Coagulation and Transfusion Medicine / Transfusion Protocol With Higher FFP/RBC Ratio
A Massive Transfusion Protocol Incorporating a Higher
FFP/RBC Ratio Is Associated With Decreased Use of
Recombinant Activated Factor VII in Trauma Patients
Josenia N.M. Tan, MD,1 Peter A. Burke, MD,2 Suresh K. Agarwal, MD,2
Nelson Mantilla-Rey, MT(BB),1 and Karen Quillen, MD1
Key Words: Trauma; Massive transfusion; Plasma/red cell ratio
DOI: 10.1309/AJCPQZNCHM5PIK8O
CME/SAM
Upon completion of this activity you will be able to:
describe the rationale of a massive transfusion protocol in trauma.
describe the effects of plasma transfusion and recombinant activated
factor VII as part of a massive transfusion protocol.
list the potential adverse effects of massive transfusion.
Abstract
We implemented a protocol incorporating a
higher fresh frozen plasma (FFP)/RBC ratio for the
management of trauma patients requiring massive
transfusion in 2007. This study aims to identify issues
that affected the effective deployment of the massive
transfusion protocol (MTP) and compare outcome
variables with a historic cohort. Data from 49 trauma
patients who received at least 10 units of packed RBCs
within 24 hours were analyzed and compared with a
historic massively transfused cohort who had received
recombinant activated factor VII (rFVIIa).
Of the patients, 28 received an FFP/RBC ratio
of 1:1 to 1:2; 12 received a lower ratio of 1:2 to 1:4;
3 received more than 1:1 and 6 had less than 1:4.
Compared with the historic cohort, the 1:1-1:2 group
received significantly fewer blood components and did
not require rescue rFVIIa. An MTP incorporating a
higher FFP/RBC ratio of 1:1 to 1:2 is associated with
decreased use of blood components and may obviate
the need for rFVII.
566 Am J Clin Pathol 2012;137:566-571
566 DOI: 10.1309/AJCPQZNCHM5PIK8O
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credit commensurate with the extent of their participation in the activity.
This activity qualifies as an American Board of Pathology Maintenance of
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The authors of this article and the planning committee members and staff
have no relevant financial relationships with commercial interests to disclose.
Questions appear on p 672. Exam is located at www.ascp.org/ajcpcme.
Civilian trauma deaths constitute the leading cause of
mortality in young people younger than 45 years.1 They can
be classified as immediate, early, or late. Immediate death
occurs due to nonsalvageable injuries such as rupture of the
heart and great vessels.2 Early death happens during the first
6 hours and is typically due to hemorrhage. Early deaths are
considered preventable via interventions to prevent exsangui-
nation. This involves rapid control of bleeding via damage-
control surgery, selective angiographic embolization, and
blood component resuscitation. Late deaths occur after days
or weeks and are due to sepsis or organ failure.
The hemostatic system is a balance of procoagulants
and anticoagulants. The pathophysiology of coagulopathy
in trauma is complex and multifactorial.3,4 Acute traumatic
coagulopathy leads to hyperfibrinolysis as early as 20 min-
utes; fibrinolytic activity remains elevated longer in patients
with more severe injuries.4 Other risk factors for coagulopathy
include an Injury Severity Score (ISS) of more than 25, a sys-
tolic blood pressure of less than 70 mmHg, acidosis with a pH
of less than 7.10, and hypothermia with a body temperature
of less than 34C.3 Mortality reaches 100% when hypother-
mia occurs in conjunction with acidosis in the presence of
bleeding.5,6 Dilutional coagulopathy compounds the problem
if aggressive crystalloid resuscitation is followed by packed
RBCs (PRBCs).
Recombinant activated factor VII (rFVIIa) has been used
empirically to treat the coagulopathy of massive transfu-
sion. Tissue factor exposed at the site of endothelial injury
complexes with FVIIa to generate thrombin. rFVIIa also
enhances factor Xa and factor IXa levels on the surface of
activated platelets, adding to the thrombin burst, which leads
American Society for Clinical Pathology

to a fibrin clot. Since 2004, our institution has had a policy to
use low-dose rFVIIa in refractory bleeding after appropriate
component therapy in massive transfusion.
Trauma transfusion protocols incorporating higher plas-
ma/PRBC ratios have been derived from military experience
in combat casualties.7 Our facility implemented one such
algorithm for the management of trauma patients requiring
massive transfusion in 2007. At our blood bank, 4 U of type
AB, 4 U of type O, 2 U of type A, and 2 U of type B thawed
plasma (with a 5-day expiration date) are available at all times
and replenished as necessary.
We undertook a retrospective analysis of the implementa-
tion of the massive transfusion protocol (MTP) to document
the actual blood component delivery for each activation that
occurred and to track timely receipt of a blood bank specimen
to permit the use of type-specific components whenever pos-
sible. We noticed a dramatic decrease in the request for rescue
use of rFVIIa after the implementation of the new MTP proto-
col. We then compiled a historic cohort of recipients of mas-
sive transfusion who had received rFVIIa as rescue therapy
after traditional blood component therapy and damage-control
surgery or embolization had failed to control hemorrhage.
Materials and Methods
A retrospective analysis was performed to assess the
utilization of our MTP. Records of trauma patients for whom
the MTP was activated from January 1, 2009, to July 8, 2010,
were analyzed. Massive transfusion was defined as receipt of
10 U of PRBCs within 24 hours of admission. Patients with
nontraumatic causes of bleeding and patients with traumatic
brain injury were excluded from this analysis.
When the MTP is activated by the trauma attending
physician, the blood bank is called for the emergency release
of the first cooler of 4 U of PRBCs. As soon as the first set
of components is issued, a second set consisting of 4 U of
PRBCs and 4 U of type AB FFP are prepared for the next
pickup. At the same time, the type and screen is performed
with subsequent crossmatch of 4 U of type-specific PRBCs
and preparation of type-specific plasma. After the second set
of blood components, 2 packs of platelets are also prepared.
Cryoprecipitate is not routinely included in the algorithm. The
decision to activate the MTP is made by the trauma attending
physician based on clinical criteria such as proximal limb
amputation, hypotension, or coagulopathy on admission.
Our institutional protocol for off-label use of rFVIIa
in massive transfusion requires that the trauma team use all
standard attempts at hemostasis including surgery and/or
angiographic embolization and that patients be normothermic
and with pH more than 7.20. Our institutional policy is to use
rFVIIa at a low dose of 10 to 20 g/kg.
American Society for Clinical Pathology
Coagulation and Transfusion Medicine / Original Article
The outcome variables analyzed for each cohort of
patients include mortality, length of intensive care unit (ICU)
stay and number of ventilator days, and 24-hour blood com-
ponent use. For the purpose of this report, the term FFP
refers to thawed plasma. Laboratory parameters recorded
included international normalized ratio (INR) and PTT val-
ues on admission. Data on specific complications including
thrombosis, bacteremia/sepsis, and acute lung injury were
obtained by searching the trauma registry, the medical record,
and pharmacy data (the latter specifically for the use of thera-
peutic anticoagulation).
While rFVIIa had remained part of the MTP for refrac-
tory bleeding, we observed that none of the patients in this
MTP series required rFVIIa. We retrieved a historic cohort
of patients who had received massive transfusions and had
received rFVIIa in the 2 years before the implementation of
the current MTP.
Statistical analysis was performed using logistic regres-
sion and Cox proportional hazards model with SAS software
(SAS Institute, Cary, NC).
Results
A total of 49 patients for whom the MTP was activated
were trauma patients who received 10 or more units of PRBCs
within 24 hours. Demographic data are summarized in Table
1. The patients were predominantly young males (mean age,
38 years). The proportion of injury by a blunt vs penetrating
mechanism was evenly divided. The patients had severe inju-
ries with a mean ISS of 29 and early coagulopathy, as reflect-
ed by abnormal coagulation studies on admission (mean INR,
1.5, and PTT, 45 seconds). The hospital mortality rate was
53%, with most deaths occurring within the first 24 hours.
The median FFP/RBC ratio among the entire cohort was
1:1.7. Of the patients, 40 had ratios within the 1:1 to 1:4 range,
Table 1
Demographic Characteristics and Overall Outcome in 49
Trauma Cases*
Characteristic Result
Mean SEM age (y) 38 2
Male sex 44 (89)
Blunt mechanism of injury 25 (51)
Mean SEM ISS 29 2
Mean SEM admission INR (n = 36) 1.5 0.07
Mean SEM admission PTT (n = 36) 45 4
Median overall FFP/RBC ratio 1.7
24-hour mortality 23 (47)
In-hospital mortality 26 (53)
FFP, fresh frozen plasma; INR, international normalized ratio; ISS, Injury Severity
Score; PTT, partial thromboplastin time.
* Data are given as number (percentage) unless otherwise indicated.
Am J Clin Pathol 2012;137:566-571 567
567 DOI: 10.1309/AJCPQZNCHM5PIK8O 567
Tan et al/ Transfusion Protocol With Higher FFP/RBC Ratio

3 had more FFP than 1:1, and 6 had less FFP than 1:4. The lat-
ter 2 groups were considered outliers. Since our original goal
was to approximate a ratio of 1:2, we segregated the 40 cases
further into 2 groups of 1:1 to 1:2 and 1:2 to 1:4 ratios to help
identify issues that affected the effective deployment of the
MTP. For comparison, demographic data, blood component
use, and outcome variables were obtained for the historic
rFVIIa cohort.
Among the 40 patients who received FFP and RBC
within the 1:1 to 1:4 ratio, 28 received a higher ratio of 1:1 to
1:2 and 12 received a lower ratio of 1:2 to 1:4 Table 2. The
number of universal group O PRBCs received by the 1:2 to
1:4 group was slightly higher, but the median total number of
PRBCs transfused (16-17 U) was not significantly different
for the 2 groups. The 1:1-1:2 group received more aggressive
replacement of coagulation factors with plasma, platelets, and,
therefore, total components (45 vs 31).
High mortality (92%) was observed in the 1:2-1:4 group;
all deaths occurred within 6 hours of admission with a mean
of 3.12 hours. Only 1 patient survived to discharge at hospital
day 45. The 1:2-1:4 group presented with a much higher mean
ISS of 41. In contrast, the 1:1-1:2 group had a mean ISS of 26,
in-hospital mortality of 25%, and 24-hour mortality of 18%.
The mean hospital stay for nonsurvivors was 3.3 days. The
mean hospital stay for survivors was 27.3 days with 13.7 ICU
days and 8.6 ventilator days. We believe the higher number
of blood components received reflects a survival bias in the
1:1-1:2 group.
The historic rFVIIa cohort had a mean ISS of 34 and an
in-hospital mortality of 41%, not statistically significant from
the referent 1:1-1:2 group. The median FFP/RBC was 1:1.9,
but the total number of blood products transfused was much
higher than in the current MTP cohort (73 vs 45). Compared
with the 1:1-1:2 MTP group, the historic rFVIIa cohort dem-
onstrated a trend toward a longer hospital stay (mean, 29 vs
21 days), more days in ICU (17 vs 14), and more days on the
ventilator (16 vs 9), but these trends did not reach statistical
significance.
Logistic regression analysis showed that an ISS of 25 or
more is an independent predictor of overall mortality (odds
ratio, 9.5; 95% confidence interval [CI], 1.64-54.85). Being
in the 1:2-1:4 MTP group compared with the 1:1-1:2 group
was associated with increased overall mortality after adjust-
ment for age and ISS (odds ratio, 36; 95% CI, 2.49-508.71).
Cox proportional hazards modeling showed that ISS did
not predict the length of hospital or ICU stay or duration of

Table 2
Blood Component Transfusion, Demographic Characteristics, and Outcome by Cohort*

FFP/RBC Ratio

1:1-1:2 (n = 28) 1:2-1:4 (n = 12) rFVIIa Cohort (n = 17) P

Mean (SD) age (y) 36.9 (17.6) 41.1 (17.3) 33.7 (18.7) .553
Sex .867
Male 26 (93) 11 (92) 15 (88)
Female 2 (7) 1 (8) 2 (12)
Blunt mechanism of injury 13 (46) 8 (67) 11 (65)
Mean (SD) ISS 26 (15.1) 41 (18.6) 34 (22.1) .05
ISS .028
Low (<25) 15 (54) 1 (8) 7 (41)
High (>25) 13 (46) 11 (92) 10 (59)
24-hour mortality 5 (18) 11 (92) 2 (12) <.0001
In-hospital mortality 7 (25) 11 (92) 7 (41) .0005
Mean (range) hospital LOS (d) 21.3 (0.2-82) 3.8 (0.8-44.5) 29.2 (1-82) .006
Survivors 27.3 (7-82) 44.5 39.1 (20.8-75.9)
Nonsurvivors 3.3 (0.2-19) 0.13 (0.08-0.22) 13.7 (0.25-81.9)
Mean (range) ICU LOS (d) 13.7 (1-49) 44.5 16.8 (1-65) .003
Mean (range) ventilation days 8.6 (0-52) 44.5 15.6 (1-73) .008
Median (range) blood component transfusions
Type O RBCs 6 (0-22) 9.5 (3-60) 6 (0-18)
Total RBCs 16 (10-48) 17 (10-61) 28 (11-47)
Type AB FFP 2 (0-13) 2 (0-18) 2 (0-5)
Total FFP 10 (5-31) 7 (3-28) 13 (2-35)
FFP/RBC 1:1.5 (1:1-1:1.9) 1:2.8 (1:2-1:4) 1:1.9 (1:1-1:3.1)
Platelets 15 (5-30) 5 (0-55) 20 (10-65)
Cryoprecipitate 0 (0-50) 0 (0-20) 10 (0-70)
Total blood components 45 (21-131) 31 (13-164) 73 (29-217)

FFP, fresh frozen plasma; ICU, intensive care unit; ISS, Injury Severity Score; LOS, length of stay; NS, not significant; rFVIIa, recombinant activated factor VII.
* Data are given as number (percentage) unless otherwise indicated.
Only 1 survivor in the group.
Number of units.

568 Am J Clin Pathol 2012;137:566-571 American Society for Clinical Pathology

568 DOI: 10.1309/AJCPQZNCHM5PIK8O
 Coagulation and Transfusion Medicine / Original Article

ventilator support. Being in the 1:1-1:2 MTP cohort compared Table 3

with the rFVIIa cohort was not associated with length of stay Complications in Patients Who Survived for More Than 24
Hours*
(hazard ratio [HR], 0.53; 95% CI, 0.24-1.16), ICU stay (HR,
0.51; 95% CI, 0.23-1.13), or ventilator days (HR, 0.40; 95% FFP/RBC Ratio rFVIIa Cohort
Complication 1:1-1:2 (n = 28) (n = 17)
CI, 0.18-90) after adjustment for age and ISS.
Complications seen in trauma patients who survive for Sepsis 7 (25) 6 (35)
more than 24 hours include sepsis, thrombosis, and acute lung Gram-negative rod 3 (11) 4 (24)
Staphylococcus aureus 1 (4) 2 (12)
injury. These complications are shown in Table 3 for the Coagulase-negative Staphylococcus 3 (11) 3 (18)
MTP cohort (1:1-1:2 group) and the historic rFVIIa cohort. Candida albicans 0 (0) 1 (6)
Thrombosis 4 (14) 1 (6)
The lone survivor from the 1:2-1:4 group (data not included Deep vein thrombosis 1 1
in the table), had documented bacteremia with gram-negative Pulmonary embolism 2 0
Arterial thrombosis 1 0
rods. The most common organisms isolated in the MTP and Pulmonary complications
rFVIIa survivors were gram-negative rods and coagulase-neg- Respiratory failure 2 (7) 1 (6)
Pneumonia 7 (25) 2 (12)
ative Staphylococcus. There was 1 case of Candida albicans
and 1 case of polymicrobial sepsis in the rFVIIa cohort. The rFVIIa, recombinant activated factor VII.
* Data are given as number (percentage) or number of cases.
incidence of thrombosis was low in both groups and not sta-
tistically significant. Acute lung injury is a major concern in
trauma patients who receive massive transfusion and aggres-
sive plasma replacement, but the incidence in our MTP series major observation is that the majority (63%) of the severely
was not statistically different from the historic cohort. The injured patients received component therapy at a ratio of 1:1
mean duration of ventilator support was actually longer in the to 1:2 FFP/RBC, with low use of type AB plasma and no need
rFVIIa cohort than in the MTP 1:1-1:2 cohort (16 vs 9 days). for rescue rFVIIa. The MTP patients received significantly
In Table 4 we list the outlier patients who received fewer total blood components than the historic rFVIIa cohort.
greater than 1:1 FFP/RBC resuscitation or less than 1:4 FFP/ MTP was not associated with any increase in lung injury or
RBC. The latter group of 6 patients had a median ISS of 25 infectious complications.
and died at a median of 3.6 hours after arrival. In 3 of the 6 The patients who received less than the optimal FFP/
outlier cases with a low plasma ratio, 5 to 8 plasma units had RBC ratio per our institutional MTP had a much higher ISS
been issued, but more than half were returned because the and very high mortality. Some studies point to improved
patient died. prehospital trauma care, which results in more severely
injured trauma patients who are transported to hospitals but
die shortly after arrival.8 The nonsurvivors in our study who
received a low FFP/RBC ratio died within 3 hours after hos-
Discussion
pital arrival. Survival bias is introduced as patients who died
This study examined blood component use in trauma early were pegged at a low FFP/RBC ratio.9,10 Patients who
patients after implementation of a new MTP protocol. The survived longer were able to receive more component therapy.

Table 4
Transfusion Data, Clinical Issues, and Outcome of the Outliers*

Outcome No. of Days

ISS FFP RBC PLT CRYO (A/D) to Death Comment

Recipients of >1:1 FFP/RBC

1 20 37 36 75 30 D 10.3 HCV/HIV, ARDS, pedestrian struck
2 25 24 18 25 0 D 0.96 MVA, arrived via helicopter; cardiac arrest on arrival
3 17 30 27 25 10 A GSW, arrived via helicopter
Recipients of <1:4 FFP/RBC
1 33 4 24 10 0 D 0.18 Multiple stab wounds
2 29 6 27 10 0 D 0.11 MVA with liver laceration
3 17 3 16 5 0 D 0.4 GSW; cardiac arrest on arrival
4 42 1 13 10 0 D 0.35 GSW; 7/8 FFP units returned
5 20 2 14 5 0 D 0.06 25-ft fall, bilateral flail chest, 3/5 FFP units returned
6 17 2 21 5 0 D 0.08 GSW; 4/6 FFP units returned

A, alive; ARDS, acute respiratory distress syndrome; CRYO, cryoprecipitate; D, died; FFP, fresh frozen plasma; GSW, gunshot wound; HCV, hepatitis C virus; MVA, motor
vehicle accident; PLT, platelets.
* Data for FFP, RBC, PLT, and CRYO are given as number of units.

American Society for Clinical Pathology Am J Clin Pathol 2012;137:566-571 569

569 DOI: 10.1309/AJCPQZNCHM5PIK8O 569
Tan et al/ Transfusion Protocol With Higher FFP/RBC Ratio
Death due to trauma has a trimodal distribution: early
deaths occur within hours and are considered preventable
with optimal trauma care to prevent exsanguination.2,7 With
the improvement in trauma resuscitation, studies have shown
a shift in the distribution toward survival from early death.7
However, there is increased morbidity associated with cel-
lular damage due to ischemia reperfusion injury subsequently
resulting in multiple organ dysfunction, such as acute respi-
ratory distress syndrome, renal failure, cardiac dysfunction,
infection, and sepsis.3,11
Several studies have shown improvement in survival with
a high ratio of FFP/RBC resuscitation, starting with combat
casualties and later extrapolated to civilian trauma.7,12-15
The relationship between volume of blood loss, reduction of
coagulation factors, platelet levels, and the functionality of the
hemostatic system is difficult to establish in trauma patients
despite mathematical modeling.16 Routine coagulation studies
such as INR and PTT may not reflect ongoing coagulopathy.3
The bodys physiologic response to injury often results in aci-
dosis and hypothermia, and, together with coagulopathy, this
triad is a vicious circle and often results in exsanguination.3,5,6
Two important factors in restoring hemostasis are time to
coagulation factor replacement and amount replaced. Timely
and adequate replacement of coagulation factors results in
better control of bleeding in the setting of damage-control sur-
gery. Most trauma hospitals now have institutional algorithms
that include fixed FFP/RBC ratios and universal group AB
plasma availability. FFP and thawed plasma contain all the
coagulation factors, including procoagulants and anticoagu-
lants including antifibrinolytic factors. The optimal FFP/RBC
ratio is not known. Although military data suggest 1:1, more
recent civilian trauma experience suggests that the optimal
ratio is closer to 1:2.12,17 Davenport et al17 reported that the
hemostatic effects of FFP may be maximal at ratios of 1:2 in
a prospective study quantifying the changes in clot strength
by rotational thromboelastography with different ratios. When
this ratio is achieved early, it may preempt secondary dilu-
tional coagulopathy and lead to an overall decrease in blood
component use, with no increase in the observed incidence of
lung injury or nosocomial infection.
rFVIIa induces hemostasis at the site of tissue injury by
complexing with exposed tissue factor to activate factor X
and enhancing factor Xa production on activated platelets
to generate additional thrombin. It obviates the concern for
volume overload with large-volume plasma administration
and is associated with decreased blood component use and
even cost.18-20 However, thrombosis is a major complication
of rFVIIa use, and there is no proven mortality benefit.21,22
Our institutional practice of using low-dose rFVIIa probably
accounts for the low baseline incidence of thrombosis in the
historic cohort of trauma patients who had received rescue
rFVIIa after massive transfusion.23
570 Am J Clin Pathol 2012;137:566-571
570 DOI: 10.1309/AJCPQZNCHM5PIK8O
Since the institution of an MTP at our institution incor-
porating a higher FFP/RBC ratio, the use of rFVIIa has
decreased tremendously. We estimate that the overall lower
blood component utilization and avoidance of rFVIIa use
leads to an average cost savings of $13,270 per MTP patient
based on blood charges by suppliers, including the technical
component20 Figure 1. It seems that earlier incorporation of
plasma in blood component resuscitation may indeed mitigate
trauma-induced coagulopathy, in conjunction with damage-
control surgery or embolization. However, with all the limita-
tions imposed by the retrospective nature of our study, there
is no evidence that MTP has improved mortality in this subset
of severely injured patients.
The limitations of our study are in keeping with those of
any small single-institution retrospective analysis. These limi-
tations should not discourage trauma centers from examining
their empiric practice of adopting new MTPs because trauma
demographics and blood component practice and transport
within hospitals vary. For instance, our institution has a
relatively high proportion of blunt trauma, thawed plasma
had been in use for some time before the current MTP, and
the blood bank is located in proximity to the operating room.
Reliance on type AB plasma should be monitored because it
is a scarce resource and because there is an anecdotal associa-
tion between type AB plasma use and morbidity.24 Although
a recent report suggests that cryoprecipitate may be associ-
ated with improved outcomes,25 our experience suggests that
fibrinogen replacement is often adequate with the current
MTP (data not shown). The optimal use of cryoprecipitate
merits further study before its universal incorporation into
an MTP. Finally, the timing of early plasma administration,
90 $40,000
RBC
80 FFP $35,000
PLT
70
CRYO $30,000
Mean No. of Units
Mean Unit Cost
60 Total
$25,000
50
$20,000
40
$15,000
30
$10,000
20
10 $5,000
0 $0
MTP Historic MTP Historic
No. of Blood Blood Components
Components Cost
Figure 1 Comparison of blood component use and cost
between current massive transfusion protocol (MTP)
and historic recombinant factor VII (rFVII) cohorts. CRYO,
cryoprecipitate; FFP, fresh frozen plasma; PLT, platelets.
American Society for Clinical Pathology

within the first 6 hours, is critical.15 We will be prospectively
monitoring the exact timing of plasma administration in an
ongoing effort to optimize our MTP.
From the 1Department of Pathology and Laboratory Medicine,
Boston University Medical Center, Boston, MA; and 2Department
of General Surgery, Boston University Medical Center, Boston.
Address reprint requests to Dr Tan: Dept of Pathology and
Laboratory Medicine, Boston University Medical Center, One
Boston Medical Center Place, Boston, MA 02118.
Acknowledgment: We thank Christine Lloyd-Traviglini for
her assistance in statistical analysis.
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Am J Clin Pathol 2012;137:566-571 571
571 DOI: 10.1309/AJCPQZNCHM5PIK8O 571
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