Figure. Survival plot of patients who
received tranexamic acid and cryoprecipitate (TXA/CRYO), tranexamic
acid alone (TXA), cryoprecipitate alone (CRYO), or neither product
(no TXA/CRYO) as part of a component-based hemostatic resuscitation
following combat injury.
Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of Cryoprecipitate and Tranexamic Acid With Improved
Survival Following Wartime InjuryFindings From the MATTERs II Study. JAMA Surg. 2013;148(3):218–225. doi:10.1001/jamasurg.2013.764
Author Affiliations: National Institute
of Health Research, New Queen Elizabeth Hospital (Dr Morrison), and
The Academic Department of Military Surgery & Trauma, Royal Centre
for Defence Medicine (Drs Morrison and Midwinter), Birmingham, and
144 Parachute Medical Squadron, 16 (Air Assault) Medical Regiment,
Colchester (Dr Jansen), England; The US Army Institute of Surgical
Research, Fort Sam Houston (Drs Morrison and Rasmussen), and 59th
Medical Wing Science and Technology Office, Lackland Air Force Base
(Dr Ross), San Antonio, Texas; and C-STARS Baltimore, R Adams Cowley
Shock Trauma Center, Baltimore (Dr Dubose), and The Norman M. Rich
Department of Surgery, the Uniformed Services University of the Health
Sciences, Bethesda (Dr Rasmussen), Maryland.
Objective To quantify the impact of fibrinogen-containing cryoprecipitate
in addition to the antifibrinolytic tranexamic acid on survival in
Design Retrospective observational study comparing the mortality of
4 groups: tranexamic acid only, cryoprecipitate only, tranexamic acid
and cryoprecipitate, and neither tranexamic acid nor cryoprecipitate.
To balance comparisons, propensity scores were developed and added
as covariates to logistic regression models predicting mortality.
Setting A Role 3 Combat Surgical Hospital in southern Afghanistan.
Patients A total of 1332 patients were identified from prospectively
collected UK and US trauma registries who required 1 U or more of
packed red blood cells and composed the following groups: tranexamic
acid (n = 148), cryoprecipitate (n = 168), tranexamic
acid/cryoprecipitate (n = 258), and no tranexamic acid/cryoprecipitate
(n = 758).
Main Outcome Measure In-hospital mortality.
Results Injury Severity Scores were highest in the cryoprecipitate (mean
[SD], 28.3 [15.7]) and tranexamic acid/cryoprecipitate (mean [SD],
26 [14.9]) groups compared with the tranexamic acid (mean [SD], 23.0
[19.2]) and no tranexamic acid/cryoprecipitate (mean [SD], 21.2 [18.5])
(P < .001) groups. Despite greater
Injury Severity Scores and packed red blood cell requirements, mortality
was lowest in the tranexamic acid/cryoprecipitate (11.6%) and tranexamic
acid (18.2%) groups compared with the cryoprecipitate (21.4%) and
no tranexamic acid/cryoprecipitate (23.6%) groups. Tranexamic acid
and cryoprecipitate were independently associated with a similarly
reduced mortality (odds ratio, 0.61; 95% CI, 0.42-0.89; P = .01 and odds ratio, 0.61; 95% CI, 0.40-0.94; P = .02, respectively). The combined
tranexamic acid and cryoprecipitate effect vs neither in a synergy
model had an odds ratio of 0.34 (95% CI, 0.20-0.58; P < .001), reflecting nonsignificant interaction
(P = .21).
Conclusions Cryoprecipitate may independently add to the survival benefit
of tranexamic acid in the seriously injured requiring transfusion.
Additional study is necessary to define the role of fibrinogen in
resuscitation from hemorrhagic shock.
Hemorrhage resultant from vascular disruption remains the predominant
cause of preventable battlefield mortality1,2 and the leading cause of
preventable death in civilian trauma.3- 5 Acute traumatic
coagulopathy is associated with a 4-fold increase in mortality and
is characterized by both anticoagulation and fibrinolysis.6 Fibrinolysis is a key protective or regulatory
mechanism that prevents the extension of formed clot beyond the site
of injury7 but may become pathologic
following injury and shock.8 When
present in the setting of trauma, excessive fibrinolysis (ie, hyperfibrinolysis)
is associated with a mortality rate of 48% to 100%.9- 12
Treatment with antifibrinolytic agents has been shown to reduce
mortality following trauma in civilian and military settings.13 The prospective CRASH-2 trial demonstrated
lower mortality from hemorrhage in civilian patients randomized to
receive tranexamic acid (4.9% vs 5.7%; P = .008).14 Subsequently the Military Application of
Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study
showed a 6.5% absolute reduction in mortality in those receiving tranexamic
acid following wartime injury.15 An
unexpected but important observation from MATTERs was the greater
volume of cryoprecipitate received by the tranexamic acid cohort.
Cryoprecipitate is a rich source of fibrinogen, which is the
first coagulation factor to be exhausted in major bleeding16 and observational studies have shown a
reduction in mortality in trauma patients receiving this factor during
massive transfusion.17,18 Traditionally, cryoprecipitate has been administered late in the
course of component-based resuscitation after the use of packed red
blood cells and plasma. However, recent evidence has increased interest
in the early administration of cryoprecipitate and resulted in calls19 for prospective studies on the use of purified
Despite the intuitive rationale for replacing depleted fibrinogen
while inhibiting fibrinolysis in the setting of trauma, to our knowledge,
there have been no studies investigating this therapeutic strategy.
The objective of this MATTERs II study was to examine the effect on
mortality of cryoprecipitate administered alone and in conjunction
with tranexamic acid as part of component-based resuscitation following
This is a retrospective cohort study on prospectively gathered
injury, injury management, and outcomes data on combat casualties
in the US and UK Joint Theater Trauma registries. Patients were treated
between March 1, 2006, and March 31, 2011, at the field hospital at
Camp Bastion, Helmand Province, Afghanistan, and received at least
1 U of packed red blood cells following wartime injury. Permission
for the study was obtained from the UK Joint Medical Command Research
Pillar and the US Army Medical Research and Material Command.
The medical treatment facility at Camp Bastion has the equivalent
facilities to a US level I trauma center. Transfusion strategies have
evolved over the study period toward a coherent damage control resuscitation
strategy summarized in clinical practice guidelines.21,22 This included the prehospital
administering of packed red blood cells and plasma in critical casualties
on helicopter retrievals in the study's final 24 months. However,
the use of tranexamic acid, cryoprecipitate, and recombinant factor
VIIa was left to the treating physician's discretion during the initial
part of the study.
A unit of cryoprecipitate administered in this study was pooled
from 10 donors with a fibrinogen concentration of around 15 g/L.23 This is in contrast to fresh frozen plasma,
which has a concentration of around 2.5 g/L.24 Tranexamic acid was administered as a bolus
of 1 g intravenous, followed by further doses at the clinician's discretion.
Patients were identified from the UK and US Joint Theater Trauma
registries and data included demographic details, injury characteristics,
resuscitation requirements, and mortality. Coalition military personnel
including US and UK troops were designated as North Atlantic Treaty
Organization and all patients of Afghan origin were designated Host
Nationals. The study population was divided into 4 cohorts: casualties
who received cryoprecipitate but not tranexamic acid, casualties who
received tranexamic acid but not cryoprecipitate, those who received
both tranexamic acid and cryoprecipitate, and patients who received
neither tranexamic acid nor cryoprecipitate as part of their resuscitation.
Injury pattern and severity were described using Abbreviated Injury
Scale scores.25 Severe injury to
a body region was defined as an Abbreviated Injury Scale score of
3 or greater. Abbreviated Injury Scale scoring was also used to calculate
an Injury Severity Score, ranging from 1 to 75, where a higher score
represents a greater burden of injury.26
The primary end point of the study was mortality. For North
Atlantic Treaty Organization casualties, who were tracked through
all stages of care, mortality was defined as death within 30 days
of wounding. For Host National casualties, who were discharged into
their indigenous health care system when clinically appropriate, mortality
was defined as death prior to discharge from the medical treatment
facility (ie, in-hospital mortality).
Parameters were compared across the 4 treatment cohorts by analysis
of variance for continuous measures and logistic regression for proportions.
A pair of propensity scores that contributed to selection for tranexamic
acid and cryoprecipitate treatments were developed using previously
described methods.27,28 The first score was developed without regard to the number of missing
values of variables related to the treatment choice. The second score
included only variables with less than 30 missing values. The C statistic
was used as a measure of how well either score discriminated between
groups (closer to 1.00 indicates better discrimination). The score
with the highest C statistic was selected to alleviate confounders
estimating the association of each treatment with mortality.
When developing the scores, in recognition of temporal changes
in transfusion practice, admission date was specifically included
in the regression modeling. Furthermore, particular attention was
paid to balancing for noncryoprecipitate blood components and when
there were significant differences, further scores were developed
to ensure that any important interactions were recognized.
The selected propensity scores were then used as adjustments
in nonordinal polytomous logistic regression for proportions and analysis
of covariance for continuous measures as an aid to assess the balance
between groups. The selected propensity scores were also added as
covariates to logistic regression models predicting mortality with
treatments as predictors to identify the isolated contribution of
tranexamic acid, cryoprecipitate, and the combination of tranexamic
acid and cryoprecipitate to mortality. Analyses were performed using
SAS version 9.2 (SAS Institute Inc).
Over the 5-year period, 1332 patients required at least 1 U
of red blood cell concentrate as part of their resuscitation following
combat injury. The baseline characteristics of the 4 cohorts are shown
in Table 1. As part of resuscitation,
11.1% (n = 148) of the cohort received tranexamic acid only,
12.6% (n = 168) received cryoprecipitate only, 19.4% (n = 258)
received both tranexamic acid and cryoprecipitate, and 56.9% (n = 758)
received neither treatment.
The C statistics for the propensity scores were as follows:
tranexamic acid with missing data: C = 0.873; tranexamic
acid all data: C = 0.850; cryoprecipitate with missing data:
C = 0.944; and cryoprecipitate all data: C = 0.945.
Because missing data were not significantly associated with treatment
choice, we concluded it reasonable to assume that excluding cases
with missing data would not introduce bias. Thus, the propensity scores
were developed using subjects with no missing data, which meant excluding
412 patients with missing physiological parameters and 26 patients
with missing Injury Severity Scores.
The following variables were found to be significant in developing
propensity scores for the tranexamic acid group: admission date, nation
status, systolic blood pressure, Glasgow Coma Scale score, lower extremity
injury, and prehospital blood, fresh frozen plasma, packed red blood
cell, and platelet administration. The following were significant
when developing the cryoprecipitate group score: Injury Severity Score,
lower extremity injury, recombinant factor VIIa use, and fresh frozen
plasma and platelet administration.
Unadjusted univariate comparison revealed similar distributions
of age and sex across the 4 study groups. However, a greater proportion
of Host National patients received either tranexamic acid in isolation
or neither treatment. Additionally, the prehospital use of blood products
by a physician-led retrieval team was also different among groups.
Specifically, patients in the no tranexamic acid/cryoprecipitate group
were the least likely to receive these prehospital interventions.
Furthermore, patients in the tranexamic acid/cryoprecipitate group
were more likely to have been involved in an explosive injury than
patients receiving neither therapy. There were also significant differences
in admission physiology because patients in the tranexamic acid/cryoprecipitate
group had a lower level of consciousness and were more hypotensive.
The least physiologically disturbed group was the no tranexamic acid/cryoprecipitate
group. Postadjustment, all parameters became statistically similar
(P > .05) except for the patients
with a reduced consciousness level (Table
Preadjustment, the Injury Severity Scores of the 4 groups varied
significantly (Table 2). The
most severely injured patients were observed to be in the cryoprecipitate
group, with decreasing injury severity in the cryoprecipitate/tranexamic
acid, tranexamic acid, and no cryoprecipitate/tranexamic acid groups,
respectively. The main difference in injury pattern was due to a relatively
small number of severe head injuries, but a large number of severe
extremity wounds, in the tranexamic acid/cryoprecipitate group. The
rate of severe torso wounding was similar across all 4 groups. Differences
in the proportions of casualties in each Injury Severity Score band
remained statistically significant after propensity adjustment (P = .04), but there were no differences
in the mean Injury Severity Score, or the proportion of severe injuries
in each body region, across the 4 cohorts (Table 2).
Before adjustment, patients in the tranexamic acid/cryoprecipitate
group required more than 4-fold the number of units of packed red
blood cells, plasma, and platelets than patients in the no tranexamic
acid/cryoprecipitate group (Table 3). There was no difference in the number of units of cryoprecipitate
administered to the cryoprecipitate and tranexamic acid/cryoprecipitate
groups (2.1 and 2.3 U, respectively; P = .15).
However, there was a greater amount of tranexamic acid administered
to patients in the tranexamic acid/cryoprecipitate group than to patients
in the tranexamic acid group (mean, 2.4 and 1.9 g, respectively; P < .001) (Table 3). Recombinant factor VIIa was administered most
frequently in the cryoprecipitate and tranexamic acid/cryoprecipitate
groups and used less frequently in the tranexamic acid and no tranexamic
acid/cryoprecipitate group (P < .001).
Propensity scoring was able to adjust for differences in the number
of units of red blood cell concentrate and plasma transfused and the
dose of tranexamic acid administered, but not the number of units
of platelets transfused or the amount of recombinant factor VIIa administered
The mean (SD) follow-up of the cohort was 13.0 (12.7) days.
Mortality was highest in the no tranexamic acid/cryoprecipitate group
(23.6%) and lowest in the tranexamic acid/cryoprecipitate group (11.6%)
(P = .001) (Figure). This difference persisted after
propensity adjustment (Table 1). The benefits of tranexamic acid and cryoprecipitate were similar;
both associated with an odds ratio (OR) of 0.61 and 95% CIs of 0.42
to 0.89 and 0.40 to 0.94, respectively (Table 4). The effect of tranexamic acid was not found to
interact with cryoprecipitate, as demonstrated by a synergy model
(P = .21). A further model was
also developed to adjust for platelet administration: the ORs (95%
CI) of tranexamic acid and cryoprecipitate were 0.62 (0.43-0.90) and
0.59 (0.39-0.91), respectively.
The effect of tranexamic acid and cryoprecipitate in combination
was associated with an OR (95% CI) of 0.34 (0.20-0.58) (P < .001). This did not differ markedly from
the OR estimated from the independent additive model (0.61 × 0.61 = 0.37).
This was also the case when adjusting for platelets (OR, 0.34; 95%
CI, 0.20-0.58; P < .001).
To our knowledge, this study is the first to report the effect
on mortality of cryoprecipitate alone and in combination with tranexamic
acid as part of a blood component–based resuscitation in trauma.
Despite a more severe constellation of injuries and greater resuscitation
requirements, patients who received cryoprecipitate and/or tranexamic
acid had improved survival compared with those who received neither.
The mortality benefit with cryoprecipitate and tranexamic acid was
additive and present after propensity adjustment to optimize the comparability
of groups. Findings from this investigation suggest that fibrinogen
replacement may be as important as the inhibition of fibrinolysis
in improving survival following wartime injury.
The current investigation confirms and extends the findings
from the CRASH-2 trial14 and the
MATTERs study15 that tranexamic acid
is beneficial in trauma. The present analysis was prompted by the
finding in the MATTERs study that those in the tranexamic acid cohort
also received a greater volume of cryoprecipitate. By using a longer
study period and a greater number of patients than the MATTERs study,
a more comprehensive analysis of the subgroups receiving cryoprecipitate
alone and in combination with tranexamic acid was possible.
Findings from this investigation substantiate work reported
by Stinger et al,18 who examined
the effect of exogenous fibrinogen in blood products administered
to combat casualties between 2004 and 2005. In that report, Stinger
et al examined the fibrinogen to packed red blood cell ratio in 252
casualties who received massive transfusion and identified a 50% relative
reduction in mortality in those receiving a high compared with a low
ratio. From that study, Stinger et al recommended administration of
250 mg of fibrinogen or one 15-mL unit of cryoprecipitate per unit
of packed red blood cells (fibrinogen to packed red blood cell ratio >
0.2 g) during resuscitation from severe trauma. However, the precise
dose of fibrinogen in fresh frozen plasma and cryoprecipitate is variable
and difficult to accurately assess in retrospective studies.29 However, using their method, the crude
fibrinogen to red blood cell ratios of the groups in the current study
were tranexamic acid/cryoprecipitate, 0.7 g; cryoprecipitate, 0.66
g; tranexamic acid, 0.39 g; and no tranexamic acid/cryoprecipitate,
Civilian investigators have also identified the importance of
fibrinogen metabolism in severely injured patients noting that fibrinogen
is the first to be exhausted in trauma coagulopathy.16 Excess fibrinolysis identified using thromboelastography
has been noted to be associated with mortality rates between 48% and
100%.9- 12 Schöchl et al19 reported
on severely injured patients who received fibrinogen concentrate based
on thromboelastography findings and reported a 50% reduction in actual,
compared with expected, mortality using Trauma Related Injury Severity
Score methods. In aggregate, these findings have prompted investigators
to advocate for earlier administration of fibrinogen as part of resuscitation
following severe trauma and resulted in at least 1 prospective, randomized
trial of the prehospital use of fibrinogen concentrate.30
Findings from these studies point to a mechanistic process that
includes maintenance of a fibrinogen threshold in the acute setting
following trauma and hemorrhage. One theory that addresses the dynamic
nature of fibrinogen metabolism in this scenario relates to the effect
of relative hypoxia on the vascular endothelium in the setting of
hemorrhagic shock. Brohi et al8 and
others have postulated that reduced oxygen-carrying capacity in the
setting of shock enhances endothelial expression of thrombomodulin,
which results in pathological activation of protein C, an endogenous
anticoagulant.31 In addition to inhibiting
factors V and VIII, activated protein C leads to inhibition and degradation
of the principle inhibitor of tissue plasminogen activator, plasminogen
activator inhibitor-1.32,33 In this setting, increased plasminogen activity promotes fibrinolysis
and fibrin depletion. The results of the current study extend the
work of these investigators,8 suggesting
that both early inhibition of fibrinolysis as well as repletion of
fibrinogen stores may have an additive effect at reducing mortality.
The potential mortality benefit of cryoprecipitate and tranexamic
acid in the setting of trauma may not be solely related to achieving
hemostasis acutely following injury. This is an important consideration
because a portion of the survival benefit of cryoprecipitate and tranexamic
acid is observed in the days and weeks following injury and resuscitation
(Figure). In this context,
it is plausible that the interaction and cross-talk between the coagulation
and inflammatory pathways plays a role in improving survival.34
Specifically, tranexamic acid has a known anti-inflammatory
effect achieved in part through the reduction of circulating plasmin
levels.35 This effect has been reported
extensively in the setting of cardiac surgery where tranexamic acid
has been shown to be associated with decreased circulating markers
of inflammation, less inotropic support, and fewer ventilatory days.36,37 These findings have led
to speculation that tranexamic acid–related survival may be
due to an attenuated inflammatory response reducing organ failure
In recent and compelling work, Cohen and colleagues30 have shown that activated protein C plays
a central role in delayed organ dysfunction and death following severe
trauma. Findings from the current study point to the possibility that
stabilization of fibrinogen with cryoprecipitate and tranexamic acid
early after injury plays a role in mitigating this adverse response
days and weeks after injury. In this context, cryoprecipitate is a
complex preparation containing more than fibrinogen alone including
some components, such as fibrinonectin and platelet microparticles,
that have direct immunomodulatory effects.29
The propensity scoring method used in this study has been able
to be adjusted for most known variables and thus has enabled the controlled
comparison of relatively heterogeneous subgroups. Specifically, propensity
scoring was able to control for the majority of important variables
such as injury severity and the administration of other fibrinogen-containing
blood products. However, there are a number of important limitations
that need to be recognized, specifically the areas of prehospital
data and the trends in institutional practice.
This study reports limited prehospital data but is able to identify
patients retrieved by a physician-led team that was able to undertake
a greater array of interventions including intubation and blood product
administration. While physician-led retrieval was not identified as
a significant parameter in the regression model per se, it is possible
that unquantified interventions have subtle interaction that cannot
be completely controlled. For example, significantly more patients
in the tranexamic acid/cryoprecipitate group had a Glasgow Coma Scale
score less than 8; it is conceivable that some patients underwent
prehospital intubation, artificially reducing their consciousness
level. In the case of prehospital blood use, a significant interaction
was identified (P < .001) and
controlled for postadjustment (P = .88).
A further limitation relates to the temporal trend in military
transfusion practice and institutional experience that had undoubtedly
evolved over the study period. Date of admission was found to be a
significant parameter within the regression analysis and was controlled
for within the propensity scores. This is not surprising because the
administration of cryoprecipitate and tranexamic acid was only protocolized
in the last 18 months of the study. Although date of admission has
been controlled for, there may be other unrecognized temporal relationships
that remain unadjusted, influencing mortality. However, it was this
variation in practice that made this study possible by permitting
the analysis of subgroups.
A further assumption of this study is that the potential mortality
benefit observed with cryoprecipitate relates strictly to fibrinogen.
Although comprising mostly factor I, cryoprecipitate also contains
varying amounts of von Willebrand factor and factor VIII, either of
which may have influenced the observed mortality benefit.29 Finally, without information pertaining
to inflammatory markers, organ dysfunction, or cause of death, this
study is not able to draw a definite link between fibrinogen metabolism
and inflammation. Despite these limitations, this study provides new
data showing a survival benefit with the use of cryoprecipitate and
tranexamic acid in the setting of trauma and provides a foundation
for detailed study of these compounds including prospective trials
of fibrinogen concentrate.
In conclusion, this study demonstrates that the administration
of cryoprecipitate and tranexamic acid may improve the survival in
the seriously injured requiring transfusion. The effect of cryoprecipitate
appears to be additive to that of tranexamic acid, suggesting that
repletion of fibrinogen may be as important as preventing its degradation
in this setting. Additional study is necessary to define the role
of fibrinogen in resuscitation from hemorrhagic shock.
Correspondence: Todd E. Rasmussen,
MD, San Antonio Military Vascular Surgery, US Army Institute of Surgical
Research, 3400 Rawley E. Chambers Ave, Ste B, Ft Sam Houston, San
Antonio, TX 78234-6315 (email@example.com).
Accepted for Publication: June 25,
Published Online: November 19, 2012.
Author Contributions:Study concept and design: Morrison, Ross, Dubose, Midwinter,
and Rasmussen. Acquisition of data: Morrison,
Dubose, Midwinter, and Rasmussen. Analysis and interpretation
of data: Morrison, Ross, Dubose, Jansen, Midwinter, and Rasmussen. Drafting of the manuscript: Morrison, Ross, Jansen,
Midwinter, and Rasmussen. Critical revision of the
manuscript for important intellectual content: Morrison, Ross,
Dubose, Jansen, Midwinter, and Rasmussen. Statistical
analysis: Morrison and Rasmussen. Obtained
funding: Midwinter and Rasmussen. Administrative,
technical, and material support: Morrison, Dubose, and Rasmussen. Study supervision: Dubose, Jansen, Midwinter, and
Conflict of Interest Disclosures: None
Funding/Support: This research was
funded by the Office of the US Air Force Surgeon General and created
in the performance of a contract with the Air Force Medical Support
Agency. The governments of Great Britain and the United States have
certain rights to use this work.
Disclaimer: The viewpoints expressed
in this article are those of the authors and do not reflect the official
position of the US Department of Defense or the UK Defence Medical
Previous Presentation: This study was
presented at the Advanced Technology Applications for Combat Casualty
Care 2012 Conference; August 14, 2012; Fort Lauderdale, Florida.
Additional Contributions: We are grateful
to the staff at the UK Joint Theatre Trauma Registry (Academic Department
of Military Emergency Medicine, Royal Centre for Defence Medicine,
Birmingham, England) and US Joint Theater Trauma Registry (US Army
Institute of Surgical Research, Fort Sam Houston, San Antonio, Texas)
for providing the data required for this study. We are also thankful
of Danny Sharon, MS, and colleagues of the US Air Force Medical Support
Agency, who performed elements of the statistical analysis.