5 g/L) levels (97,111). These groups were compared
by the log-rank test. Further analyses of fibrinogen levels were performed using the
continuous variable as this is superior compared to dichotomizing a continuous variable
(112). Multivariable Cox regression model with stepwise forward selection was used to
build an association model. The endpoint of the model was hours to death within 24
hours after admission. Firstly, a univariable Cox regression model with fibrinogen levels
as independent variable was built to determine the crude effect of fibrinogen level on
mortality. The following clinical relevant effect modifiers were tested: sex, age, TBI
(measured using the GCS), NISS, and mechanism of injury. A variable was considered an
effect modifier when the regression coefficient of the interaction term was significant.
The crude effect of fibrinogen was adjusted for patient’s characteristics mentioned above,
identifying confounders. These characteristics were added in three blocks: demographics,
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
18
shock-related parameters, and coagulation parameters. Categorical variables with more
than 2 categories were converted to dummy variables based on reference group coding.
Relevant confounding was found present when the regression coefficient of fibrinogen
changed more than 10% compared to the unadjusted regression coefficient of fibrinogen.
The proportional hazard assumption was tested graphically for categorical variables and
using a time-dependent covariate for continuous variables. Results are presented as
regression coefficient, standard error, and hazard ratios (HRs) with 95% confidence
interval. The Wald test was used to determine statistical significance.
Alpha (α) was set at 0.05, which states the probability to incorrectly reject a true null
hypothesis. Thus, P<0.05 was considered significant for all analyses. All performed tests
were two-tailed tests. All analyses were performed in SPSS 22 (IBM SPSS Statistics for
Windows, Version 22.0. Armonk, NY: IBM Corp.).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
19
CHAPTER 3
RESULTS
3.1 Patient’s characteristics In the time period 2004-2013, 2073 trauma patients were
treated at the UMCG. Of these, 582 patients (28.1%) met the exclusion criteria and were
therefore excluded from analyses. The remaining 1491 patients (71.9%) met the inclusion
criteria of this study. Patient’s characteristics are presented in table 1. Of all included
patients, 1377 patients (92.4%) survived and 114 patients (7.6%) died within the first 24
hours after admission. Median age (P25-P75) of all subjects was 45 (26-60). The vast
majority of included patients were male (76.3%). Mechanism of injury was mainly blunt
trauma (95.3%). Median GCS (P25-P75) of all patients was 13 (6-15). Median NISS
(P25-P75) was 33 (25-43). Mean fibrinogen level (SD) of all patients was 2.0 (1.0).
Age differed significantly between both subgroups, with a median age (P25-P75)
of 45 (28-59) of the survivors and 51 (31-68) of the non-survivors (P=0.008). Median
GCS (P25-P75) of the survivors and non-survivors were 14 (7-15) and 3 (3-4),
respectively, which resulted in a significant difference (P<0.001). Also, difference of
NISS between both subgroups was significant, with a median NISS (P25-P75) of 33 (25-
43) and 59 (50-75), respectively (P<0.001). Furthermore, mean fibrinogen level of the
survivors and non-survivors differed significantly (2.0 [SD 0.99] versus 1.2 [SD 0.85],
respectively; P<0.001). Of all characteristics, sex (P=0.819), cause of injury (P=0.230),
mechanism of injury (P=0.134), and pulse (P=0.878) were not significantly different
between both subgroups (table 1).
3.2 Survival analyses
Survival was plotted using a
Kaplan-Meier curve (figure
5). Log-rank test showed that
lower fibrinogen levels were
associated with poorer 24-
hour survival compared to
normal fibrinogen levels
(P<0.001; figure 5).
Of all non-survivors,
78 patients (68.4%) died
because of TBI. Hemorrhage
was also a major contributor
to mortality, responsible for
the death of 25 patients
(21.9%). Other causes of
deaths were suicide (3.5%),
asystole with unknown cause
(1.8%), spinal cord lesion
(1.8%), hypothermia (0.9%),
and no identifiable cause
(1.8%).
Figure 5. Kaplan-Meier survival curve for overall survival of
polytraumatized patients from admission to 24 hours after
admission, categorized by fibrinogen level at admission. Note that
probability of survival (i.e. y-axis) ranges from 80% to 100%.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
20
The Kaplan-Meier survival curve (figure 5) showed an “elbow point” at 5 hours
after admission. Therefore, all non-survivors were divided into two groups: early (≤5
hours) and late deaths (>5 hours but ≤24 hours; table 2). No significant difference of
cause of death was found between these two subgroups (P=0.424). Of the characteristics
presented in table 2, only INR, aPTT, PT, and fibrinogen level differed significantly
between early and late deaths (P=0.004, P=0.037, P<0.001, and P=0.034, respectively).
Median GCS (P25-P75) of deaths due to TBI of early and late deaths were both 3
(3-3; P=0.489). Furthermore, hemodynamic instability was present in 10 (52.6%) and 1
patient(s) (20.0%) in early and late hemorrhagic deaths, respectively (P=0.327). Focusing
on patients with critical fibrinogen level, no significant difference was found between
early and late deaths regarding GCS and hemodynamic instability (P=0.890 and P=0.099,
respectively).
In univariable Cox regression analysis, fibrinogen level at admission was
significantly associated with mortality within 24 hours after admission at the emergency
department (HR 0.343, 95% CI 0.265-0.444, P<0.001; table 3). The interaction with sex,
age, GCS, NISS, and mechanism of injury were tested to identify effect modification.
None of these interaction terms were significant (P=0.300, P=0.076, P=0.301, P=0.853,
and P=0.484, respectively). After stepwise adjusting for demographics, shock-related
parameters, and coagulation parameters, fibrinogen level was still significantly associated
with mortality at every step of analyses (table 3). All three adjusted regression
coefficients of fibrinogen level differed more than 10% compared to the unadjusted
regression coefficient. Thus, every step identified relevant confounding characteristics.
INR was omitted due to collinearity between INR and PT and because of a lower Wald
score than PT. All HRs are calculated per 1 g/L increase of fibrinogen level. The final
multivariable model resulted in a HR (95% CI) of 0.475 (0.305-0.738; P=0.001; table 3).
This states that at every point of time within 24 hours after admission, an increase of
admission fibrinogen level of 1 g/L reduces the probability of death by a factor 0.475.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
21
Table 1. Patient’s characteristics of all patients and the comparison of these characteristics between
patients based on their outcome. Patient’s
characteristics
Total (n = 1491) Survivors (n = 1377) Non-survivors
(n = 114)
P-value*
Age (years)a 45 (28-60) 45 (28-59) 51 (31-68) 0.008
Sex, n (%) 0.819
Male 1138 (76.3%) 1052 (76.4%) 86 (75.4%)
Female 353 (23.7%) 325 (23.6%) 28 (24.6%)
Cause of injury, n (%) 0.230
Motor Vehicle
Accident
837 (56.1%) 775 (56.3%) 62 (54.4%)
Fall ≥3m height 236 (15.8%) 214 (15.5%) 22 (19.3%)
Fall <3m height 200 (13.4%) 188 (13.7%) 12 (10.5%)
Violence 56 (3.8%) 54 (3.9%) 2 (1.8%)
Other 129 (8.7%) 114 (8.3%) 15 (13.2%)
Unknown 33 (2.2%) 32 (2.3%) 1 (0.9%)
Mechanism of Injury,
n (%)
0.134
Penetrating 42 (2.8%) 36 (2.6%) 6 (5.3%)
Blunt 1421 (95.3%) 1313 (95.4%) 108 (94.7%)
Unknown 28 (1.9%) 28 (2.0%) 0 (0.0%)
GCS (points) a 13 (6-15) 14 (7-15) 3 (3-4) <0.001
NISS (points) a 33 (25-43) 29 (24-41) 59 (50-75) <0.001
Shock-related
parameters
Pulse (bpm)b 85.2 (20.7) 85.2 (20.0) 85.6 (28.3) 0.878
SBP (mmHg)b 124.9 (28.2) 126.0 (25.9) 111.0 (45.6) 0.001
Hemoglobin level
(mmol/L)a
7.8 (6.7-8.6) 7.9 (6.8-8.7) 6.8 (4.7-7.7) <0.001
Arterial HCO3-
level (mmol/L)a
22.0 (19.0-24.0) 22.0 (20.0-24.0) 20.0 (15.0-22.0) <0.001
Arterial pHa 7.32 (7.25-7.37) 7.33 (7.26-7.38) 7.25 (7.08-7.31) <0.001
Coagulation
parameters
INRa 1.1 (1.1-1.2) 1.1 (1.0-1.2) 1.3 (1.2-1.9) <0.001
aPTT (sec)a 26.0 (23.8-30.0) 26.0 (23.0-29.0) 34.0 (27.0-60.0) <0.001
PT (sec)a 12.0 (11.2-13.5) 11.9 (11.2-13.2) 14.8 (12.5-20.9) <0.001
Platelet count
(x109/L)
b
206.9 (74.2) 210.5 (73.6) 165.6 (67.4) <0.001
Fibrinogen (g/L)b 2.0 (1.0) 2.1 (0.99) 1.2 (0.85) <0.001
GCS: Glasgow Coma Scale, NISS: New Injury Severity Score, SBP: Systolic Blood Pressure, INR: International
Normalized Ratio, aPTT: Activated Partial Thromboplastin Time, PT: Prothrombin Time. a values are given in median (25th-75th percentile). b values are given as mean (standard deviation). *Mann–Whitney
U test, independent-samples t-test or Fisher’s exact test, as appropriate.
Bold P-values are statistically significant (P<0.05, two-tailed).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
22
Table 2. Patient’s characteristics of early and late deaths and the comparison of these characteristics based
on their outcome.
Patient’s characteristics Early deaths (n = 87) Late deaths (n = 27) P-value*
Age (years)a 54 (31-68) 46 (32-66) 0.459
Sex, n (%) 0.076
Male 62 (71.3%) 24 (88.9%)
Female 25 (28.7%) 3 (11.1%)
NISS (points)a
59 (50-75) 66 (50-75) 0.415
GCS (points)a 3 (3-4) 3 (3-4) 0.872
Cause of death, n (%) 0.424
TBI 58 (66.7%) 20 (74.1%)
Hemorrhage 20 (23.0%) 5 (18.5%)
Suicide 4 (4.6%) 0 (0.0%)
Asystole with
unknown cause
1 (1.1%) 1 (3.7%)
Spinal cord lesion 2 (2.3%) 0 (0.0%)
Hypothermia 0 (0.0%) 1 (3.7%)
No identifiable cause 2 (2.3%) 0 (0.0%)
Hemodynamic instability,
n (%) 0.164
Yes 33 (39.3%) 6 (22.2%)
No 51 (60.7%) 21 (77.8%)
Shock-related parameters
Pulse (bpm)a 85 (61-109) 83 (74-100) 0.694
SBP (mmHg)a 100 (75-135) 125 (98-150) 0.119
Hemoglobin level
(mmol/L)a
6.8 (4.3-7.5) 6.8 (6.0-8.0) 0.123
Arterial HCO3-
level
(mmol/L)a
19.0 (15.0-22.0) 20.0 (17.0-22.0) 0.296
Arterial pHa 7.22 (7.06-7.32) 7.26 (7.18-7.31) 0.517
Coagulation parameters
INRa 1.5 (1.2-2.1) 1.2 (1.1-1.4) 0.004
aPTT (sec)a 37.0 (27.7-71.0) 31.0 (25.0-39.0) 0.037
PT (sec)a 17.0 (12.7-22.8) 12.6 (12.1-15.0) <0.001
Platelet count
(x109/L)
a
159.0 (112.0-202.0) 170.0 (115.0-240.0) 0.406
Fibrinogen (g/L)a 1.1 (0.5-1.6) 1.4 (0.9-1.8) 0.034
GCS: Glasgow Coma Scale, NISS: New Injury Severity Score, SBP: Systolic Blood Pressure. a values are given in median (25th-75th percentile). *Mann–Whitney U test or Fisher’s exact test, as appropriate.
Bold P-values are statistically significant (P<0.05, two-tailed).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
23
Table 3. Uni- and multivariable Cox regression analysis to estimate the effect of fibrinogen on mortality
within 24 hours after admission.
Determinant Regression
coefficient
Standard error Hazard Ratio (95% CI) P-value
Fibrinogen (g/L)* -1.069 0.131 0.343 (0.265-0.444) <0.001
Fibrinogen (g/L)** -0.667 0.158 0.513 (0.376-0.700) <0.001
Fibrinogen (g/L)*** -0.670 0.205 0.511 (0.342-0.765) 0.001
Fibrinogen (g/L)**** -0.745 0.225 0.475 (0.305-0.738) 0.001
*Unadjusted effect.
** Adjusted for demographic characteristics: sex, age, New Injury Severity Score, Glasgow Coma Scale, cause of
injury, and mechanism of injury.
*** Adjusted for demographic characteristics, plus for shock-related parameters: pulse, systolic blood pressure,
hemoglobin level, arterial pH, and arterial bicarbonate.
**** Adjusted for demographic characteristics and shock-related parameters, plus for coagulation parameters:
platelet count, prothrombin time, and activated partial thromboplastin time.
Bold P-values are statistically significant (P<0.05).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
24
CHAPTER 4
DISCUSSION
4.1 Main findings The main objective of this study was to estimate the adjusted effect of
fibrinogen level at admission on 24-hour mortality in polytraumatized patients.
Additionally, we tried to determine if this relationship is different for sex, age, and
traumatic brain injury. Univariable analysis showed that an increase of admission
fibrinogen level is associated with a lower chance of dying within 24 hours after
admission (HR 0.343, 95% CI 0.265-0.444; P<0.001). This relationship was not modified
by TBI, sex, and age. However, adjusting for demographics, shock-related parameters,
and coagulation parameters is necessary as they confounded the effect of fibrinogen level
on early mortality (table 3). The HR of the final model was 0.475 (95% CI 0.305-0.738;
P=0.001). Thus, lower fibrinogen levels are associated with higher mortality,
independently of demographics, shock-related parameters, and coagulation parameters.
As preventable trauma deaths mainly occur after hemorrhage with uncontrolled bleeding
and low fibrinogen levels (111,113), results of this study indicate clinical importance as it
could reduce potential preventable deaths. Monitoring fibrinogen level routinely to
identify patients at increased risk of dying as a result of ATC and actively supplementing
fibrinogen may reduce mortality of these patients.
The study population mainly consisted of males and blunt trauma patients. Only
sex, pulse, cause and mechanism of injury were not significantly different between
survivors and non-survivors (table 1). Distribution of all characteristics between
survivors and non-survivors are similar when compared to literature, except for pulse
(5,47,62-64,114,115). Higher pulse is associated with higher mortality in literature
(116,117) while the present study found no significant difference between survivors and
non-survivors. Although pulse did not differ significantly between both groups, systolic
blood pressure did. Non-survivors had lower systolic blood pressure with the same pulse
as survivors. Hence, these patients were probably hypovolemic and thus may explain the
abovementioned differences with literature.
The study populations of studies investigating the association between fibrinogen
level at admission and mortality are different compared to the population studied in the
present study. Firstly, two studies reported younger patients (62,63) whereas a third study
investigated an older population (64). Of the first mentioned two studies, one did not
have an age inclusion criterion (63) while the other had an inclusion criterion of ≥16
years (62). This study included patients of age 18-80 years because our population of
interest was adults. This may explain the difference in age between those and the present
study. The third study examined older patients compared to the present study (64). We
could not find differences in study design which could explain this difference. Secondly,
compared to the present study, lower median or mean ISS (5,62,63) or NISS (64) were
reported elsewhere. This may be explained due to the inclusion of patients with
(N)ISS<16 by the mentioned studies. We did not include patients with NISS<16 because
those patients had insufficient and inadequate records for evaluation. We used NISS
instead on ISS in the present study because it is more accurate to predict in-hospital death
(118). Furthermore, due to the differences in calculation of the ISS and NISS (see section
2.3), NISS is generally higher than ISS (118). This may also contribute to the difference
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
25
in mean or median (N)ISS compared to other studies. Lastly, one study only included
massively transfused patients (63). These patients are, by definition, in a critical state and
mortality in this group of patients is higher compared to non-massively transfused
patients (119). Due to these differences, comparison with the present study is difficult.
The Kaplan-Meier survival curve for overall survival and the log-rank test showed
that critical fibrinogen levels are associated with poorer 24-hour survival compared to
normal fibrinogen levels (figure 5). To our knowledge, only one study have performed a
similar analysis (63). These results correspond with our results. However, as mentioned
before, the authors only included massively transfused patients and thus, comparison
must be done with caution. The Kaplan-Meier curve showed an elbow point at 5 hours
after admission in both subgroups. Other studies have found similar results
(114,120,121). Therefore, we focused on causes of death. The distribution of causes of
death is similar to the literature (3,120-122). No significant difference in cause of death
between patients who died within 5 hours or 5 to 24 hours after admission was found.
This corresponds to literature as CNS injury and hemorrhage remains the main causes of
early deaths (3,121). Of all TBI deaths, early and late deaths had minimum GCS and no
significant difference was found. This is in accordance with literature as well, as CNS
injury is the primary cause of death from 1 to 72 hours after trauma (121). Also, GCS did
not differ significantly between early and late deaths when focusing on patients with
critical fibrinogen level. Focusing on hemorrhagic deaths, we found no significant
difference in the presence of hemodynamic instability between early and late deaths.
Additionally, the presence of hemodynamic instability did not differ significantly
between early and late deaths of patients with critical fibrinogen levels. This may be the
result of a small sample size of hemorrhagic deaths (n = 25) because the present study
found that INR, aPTT, PT, and fibrinogen level are significantly different between early
and late deaths (table 2). All of these significantly different characteristics were worse in
the subgroup of early deaths. Furthermore, other studies have shown that the presence of
hemodynamic instability is associated with mortality within 2 to 6 hours after trauma
(114,115). However, these studies are relatively old and further research is therefore
needed to clarify this.
Univariable analysis showed that fibrinogen level at admission is significantly
associated with 24-hour mortality (HR 0.343, 95% CI 0.265-0.444; P<0.001; table 3).
Only one study has presented an unadjusted effect of fibrinogen level on mortality (64).
The authors regressed fibrinogen level on 7-day mortality (HR 0.98, 95% CI 0.978-0.987;
P<0.001). Hemorrhage is a major contributor to mortality within 24 hours after
admission. Mortality beyond 24 hours and within 28 days is more often the result of
sepsis and multi-organ failure (3,8,121,123). Very few hemorrhagic deaths occur after 24
hours (3,4,6,8,63,121,123). Hence, 24-hour mortality is a better endpoint to study
hemorrhagic mortality. In addition, the study included patients with lower NISS and older
age. Hypofibrinogenemia is more frequently found in younger patients compared to older
patients (5,39,64), which could be due to higher plasma fibrinogen levels in the latter
population (124). In addition, injury severity is correlated with a pathophysiological
response indicative of ATC in younger trauma patients and older patients show a
nonadaptive response irrespectively of severity of injury. These older, less severely
injured patients could, therefore, partly explain why the authors found an HR close to 1
(125).
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
26
Multivariable analysis of this study showed that lower levels of fibrinogen are
associated with higher mortality, independent of demographics, shock-related
parameters, and coagulation parameters (HR 0.475, 95% CI 0.305-0.738; P=0.001; table
3). No relevant effect modification was found. However, stepwise addition of
demographics, shock-related and coagulation parameters in blocks revealed relevant
confounding at each step. Thus, adjusting for these characteristics is necessary. Several
authors have investigated whether fibrinogen level is an independent predictor of
mortality in trauma patients by building a prediction model, adjusting for several
patient’s characteristics (5,62-64). All of these studies have shown a significant
association between fibrinogen level and mortality. However, the degree of association
differs and this may be explained by the difference in study designs and characteristics
included in these models. As mentioned before, endpoint of this study was 24-hour
mortality due to the high hemorrhagic mortality in this time frame and few hemorrhagic
deaths after 24 hours. Other studies have focused on 24-hour (63), 7-day (64) or 28-day
mortality (5,62). Inaba et al. focused on 24-hour mortality (OR 3.97; 95% CI 1.34-11.74;
P=0.013) (63). Kimura et. al regressed fibrinogen on 7-day mortality (HR 0.99, 95% CI
0.98-0.998; P=0.01) (64). Hagemo et al. regressed fibrinogen level on 28-day mortality
(OR 0.46; 95% CI 0.31-0.67; P<0.001) (5). Rourke et al. also focused on 28-day
mortality (OR 0.22; 95% CI 0.10-0.47; P<0.001) (62). Although Inaba et al. focused on
24-hour mortality, all continuous variables were converted to dichotomous variables (e.g.
fibrinogen into ≤100 mg/dL and >100 mg/dL), resulting in a loss of power and a possible
biased estimate (112). Conversion to dichotomous variables may also explain the wide CI
(112). Furthermore, the present study showed the importance of adjusting for important
characteristics (table 3). Several important characteristics are lacking in the
abovementioned studies, like GCS (5,62,64), shock-related parameters (5,62-64), and
coagulation parameters (64). Kimura et al. did include the Triage Revised Trauma Score
(T-RTS). Although this score is based on GCS, systolic blood pressure, and pulse, it does
not include these three parameters in the model independently. Consequently, the effect
of fibrinogen level is not adjusted for these three important parameters independently to
predict mortality and thus could explain the difference of results. TBI is associated with
coagulopathy and GCS should therefore be included in a model to predict mortality
(11,103). Shock-related parameters are crucial as septic shock may occur, especially if
focused on mortality beyond 24 hours. Furthermore, several studies used ISS instead of
NISS (5,62,63). Altogether, this may have contributed to the differences in results.
A study conducted in 2011 showed an insignificant association between
fibrinogen level at admission and mortality within 24 hours after admission (75).
However, the authors focused on predicting mortality based on coagulation parameters.
Demographics (e.g. age, gender, and [N]ISS) and shock-related parameters were not
included in their analyses. This may have resulted in the insignificant association
between fibrinogen level and mortality.
The present study demonstrates that the association of fibrinogen level and 24-
hour mortality is not modified by age, sex, or TBI. The latter was measured using the
GCS. We tested these effect modifiers in particular as several studies have mentioned that
these characteristics may play an important role in ATC (5,11,62,64).
Hypofibrinogenemia is observed more frequently in younger patients (5,39,64).
Furthermore, TBI is associated with coagulopathy in both isolated TBI and
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
27
polytraumatized patients (11,63). Male gender is associated with higher mortality
compared to female gender (5,62). Although demographics revealed relevant
confounding in the present study, these characteristics did not modify the effect of
fibrinogen level on 24-hour mortality. Thus, the effect of fibrinogen level found in the
final model demonstrated in this study (table 3) is applicable to all patients included in
this study, regardless of age, sex, or TBI.
This study, like the abovementioned studies (62-64), assumed a linear relationship
between fibrinogen level and mortality. However, several authors suggest a piecewise
logistic relationship between fibrinogen and mortality (5,126). Besides the mentioned
logistic model, Hagemo et al. also built a piecewise logistic model (i.e. a segmented
regression model) (5). Breakpoint of this model was a fibrinogen level of 2.29 g/L. The
association of fibrinogen level and 28-day mortality of the lower segment was significant
(OR 0.08; 95% CI 0.03-0.20; P<0.001) while this was insignificant in the upper segment
(OR 1.77; 95% CI 0.94-3.32; P=0.076). This suggests that mortality increases rapidly if
fibrinogen level falls below their breakpoint and that fibrinogen level is not associated
with mortality in the upper segment. The present study found one HR of the final model
for all patients. This may explain the difference in results. The discrepancy between a
linear and piecewise logistic model indicates that our results may underestimate the
negative impact of low fibrinogen levels in trauma patients. Further research is needed to
identify the type of model (e.g. linear, piecewise logistic, or polynomial) which is best to
estimate this relationship.
The cause of low fibrinogen level is assumed multifactorial. ATC results in a
hypocoagulation and hyperfibrinolysis. Hyperfibrinolysis lowers fibrin level, driving the
conversion of fibrinogen into fibrin (59-61). Additionally, hyperfibrinogenolysis occurs,
which lowers fibrinogen levels (4,52-54). Furthermore, fibrinogen is lost due to
hemorrhage. Dilution through resuscitation with fibrinogen-poor fluids also lowers
fibrinogen levels (63). Lastly, acidosis enhances fibrinogen breakdown (41) and
hypothermia affects fibrinogen levels by inhibiting synthesis of it (40).
Noteworthy, all the abovementioned studies have built a prediction model (5,62-
64). In this study, however, an association model was built to estimate the adjusted effect
of fibrinogen on early mortality. The differences between these models is that an
association model estimates the effect of a central determinant (i.e. fibrinogen level) on
outcome (i.e. early mortality) as purely as possible whereas a prediction model is used to
predict an outcome as best as possible using several different determinants. To our
knowledge, no association model has been built that estimates the adjusted effect of
fibrinogen level on (early) mortality. Furthermore, the present study used a Cox
regression model instead of a logistic regression model. Only the model of Kimura et al.
(2014) was built using Cox regression. A logistic model does not take time to event (i.e.
death) into account, only the occurrence of event (dichotomous variable). Time to death
is important, especially in an acute situation when treating polytraumatized patients. If
patients are more probable to die sooner, early, aggressive treatment may reduce
mortality. The difference in used models may explain the difference in results between
the current study and literature. Further research including studies with association
models is needed to clarify this.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
28
4.2 Strengths and limitations This study has several strengths and limitations. One of
the strengths of this study was the large sample size (n = 1491). Furthermore, we built an
association model instead of a prediction model, which is necessary to estimate the
adjusted effect of fibrinogen level on mortality. Also, we tested clinically relevant effect
modifiers and we adjusted for several important characteristics based on literature.
Finally, we looked at mortality within 24 hours after trauma. Several studies suggest that
hemorrhage is a major contributor to mortality within 24 hours after trauma and that late
in-hospital deaths (e.g. >24 hours) have other causes of death (3,4,6,63). Thus, to
determine the effect of fibrinogen levels on hemorrhagic mortality, it is necessary to
focus on early mortality.
An important limitation of this study was bias inherent to retrospective studies.
Furthermore, patients who died at the site of injury were not included in this study,
potentially resulting in selection bias. In addition, we recruited all patients from one
medical center. This could have a potential biased effect based on location and treatment.
Additionally, this study did not include temperature in the final model due to a large
number of missing values. Body core temperature is a main contributor of the ‘triad of
death’ and studies have shown that mortality increases dramatically in the presence of
hypothermia (38,39). Thus, temperature may be a confounder which is not taken into
account in this current study. Other studies have also mentioned a large number of
missing temperature values in trauma patients (5,6). Prospective research could avoid this
limitation. Finally, we assumed a linear relation between fibrinogen level and mortality.
However, several authors demonstrated a piecewise logistic relation between fibrinogen
and mortality (5,126). As mentioned before, this may have underestimated the effect of
low fibrinogen levels on mortality in trauma patients.
4.3 Clinical message and recommendations Since preventable trauma deaths mainly
occur after hemorrhage with uncontrolled bleeding and low fibrinogen levels, results of
this study have clinical impact as it could reduce potentially preventable deaths
(111,113). The present study shows an adjusted HR of 0.475 for every 1 g/L increase of
fibrinogen level at admission on 24-hour mortality. Therefore, monitoring fibrinogen
level routinely to identify patients at increased risk of dying as a result of ATC and
actively supplementing fibrinogen may reduce mortality of these patients. Other authors
agree with early and aggressive treatment of hypofibrinogenemia (93,98-101). However,
these results, including the results of the present study, should be interpreted with caution
due to the retrospective nature of these studies. Prospective research is therefore
recommended to provide additional evidence. Furthermore, the fibrinogen level as a
trigger to initiate treatment and the target level in trauma patients is not clear (5,63,97).
Thus, further research, preferably prospective, is needed to identify this. Additionally, the
studies mentioned above and the present study only focused on fibrinogen level at
admission. However, fibrinogen level fluctuates during critical care stay as a result of
continuous hemorrhage and its treatment (73). Hence, research regarding this fluctuation
and the effect on mortality is needed. Finally, high-quality studies regarding the optimal
source of supplementation are absent (67,93,127). More research, especially double-
blinded randomized controlled trials are required to determine the optimal source of
fibrinogen.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
29
4.4 Conclusion In summary, the present retrospective study demonstrates a significant
adjusted association between fibrinogen level at admission and 24-hour mortality in
polytraumatized patients. This relationship was not modified by traumatic brain injury,
sex, or age. Monitoring fibrinogen level routinely and actively supplementing fibrinogen
may reduce mortality of polytraumatized patients with ATC. Further research is needed
to determine the fibrinogen level as trigger to initiate treatment and to determine the
target level of treatment. Finally, research regarding the fluctuation of fibrinogen levels
during critical care stay and the optimal source of fibrinogen supplementation is
recommended.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
30
CHAPTER 5
REFERENCES
(1) Peden M, McGee K, Sharma G. The injury chart book: a graphical overview of the
global burden of injuries. 2002;Geneva, World Health Organization.
(2) CDC: Web-based Injury Statistics Query and Reporting System (WISQARS). In: U.S.
Department of Health and Human Services, CDC, National Center for Injury Prevention
and Control. 2002.
(3) Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an
overview of epidemiology, clinical presentations, and therapeutic considerations. J
Trauma 2006 Jun;60(6 Suppl):S3-11.
(4) Davenport R, Manson J, De'Ath H, Platton S, Coates A, Allard S, et al. Functional
definition and characterization of acute traumatic coagulopathy. Crit Care Med 2011
Dec;39(12):2652-2658.
(5) Hagemo JS, Stanworth S, Juffermans NP, Brohi K, Cohen MJ, Johansson PI, et al.
Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre
observational study. Crit Care 2014 Mar 26;18(2):R52.
(6) Maegele M, Lefering R, Yucel N, Tjardes T, Rixen D, Paffrath T, et al. Early
coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724
patients. Injury 2007 Mar;38(3):298-304.
(7) Gruen RL, Jurkovich GJ, McIntyre LK, Foy HM, Maier RV. Patterns of errors
contributing to trauma mortality: lessons learned from 2,594 deaths. Ann Surg 2006
Sep;244(3):371-380.
(8) Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, et al.
Epidemiology of trauma deaths: a reassessment. J Trauma 1995 Feb;38(2):185-193.
(9) Teixeira PG, Inaba K, Hadjizacharia P, Brown C, Salim A, Rhee P, et al. Preventable
or potentially preventable mortality at a mature trauma center. J Trauma 2007
Dec;63(6):1338-46; discussion 1346-7.
(10) Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism,
identification and effect. Curr Opin Crit Care 2007 Dec;13(6):680-685.
(11) Epstein DS, Mitra B, O'Reilly G, Rosenfeld JV, Cameron PA. Acute traumatic
coagulopathy in the setting of isolated traumatic brain injury: a systematic review and
meta-analysis. Injury 2014 May;45(5):819-824.
(12) Manley G, Knudson MM, Morabito D, Damron S, Erickson V, Pitts L. Hypotension,
hypoxia, and head injury: frequency, duration, and consequences. Arch Surg 2001
Oct;136(10):1118-1123.
(13) Chesnut RM, Marshall SB, Piek J, Blunt BA, Klauber MR, Marshall LF. Early and
late systemic hypotension as a frequent and fundamental source of cerebral ischemia
following severe brain injury in the Traumatic Coma Data Bank. Acta Neurochir Suppl
(Wien) 1993;59:121-125.
(14) DAVIE EW, RATNOFF OD. Waterfall Sequence for Intrinsic Blood Clotting.
Science 1964 Sep 18;145(3638):1310-1312.
(15) MACFARLANE RG. An Enzyme Cascade in the Blood Clotting Mechanism, and
its Function as a Biochemical Amplifier. Nature 1964 May 2;202:498-499.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
31
(16) Kreuz W, Meili E, Peter-Salonen K, Dobrkovska A, Devay J, Haertel S, et al.
Pharmacokinetic properties of a pasteurised fibrinogen concentrate. Transfus Apher Sci
2005 Jun;32(3):239-246.
(17) Davie EW. A brief historical review of the waterfall/cascade of blood coagulation. J
Biol Chem 2003 Dec 19;278(51):50819-50832.
(18) Veldman A, Hoffman M, Ehrenforth S. New insights into the coagulation system
and implications for new therapeutic options with recombinant factor VIIa. Curr Med
Chem 2003 May;10(10):797-811.
(19) Vine AK. Recent advances in haemostasis and thrombosis. Retina 2009 Jan;29(1):1-
7.
(20) Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue
factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad
Sci U S A 1977 Dec;74(12):5260-5264.
(21) Marlar RA, Kleiss AJ, Griffin JH. An alternative extrinsic pathway of human blood
coagulation. Blood 1982 Dec;60(6):1353-1358.
(22) Gailani D, Broze GJ,Jr. Factor XI activation in a revised model of blood coagulation.
Science 1991 Aug 23;253(5022):909-912.
(23) Hoffman M, Monroe DM,3rd. A cell-based model of hemostasis. Thromb Haemost
2001 Jun;85(6):958-965.
(24) Mann KG, Krishnaswamy S, Lawson JH. Surface-dependent hemostasis. Semin
Hematol 1992 Jul;29(3):213-226.
(25) McMichael M. New models of hemostasis. Top Companion Anim Med 2012
May;27(2):40-45.
(26) Hoffman M. Remodeling the blood coagulation cascade. J Thromb Thrombolysis
2003 Aug-Oct;16(1-2):17-20.
(27) Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue
factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J
Pathol 1989 May;134(5):1087-1097.
(28) Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor
antigen by immunostaining with monospecific, polyclonal anti-human tissue factor
antibody. Thromb Res 1990 Jul 15;59(2):421-437.
(29) Flossel C, Luther T, Muller M, Albrecht S, Kasper M. Immunohistochemical
detection of tissue factor (TF) on paraffin sections of routinely fixed human tissue.
Histochemistry 1994 Jul;101(6):449-453.
(30) Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation
in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2007 Aug;27(8):1687-
1693.
(31) Mackman N, Sawdey MS, Keeton MR, Loskutoff DJ. Murine tissue factor gene
expression in vivo. Tissue and cell specificity and regulation by lipopolysaccharide. Am J
Pathol 1993 Jul;143(1):76-84.
(32) Colman RW, Schmaier AH. Contact system: a vascular biology modulator with
anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997
Nov 15;90(10):3819-3843.
(33) Monroe DM, Hoffman M, Roberts HR. Transmission of a procoagulant signal from
tissue factor-bearing cell to platelets. Blood Coagul Fibrinolysis 1996 Jun;7(4):459-464.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
32
(34) Monkovic DD, Tracy PB. Activation of human factor V by factor Xa and thrombin.
Biochemistry 1990 Feb 6;29(5):1118-1128.
(35) Allen DH, Tracy PB. Human coagulation factor V is activated to the functional
cofactor by elastase and cathepsin G expressed at the monocyte surface. J Biol Chem
1995 Jan 20;270(3):1408-1415.
(36) Tanaka KA, Key NS, Levy JH. Blood coagulation: hemostasis and thrombin
regulation. Anesth Analg 2009 May;108(5):1433-1446.
(37) Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood
Rev 2003 Sep;17 Suppl 1:S1-5.
(38) Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B.
Predicting life-threatening coagulopathy in the massively transfused trauma patient:
hypothermia and acidoses revisited. J Trauma 1997 May;42(5):857-61; discussion 861-2.
(39) Frith D, Brohi K. The acute coagulopathy of trauma shock: clinical relevance.
Surgeon 2010 Jun;8(3):159-163.
(40) Martini WZ. The effects of hypothermia on fibrinogen metabolism and coagulation
function in swine. Metabolism 2007 Feb;56(2):214-221.
(41) Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on
fibrinogen synthesis and breakdown in pigs. Ann Surg 2007 Nov;246(5):831-835.
(42) Martini WZ, Chinkes DL, Pusateri AE, Holcomb JB, Yu YM, Zhang XJ, et al. Acute
changes in fibrinogen metabolism and coagulation after hemorrhage in pigs. Am J
Physiol Endocrinol Metab 2005 Nov;289(5):E930-4.
(43) Engels PT, Rezende-Neto JB, Al Mahroos M, Scarpelini S, Rizoli SB, Tien HC. The
natural history of trauma-related coagulopathy: implications for treatment. J Trauma
2011 Nov;71(5 Suppl 1):S448-55.
(44) Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute
traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C
pathway? Ann Surg 2007 May;245(5):812-818.
(45) Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M, Barnett C, et al. Primary
fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg
2010 Sep;252(3):434-42; discussion 443-4.
(46) Ostrowski SR, Sorensen AM, Larsen CF, Johansson PI. Thrombelastography and
biomarker profiles in acute coagulopathy of trauma: a prospective study. Scand J Trauma
Resusc Emerg Med 2011 Oct 26;19:64-7241-19-64.
(47) MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy
predicts mortality in trauma. J Trauma 2003 Jul;55(1):39-44.
(48) Rugeri L, Levrat A, David JS, Delecroix E, Floccard B, Gros A, et al. Diagnosis of
early coagulation abnormalities in trauma patients by rotation thrombelastography. J
Thromb Haemost 2007 Feb;5(2):289-295.
(49) Frith D, Goslings JC, Gaarder C, Maegele M, Cohen MJ, Allard S, et al. Definition
and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J
Thromb Haemost 2010 Sep;8(9):1919-1925.
(50) Wafaisade A, Wutzler S, Lefering R, Tjardes T, Banerjee M, Paffrath T, et al.
Drivers of acute coagulopathy after severe trauma: a multivariate analysis of 1987
patients. Emerg Med J 2010 Dec;27(12):934-939.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
33
(51) Rugeri L, Levrat A, David JS, Delecroix E, Floccard B, Gros A, et al. Diagnosis of
early coagulation abnormalities in trauma patients by rotation thrombelastography. J
Thromb Haemost 2007 Feb;5(2):289-295.
(52) Palmer L, Martin L. Traumatic coagulopathy--part 1: Pathophysiology and
diagnosis. J Vet Emerg Crit Care (San Antonio) 2014 Jan-Feb;24(1):63-74.
(53) Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated
intravascular coagulation: lessons from the classical literature. Ann Surg 2011
Jul;254(1):10-19.
(54) Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive
catecholamine induced endothelial activation and damage by fluid phase anticoagulation.
Med Hypotheses 2010 Dec;75(6):564-567.
(55) Brohi K. Trauma induced coagulopathy. J R Army Med Corps 2009
Dec;155(4):320-322.
(56) Bouillon B, Brohi K, Hess JR, Holcomb JB, Parr MJ, Hoyt DB. Educational
initiative on critical bleeding in trauma: Chicago, July 11-13, 2008. J Trauma 2010
Jan;68(1):225-230.
(57) Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism,
identification and effect. Curr Opin Crit Care 2007 Dec;13(6):680-685.
(58) Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, et al. Acute
coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and
hyperfibrinolysis. J Trauma 2008 May;64(5):1211-7; discussion 1217.
(59) Ostrowski SR, Sorensen AM, Larsen CF, Johansson PI. Thrombelastography and
biomarker profiles in acute coagulopathy of trauma: a prospective study. Scand J Trauma
Resusc Emerg Med 2011 Oct 26;19:64-7241-19-64.
(60) Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive
catecholamine induced endothelial activation and damage by fluid phase anticoagulation.
Med Hypotheses 2010 Dec;75(6):564-567.
(61) Johansson PI, Sorensen AM, Perner A, Welling KL, Wanscher M, Larsen CF, et al.
Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after
trauma? An observational study. Crit Care 2011;15(6):R272.
(62) Rourke C, Curry N, Khan S, Taylor R, Raza I, Davenport R, et al. Fibrinogen levels
during trauma hemorrhage, response to replacement therapy, and association with patient
outcomes. J Thromb Haemost 2012 Jul;10(7):1342-1351.
(63) Inaba K, Karamanos E, Lustenberger T, Schochl H, Shulman I, Nelson J, et al.
Impact of fibrinogen levels on outcomes after acute injury in patients requiring a massive
transfusion. J Am Coll Surg 2013 Feb;216(2):290-297.
(64) Kimura Y, Kimura S, Sumita S, Yamakage M. Predictors of hypofibrinogenemia in
blunt trauma patients on admission. J Anesth 2014 Aug 12.
(65) Chambers LA, Chow SJ, Shaffer LE. Frequency and characteristics of coagulopathy
in trauma patients treated with a low- or high-plasma-content massive transfusion
protocol. Am J Clin Pathol 2011 Sep;136(3):364-370.
(66) Maung AA, Kaplan LJ. Role of fibrinogen in massive injury. Minerva Anestesiol
2014 Jan;80(1):89-95.
(67) Wikkelso A, Lunde J, Johansen M, Stensballe J, Wetterslev J, Moller AM, et al.
Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev 2013 Aug
29;8:CD008864.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
34
(68) Blome M, Isgro F, Kiessling AH, Skuras J, Haubelt H, Hellstern P, et al.
Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and
postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost 2005
Jun;93(6):1101-1107.
(69) Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H, et al. The
decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J
Thromb Haemost 2007 Feb;5(2):266-273.
(70) Fenger-Eriksen C, Anker-Moller E, Heslop J, Ingerslev J, Sorensen B.
Thrombelastographic whole blood clot formation after ex vivo addition of plasma
substitutes: improvements of the induced coagulopathy with fibrinogen concentrate. Br J
Anaesth 2005 Mar;94(3):324-329.
(71) Karlsson M, Ternstrom L, Hyllner M, Baghaei F, Nilsson S, Jeppsson A. Plasma
fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting
surgery: a prospective observational study. Transfusion 2008 Oct;48(10):2152-2158.
(72) Ucar HI, Oc M, Tok M, Dogan OF, Oc B, Aydin A, et al. Preoperative fibrinogen
levels as a predictor of postoperative bleeding after open heart surgery. Heart Surg Forum
2007;10(5):E392-6.
(73) Innerhofer P, Westermann I, Tauber H, Breitkopf R, Fries D, Kastenberger T, et al.
The exclusive use of coagulation factor concentrates enables reversal of coagulopathy
and decreases transfusion rates in patients with major blunt trauma. Injury 2013
Feb;44(2):209-216.
(74) Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003
Jun;54(6):1127-1130.
(75) Tauber H, Innerhofer P, Breitkopf R, Westermann I, Beer R, El Attal R, et al.
Prevalence and impact of abnormal ROTEM(R) assays in severe blunt trauma: results of
the 'Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study'.
Br J Anaesth 2011 Sep;107(3):378-387.
(76) Hayakawa M, Gando S, Ono Y, Wada T, Yanagida Y, Sawamura A. Fibrinogen
Level Deteriorates before Other Routine Coagulation Parameters and Massive
Transfusion in the Early Phase of Severe Trauma: A Retrospective Observational Study.
Semin Thromb Hemost 2015 Feb;41(1):35-42.
(77) Ganter MT, Pittet JF. New insights into acute coagulopathy in trauma patients. Best
Pract Res Clin Anaesthesiol 2010 Mar;24(1):15-25.
(78) Cotton BA, Faz G, Hatch QM, Radwan ZA, Podbielski J, Wade C, et al. Rapid
thrombelastography delivers real-time results that predict transfusion within 1 hour of
admission. J Trauma 2011 Aug;71(2):407-14; discussion 414-7.
(79) Davenport R. Pathogenesis of acute traumatic coagulopathy. Transfusion 2013
Jan;53 Suppl 1:23S-27S.
(80) Afshari A, Wikkelso A, Brok J, Moller AM, Wetterslev J. Thrombelastography
(TEG) or thromboelastometry (ROTEM) to monitor haemotherapy versus usual care in
patients with massive transfusion. Cochrane Database Syst Rev 2011 Mar
16;(3):CD007871. doi(3):CD007871.
(81) Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use
of viscoelastic point-of-care coagulation devices. Anesth Analg 2008 May;106(5):1366-
1375.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
35
(82) Woolley T, Midwinter M, Spencer P, Watts S, Doran C, Kirkman E. Utility of
interim ROTEM((R)) values of clot strength, A5 and A10, in predicting final assessment
of coagulation status in severely injured battle patients. Injury 2013 May;44(5):593-599.
(83) Davenport R, Khan S. Management of major trauma haemorrhage: treatment
priorities and controversies. Br J Haematol 2011 Dec;155(5):537-548.
(84) Rizoli SB, Scarpelini S, Callum J, Nascimento B, Mann KG, Pinto R, et al. Clotting
factor deficiency in early trauma-associated coagulopathy. J Trauma 2011 Nov;71(5
Suppl 1):S427-34.
(85) Parasnis H, Raje B, Hinduja IN. Relevance of plasma fibrinogen estimation in
obstetric complications. J Postgrad Med 1992 Oct-Dec;38(4):183-185.
(86) Lissalde-Lavigne G, Combescure C, Muller L, Bengler C, Raillard A, Lefrant JY, et
al. Simple coagulation tests improve survival prediction in patients with septic shock. J
Thromb Haemost 2008 Apr;6(4):645-653.
(87) Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost
2005 Aug;3(8):1894-1904.
(88) Chambers LA, Chow SJ, Shaffer LE. Frequency and characteristics of coagulopathy
in trauma patients treated with a low- or high-plasma-content massive transfusion
protocol. Am J Clin Pathol 2011 Sep;136(3):364-370.
(89) Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ, et al.
The ratio of fibrinogen to red cells transfused affects survival in casualties receiving
massive transfusions at an army combat support hospital. J Trauma 2008 Feb;64(2
Suppl):S79-85; discussion S85.
(90) Levy JH, Szlam F, Tanaka KA, Sniecienski RM. Fibrinogen and hemostasis: a
primary hemostatic target for the management of acquired bleeding. Anesth Analg 2012
Feb;114(2):261-274.
(91) Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding:
a review of critical levels and replacement therapy. Transfusion 2014 May;54(5):1389-
405; quiz 1388.
(92) Nielsen VG, Cohen BM, Cohen E. Effects of coagulation factor deficiency on
plasma coagulation kinetics determined via thrombelastography: critical roles of
fibrinogen and factors II, VII, X and XII. Acta Anaesthesiol Scand 2005 Feb;49(2):222-
231.
(93) Levy JH, Szlam F, Tanaka KA, Sniecienski RM. Fibrinogen and hemostasis: a
primary hemostatic target for the management of acquired bleeding. Anesth Analg 2012
Feb;114(2):261-274.
(94) Sorensen B, Bevan D. A critical evaluation of cryoprecipitate for replacement of
fibrinogen. Br J Haematol 2010 Jun;149(6):834-843.
(95) Shander A, Hofmann A, Gombotz H, Theusinger OM, Spahn DR. Estimating the
cost of blood: past, present, and future directions. Best Pract Res Clin Anaesthesiol 2007
Jun;21(2):271-289.
(96) Toner RW, Pizzi L, Leas B, Ballas SK, Quigley A, Goldfarb NI. Costs to hospitals
of acquiring and processing blood in the US: a survey of hospital-based blood banks and
transfusion services. Appl Health Econ Health Policy 2011;9(1):29-37.
(97) Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et
al. Management of bleeding and coagulopathy following major trauma: an updated
European guideline. Crit Care 2013 Apr 19;17(2):R76.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
36
(98) Fries D, Martini WZ. Role of fibrinogen in trauma-induced coagulopathy. Br J
Anaesth 2010 Aug;105(2):116-121.
(99) Stanworth SJ, Hunt BJ. The desperate need for good-quality clinical trials to
evaluate the optimal source and dose of fibrinogen in managing bleeding. Crit Care
2011;15(6):1006.
(100) Tisherman SA. Is fibrinogen the answer to coagulopathy after massive
transfusions? Crit Care 2010;14(3):154.
(101) Schochl H, Maegele M, Solomon C, Gorlinger K, Voelckel W. Early and
individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma
Resusc Emerg Med 2012 Feb 24;20:15-7241-20-15.
(102) Verma AK, Roach P. The interpretation of arterial blood gases. Australian
Prescriber 2010;33(4):124-9.
(103) Epstein DS, Mitra B, Cameron PA, Fitzgerald M, Rosenfeld JV. Acute traumatic
coagulopathy in the setting of isolated traumatic brain injury: Definition, incidence and
outcomes. Br J Neurosurg 2014 Aug 25:1-5.
(104) Govaert GAM. Protocol opvang ernstig en/of meervoudig gewonde patiënten
(UMCG). 2013.
(105) Wendt KW. Massa Transfusie Trauma Protocol (UMCG). 2011.
(106) Osler T, Baker SP, Long W. A modification of the injury severity score that both
improves accuracy and simplifies scoring. J Trauma 1997 Dec;43(6):922-5; discussion
925-6.
(107) Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A
practical scale. Lancet 1974 Jul 13;2(7872):81-84.
(108) Bazarian JJ, Eirich MA, Salhanick SD. The relationship between pre-hospital and
emergency department Glasgow coma scale scores. Brain Inj 2003 Jul;17(7):553-560.
(109) LANGDELL RD, WAGNER RH, BRINKHOUS KM. Effect of antihemophilic
factor on one-stage clotting tests; a presumptive test for hemophilia and a simple one-
stage antihemophilic factor assy procedure. J Lab Clin Med 1953 Apr;41(4):637-647.
(110) Quick AJ, Stanley-Brown M, Bancroft FW. A study of the coagulation defect in
hemophilia and in jaundice. Am J Med Sci 1935;190(4):501.
(111) Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et
al. Management of bleeding following major trauma: an updated European guideline. Crit
Care 2010;14(2):R52.
(112) Royston P, Altman DG, Sauerbrei W. Dichotomizing continuous predictors in
multiple regression: a bad idea. Stat Med 2006 Jan 15;25(1):127-141.
(113) Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: its pathophysiology and
treatment in the injured patient. World J Surg 2007 May;31(5):1055-1064.
(114) Heckbert SR, Vedder NB, Hoffman W, Winn RK, Hudson LD, Jurkovich GJ, et al.
Outcome after hemorrhagic shock in trauma patients. J Trauma 1998 Sep;45(3):545-549.
(115) Franklin GA, Boaz PW, Spain DA, Lukan JK, Carrillo EH, Richardson JD.
Prehospital hypotension as a valid indicator of trauma team activation. J Trauma 2000
Jun;48(6):1034-7; discussion 1037-9.
(116) Liu NT, Holcomb JB, Wade CE, Salinas J. Improving the Prediction of Mortality
and the Need for Life-Saving Interventions in Trauma Patients Using Standard Vital
Signs With Heart-Rate Variability and Complexity. Shock 2015 Feb 13.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
37
(117) Singh A, Ali S, Agarwal A, Srivastava RN. Correlation of shock index and
modified shock index with the outcome of adult trauma patients: a prospective study of
9860 patients. N Am J Med Sci 2014 Sep;6(9):450-452.
(118) Lavoie A, Moore L, LeSage N, Liberman M, Sampalis JS. The New Injury
Severity Score: a more accurate predictor of in-hospital mortality than the Injury Severity
Score. J Trauma 2004 Jun;56(6):1312-1320.
(119) Cripps MW, Kutcher ME, Daley A, McCreery RC, Greenberg MD, Cachola LM, et
al. Cause and timing of death in massively transfused trauma patients. J Trauma Acute
Care Surg 2013 Aug;75(2 Suppl 2):S255-62.
(120) Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, et al.
Epidemiology of trauma deaths: a reassessment. J Trauma 1995 Feb;38(2):185-193.
(121) Acosta JA, Yang JC, Winchell RJ, Simons RK, Fortlage DA, Hollingsworth-
Fridlund P, et al. Lethal injuries and time to death in a level I trauma center. J Am Coll
Surg 1998 May;186(5):528-533.
(122) Ghorbani P, Falken M, Riddez L, Sundelof M, Oldner A, Strommer L. Clinical
review is essential to evaluate 30-day mortality after trauma. Scand J Trauma Resusc
Emerg Med 2014 Mar 13;22:18-7241-22-18.
(123) Hoyt DB, Bulger EM, Knudson MM, Morris J, Ierardi R, Sugerman HJ, et al.
Death in the operating room: an analysis of a multi-center experience. J Trauma 1994
Sep;37(3):426-432.
(124) Mari D, Coppola R, Provenzano R. Hemostasis factors and aging. Exp Gerontol
2008 Feb;43(2):66-73.
(125) Pfister G, Savino W. Can the immune system still be efficient in the elderly? An
immunological and immunoendocrine therapeutic perspective. Neuroimmunomodulation
2008;15(4-6):351-364.
(126) Hess JR, Lindell AL, Stansbury LG, Dutton RP, Scalea TM. The prevalence of
abnormal results of conventional coagulation tests on admission to a trauma center.
Transfusion 2009 Jan;49(1):34-39.
(127) Warmuth M, Mad P, Wild C. Systematic review of the efficacy and safety of
fibrinogen concentrate substitution in adults. Acta Anaesthesiol Scand 2012
May;56(5):539-548.
Fibrinogen level at admission is associated with 24-hour mortality in polytraumatized adults
38
APPENDIX
Figure A1.1: Massa transfusion protocol of the University Medical Center Groningen. RBC: Red Blood
Cells, FFP: Fresh Frozen Plasma, TC: Thrombocytes, SBP: Systolic Blood Pressure, HR: Heart Rate, Hb:
Hemoglobin, PT: Prothrombin Time, aPTT: Activated Partial Thromboplastin Time, Ht: Hematocrit.
Translated from “Massa Transfusie Trauma Protocol” by K.W. Wendt, 2011 (105).