Blood Reviews 23 (2009) 149155

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Blood Reviews
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REVIEW

Blood and coagulation support in trauma

Sarah B. Murthi a, Lynn G. Stansbury b, John R. Hess c,*
a
Division of Trauma and Critical Care Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
b
Division of Trauma Anesthesia, University of Maryland School of Medicine, Baltimore, MD, USA
c
The Departments of Pathology and Medicine, University of Maryland Medical Center, Blood Bank, N2W50a, 22 South Greene Street, Baltimore, Maryland 21201, USA

a r t i c l e i n f o a b s t r a c t

Keywords: Injury is the leading cause of death in young people and a major cause of loss of years of productive life
Transfusion medicine world wide. Acute surgical care can prevent injury from turning into disability or death but requires
Blood bank protocols prompt access to safe blood products to support resuscitation and restorative surgical procedures. Speed
Trauma center protocols
in delivering blood products is critical in resuscitation. Achieving prompt blood product support requires
Hemorrhage control
advanced planning and an informed balancing of risks to insure the availability of red cells and coagula-
Uncrossmatched blood use
tion products at the time and place where they are needed. Safety and diagnostic support are critical in
the post-resuscitative period where transfusion complications can delay reconstructive surgery and pro-
long intensive care unit stays. This paper reviews the epidemiology of injury and modern patterns of
trauma care against the background of developing knowledge about the coagulopathies of trauma and
blood safety.
2008 Elsevier Ltd. All rights reserved.

Introduction surgeon remain a model of clinical and intellectual collaboration

Injury is the most common cause of loss of life in people aged
144 years in the world and is therefore the most common cause
of loss of years of productive life.1 Vehicular injury, interpersonal
violence, falls, war, and work-related injury are the major causes
of physical injury. Any of these forms of injury are best prevented
through education and social and engineering controls, but when
injury does occur, surgical care that prevents injury from turning
into death or disability is cost effective.2 Blood transfusion is a crit-
ical adjunct to the surgical care of injury.
The lifesaving role of blood transfusion was rst demonstrated
in large numbers of casualties from the battleelds of World War
I.3 The beautifully written papers and books of Roger Lee, Oswald
Robertson, Walter Cannon, and Harvey Cushing, all of the Harvard
Medical Unit, remain useful sources about blood transfusion and
care of the injured.49 These men each saw and treated hundreds
of casualties a day. Between them, they described citrate as an
anticoagulant for blood, the nal phases of the human coagulation
cascade, the rst coagulation test, universal donor blood transfu-
sion, the essential elements of modern blood banking, the critical
timing of transfusion in the injured, the importance of adjunctive
care of the injured to control the coagulopathies of injury, and
the integration of modern surgical techniques into emergency care.
Their interactions as hematologist, blood banker, physiologist, and
* Corresponding author. Tel.: +410 328 3834; fax: +410 328 6816.
E-mail address: jhess@umm.edu (J.R. Hess).
for improvement of injury care.
The basic clinical problems that these pioneers rst addressed
remain important for us today: how to make blood available
quickly; how to insure its safety; when in the course of clinical care
to give blood; and how to treat the coagulopathies that often make
surgical care futile. Scientic and technical advancement have
given us better and safer blood products, clinical epidemiology
provides key insights about when to treat, and social and technical
developments provide better tools and environments for diagnosis
and care. Now, massively injured patients, who would have been
triaged in the past, expect not early death, but sophisticated clini-
cal skill and the deployment of massive resources. This paper will
attempt to address these problems from the current state of
knowledge and art.
Making red blood cells available quickly
While inspecting a French military hospital in April 1915, Har-
vey Cushing saw a young battle casualty with a supercial wound,
a large subcutaneous hematoma and extreme pallor. He wrote in
his journal that, the man would probably have beneted from a
blood transfusion if any provision had been made to provide one.9
Provision must be made so that blood for transfusion will be avail-
able, safe, effective, and cheap. Even modest clinical impediments
to transfusion cost lives. In his personal diary from 1917, Oswald
Robertson wrote, we cleared 900 casualties last night. . . (giving)
only a few transfusions, there just wasnt time for more. (Robert-
son OH, unpublished diaries) Such experiences led Robertson and

0268-960X/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.blre.2008.12.001
150 S.B. Murthi et al. / Blood Reviews 23 (2009) 149155
his commander, Roger Lee, to develop the ideas and technical capa-
bility to test blood for ABO type and syphilis, collect whole blood
anti-coagulated with citrate into one-liter glass bottles and to pack
and ship these bottles packed in ice in old ammunition cases to for-
ward surgical units. These basic insightssafe collection and stor-
age of blood, testing for potential adverse immunologic and
infectious consequences, and the capacity for rapid deployment
to areas of needremain central to modern blood-banking.
In 2004, the most recent year for which the Centers for Disease
Control has compiled complete statistics, more than 93,000 Amer-
icans died as a result of physical injuries, 4% of total mortality for
that year.10 Of these, only about half reached a hospital alive.11,12
On the battleeld, where injuries are generally more severe, almost
80% of the injured die before they reach care.13,14 Uncontrolled
hemorrhage is the leading cause of pre-hospital and early death13
in civilians and is the primary cause of death in 40% of soldiers who
die on the battleeld.15 Once patients reach care, treating uncon-
trolled hemorrhage offers the greatest potential to save lives.
Uncontrolled hemorrhage is rapidly fatal. The exact time to
death for any given untreated injured person will be a function
of their underlying health, rate of bleeding, concomitant injuries,
and other environmental stresses. In a series of 6000 consecutive
battle deaths in Vietnam, 40% of the injured died instantly, 65%
were dead in 5 min, 80% were dead in 30 min and 90% of all deaths
had occurred within 2 h of injury.14 Thirty years later, and even
after arrival at advanced trauma centers, hemorrhagic deaths still
occur quickly. In a review of all deaths over a 10 year period at
our center, the R Adams Cowley Shock Trauma Center (STC) of
the University of Maryland Medical System, time to hemorrhagic
death, even among patients who survived for at least 15 min, had
a median of just over 2 h. In this group, 42% were dead in
90 min, 63% were dead by 3 h, 82% were dead by 6 h, and 90% were
dead in 12 h. [R Dutton, personal communication] Most of these
fatal hemorrhagic injuries were truncal, in large part because most
severe bleeding from extremity injuries can be controlled with di-
rect pressure. Control of most treatable life-threatening hemor-
rhage requires access to the insides of the chest, abdomen, or
pelvis, and modern trauma care is based on the capacity to achieve
skilled surgical or radiologic intervention in the least possible time.
In this setting, prompt blood transfusion replaces blood losses,
treats shock, and buys time for these interventions to succeed.
Over the last 30 years, advanced trauma care in the US and Can-
ada has regionalized and become standardized so that there are
now 1082 trauma centers in North America accredited by the
American College of Surgeons.16 These admit more than half of
the 1.2 million people admitted to hospitals for physical injuries
in the US each year.2 The largest proportion of these patients have
relatively minor injuries and do not require transfusion. Gaining
useful insights into the transfusion support of those who are criti-
cally injured requires being able to separate the relatively small
number of severely and profoundly injured amongst a ood of
mildly and moderately injured patients.
In 2004, Como and his colleagues reviewed blood use for pri-
mary trauma admissions to the STC in calendar year 2000.17 In that
period, 5649 patients were admitted, only 9% of whom required
any blood products and only 8% of whom required RBC. Overall,
5229 units of red cells (RBC) were transfused, giving use rates of
0.9 units per injured patient and 10.2 units per transfused patient.
These rates are probably higher than typical because the STC is the
primary adult receiving center for the State of Maryland emer-
gency medical system, and many severely injured trauma patients
are brought directly to the STC under protocol by the Maryland
State Police helicopter evacuation teams while less severely in-
jured patients from the same areas are delivered by ground ambu-
lances to local hospital emergency rooms, increasing the
proportion of severely injured patients seen at our center. The
blood use rates are also high because resource planning for the
STC incorporates the expectation of simultaneous admission of
multiple, severely injured casualties. As a result, there is relatively
little triage or under-treatment of potentially salvageable injured
patents. Withal, over the 12 month period of the Como study, the
STC admitted only 90 patients who received 10 or more units of
blood in the rst 24 h of care, thus meeting a common denition
of massive transfusion.
In this same study, RBC use was greatest early after admission
when the largest numbers of patients with uncontrolled hemor-
rhage were alive. Sixty-one percent of all RBC transfused in the
course of direct admissions were given in the rst 24 h of care,
and 11% of all the RBC units given to these patients were given
in the rst hour of care as un-cross-matched group O universal-do-
nor RBC. Just slightly less than 3% of all admissions, 164 patients,
used any RBC in the rst hour of care. Use ranged from 1 to 14 units
and was associated with a 51% overall survival.17 Rate of bleeding,
as evidenced by the clinical decision to transfuse, was the most
important predictor of survival: 64% of patients who required only
1 or 2 units of uncrossmatched group O RBC in the rst hour sur-
vived; 49% of those requiring 3 or 4 units survived; 24% requiring
transfusion of 58 units survived; and 10% of those requiring 9 or
more units survived. Put more simply, the slightly-more-than-half
of patients who received only one or two units of uncrossmatched
red cells in the rst hour of care had a 64% survival, whereas those
who received more than two units had a 70% mortality.
The STC meets this episodic urgent need for red cells, in con-
junction with the blood bank, by maintaining a self-service blood
refrigerator in the Trauma Receiving Unit (TRU). (The blood bank,
while located on the same hospital oor, is more than 300 m
away.) This refrigerator contains 10 units of group O Rh positive
and 2 units of group O Rh negative red cells at all times. (The 2
units of O Rh negative red cells are there to initiate resuscitation
in women of childbearing age.) This system works because 75%
of young trauma victims are male, 85% of the US population is
Rh positive with even higher percentages in ethnic minorities in
whom traumatic injury is more common, and a third of injured
women presenting to the trauma center are greater than childbear-
ing age. Thus, of 160 patients a year who receive uncrossmatched
red cells, only 40 are women, only 6 are Rh negative, only 4 are of
childbearing age, only two will receive more than two units of red
cells, and less than one such patient a year is expected to survive.18
This risk can be reduced further by training the surgeons and TRU
nurses to call for the early release of additional uncrossmatched
group O Rh negative units when a young female patient with mas-
sive injury arrives. The net result of this system is that more than
500 valuable group O Rh negative red cell units are saved each year
to be given to patients who will benet from them.
The risk of Rh allo-immunization of women of childbearing age
are further reduced by post-exposure prophylaxis with RhIg given
within three days of exposure and by the immuno-suppression
associated with severe trauma.19 While older data suggested that
50% of Rh negative women exposed to one unit and 80% of women
exposed to multiple units of Rh positive red cells became allo-
immunized, the rate appears to be much lower in trauma pa-
tients.20 Dutton et al. found only 10 patients allo-immunized to
any of the common red cell antigens among 76 Rh negative trans-
fused survivors, though it must be admitted that follow-up was not
long in many cases.18
There are several other situations that can occur with the use
of uncrossmatched group O red cells that deserve mention
(Table 1).21 First, there are rare group-O donors who have very high
titers of anti-A or less commonly anti-B.22 Transfusing such blood
can cause acute intravascular hemolytic reactions through passive
transfer of the donor antibodies, which, as IgM, will x comple-
ment.23 At our center, we transfuse apheresis platelets, containing
 S.B. Murthi et al. / Blood Reviews 23 (2009) 149155 151

Table 1
The potential complications of using blood products, especially uncrossed group-O red cells and out of type platelets.

Complications: Causes: Frequency:

Acute hemolytic transfusion reactions 1. Mis-transfusion of non-group O RBC cross- matched to another patient in the Common 1:2000
trauma center (more common than all other causes)
2. Patients not compatible with Group O red cells such as Bombay phenotype with Rare 1:600,000
anti-H (131 cases and families worldwide)
3. Individual Group O RBC units with high titer anti-A or anti-B Uncommon
4. Rare hemolytic alloantibodies such as anti-Vel Rare
5. Type incompatible platelets with high titer anti-A or anti-B Uncommon
Delayed hemolytic transfusion reactions 1. Patients with minor antibodies (Kell, Duffy, Kidd, etc.) given minor-antigen- Common 1:500
positive units before antibody screen available
2. Patients previously alloimmunized but now with no detectable alloantibodies, Common 1:1000
leading to an amnestic response at 6 days
3. Patients newly alloimmunized with RBC antibodies developing at 212 weeks Common 1:200
Other transfusion reactions 1. Allergic urticarial, anaphylactoid, anaphylaxis Common to rare
2. Febrile non-hemolytic Common
3. Bacterial contamination Less common
4. Transfusion-related acute lung injury Less common
5. Transfusion-associate graft vs host disease Rare
6. Post-transfusion purpura Rare

A list of transfusion associated complications with an emphasis on those seen with the use of uncross-matched group O red cells and out-of-type platelets as are commonly
used in trauma patients. The estimates of frequency are from published sources where available.

ten times more plasma than do current RBC units in additive solu-
tion, across ABO incompatible lines several hundred times each
year and have not seen hemolytic reactions. However, adverse
reactions and fatalities are reported.2327 The reported incidence
of adverse reactions to platelet transfusion across ABO lines is
about one in 9000 group O platelet transfusions given to group A
individuals, but this incidence may increase now that more people
are looking for these reactions. The last reported death in the US
from ABO type incompatible platelets was reported four years
ago in an infant.24
A small number of people have preexisting allo-antibodies to
minor red cell antigen and are at risk for extravascular hemolysis.
This situation will generally be recognized as soon as a blood type
and antibody screen are performed. The trauma team needs to be
notied about this situation and the potential risk of a falling
hematocrit even after hemostasis is obtained. A similar situation
exists with patients who are allo-immunized but do not have
detectable antibodies. They are at high risk for an anamnestic reap-
pearance of their antibody with a delayed hemolytic transfusion
reaction 47 days after the transfusion episode. Again, warning
the surgical team of the presence of the recurrent antibody and
the possibility of delayed hemolysis many save the patient invasive
procedures looking for a cause of blood loss. Finally, there are rare
individuals, such as those of the Bombay phenotype, for whom no
compatible blood may be available. This genetic condition has been
reported in about 1:600,000 people, and these individuals will
make antibodies against otherwise-universal-donor group O
blood.28 A handful of units of this rare blood type are stored frozen
in rare-donor collections around the world, and if such a patient
survives the initial injury and resuscitation, type-compatible red
cells would be important in carrying such patients through a de-
layed hemolytic phase.
Once an ABO blood type is available, the use of group 0 uncross-
matched red cells for the resuscitation is converted to the patients
biologic blood type. This action both reduces the demand for the
valuable group O units, and provides a time for the blood bank to
activate the massive transfusion protocol and begin support with
appropriate ratios of red cells, plasma, and platelets. The historical
concern regarding the potential for hemolysis when biologically
group A or B patients who have been given initial transfusions of
universal-donor group O RBC are then given type-specic blood
are now less as type-specic conversion occurs sooner and blood
products are increasing screened for high-titer anti-A and anti-B.29
The coagulopathies of trauma
Coagulopathy is common after major trauma and has multiple
causes that can interact synergistically. Common causes include
loss and dilution of coagulation factors, hypothermia, acidosis,
coagulation factor and platelet consumption, and brinolysis (Ta-
ble 2).30 All of these must be actively anticipated and prevented
or treated in patients with ongoing hemorrhage.
The principle role of the clotting system is the maintenance of
vascular integrity after minor endothelial disruption, and vascular
integrity is the most important defense against bleeding. However,
vascular integrity is what has most often failed, often dramatically,
in the trauma patient. As an example of the importance of the
interplay between vascular integrity and the functional capacity
of the clotting system, leukemia patients undergoing chemother-
apy tolerate platelet counts of 520  109/L with minimal bleeding
if there are no preexisting defects in vascular integrity, but trauma
patients with less than 150  109/L platelets have excess mortality
after severe and profound injury.31 Similarly, patients on warfarin
for articial heart valves tolerate international normalization ratios
(INRs) of 5 with a small additional annual risk of bleeding and
hemorrhagic stroke, but trauma patients with INRs greater 1.3
have a marked increase in in-hospital mortality following severe
or profound injury.31
With major vascular disruption, the limited power of the clot-
ting system is easily overwhelmed. The effectors of the clotting
system, platelets and brinogen, are present in small amounts,
about 10 grams of each in the circulation of normal individuals.
Occasionally, in profoundly injured patients, the platelet count or
brinogen is low at the time of admission as a direct result of con-
sumption. Much more frequently, depletion of early factors in the
coagulation system results in prolongation of the plasma coagula-
tion times, the prothrombin time (PT) and partial thromboplastin
time (PTT). Brohi and his colleagues reported that a quarter of se-
verely injured patients brought to the trauma service of the Royal
London Hospital by helicopter had a prolonged PT at the time of
admission, when less than a liter of uids had been administered.32
In these patients, the more severe the injury, the greater was the
proportion with an abnormal PT. For equivalent injury, the pres-
ence of an abnormal PT predicted a much greater likelihood of
in-hospital death. MacLeod and her colleagues reported a similar
series of among 19,000 admissions to the Ryder Trauma Center
in Miami, where an abnormal PTT predicted a much higher likeli-
152 S.B. Murthi et al. / Blood Reviews 23 (2009) 149155
Table 2
The coagulopathies seen early in the care of trauma.
Mechanisms
Acute 1. Injury multiple endothelial microtears with exposure of tissue
Coagulopathy of factor and collagen
Trauma 2. Shock delayed clearance of thrombin
Dilutional 1. Physiologic vascular rell
Coagulopathy 2. Administration of asanguinous uids
3. Administration of plasma-poor RBC in additive solution
Hypothermic 1. Slowing of enzymes
Coagulopathy 2. Loss of vWF-GP IbIX mediated platelet activation
Coagulopathy of 1. Interference with coagulation factor complex assembly on
Acidosis negatively charged phospholipid surfaces
2. Decreased brinogen synthesis & increased destruction
Consumption 1. Intravenous tissue factor
2. Massive soft tissue injury
Fibrinolysis 1. Release of tPA
2. Failure to release TAFI
3. Inactivation of PAI-1
A list of primary mechanisms to consider in the evaluation of coagulopathic bleeding in severely injured patients. Under each primary mechanism are associated known or
probable contributing mechanisms. The references refer to the numbers of article cited in the bibliography.
hood of early death.33 This phenomenon has become known as the
acute coagulopathy of trauma or, based on Brohis subsequent
work showing that early post-trauma coagulopathy is highly asso-
ciated with the coexistence of shock, the acute coagulopathy of
trauma and shock (ACoTS).34 The authors group has reviewed
35,322 admissions to the STC over a 7-year period and demon-
strated a positive correlation between injury severity and the prev-
alence of abnormal results of the PT/INR, PTT, platelets and
brinogen.31 Increasingly abnormal results on any of the tests were
strongly associated with increased mortality.
Blood loss is the most obvious result of the disruption of a
closed vascular system. Blood loss in severely injured patients will
be 3040% of the blood volume in stage III shock with, at this de-
gree of loss, three obvious consequences. Blood pressure falls, oxy-
gen delivery decreases, and platelets and plasma proteins are lost.
Osmotic movement of tissue uids into the vascular space is a
physiologic attempt at vascular rell but also dilutes remaining
platelets and coagulation factors.35 Much of the conventional wis-
dom regarding volume resuscitation that emerged from the Viet-
nam War era was aimed at avoiding the renal failure and other
consequences of severe hypotension. However, asanguinous resus-
citation uids further dilute remaining platelets and coagulation
factors. In addition, the onset of mild hypotension with blood loss
slows blood loss through the holes in the vascular system and de-
creases pressure on new clots attempting to staunch that loss.
Bickell and his colleagues showed that civilian patients with pene-
trating torso trauma had improved survival when they were not
volume-resuscitated before surgery.36 The study echoes Walter
Cannons work from World War I suggesting that combat casual-
ties did best when made comfortable, kept warm, and not resusci-
tated until the time of surgery.7
Coldcore temperature hypothermiaalso exacerbates bleed-
ing. The enzymes of the plasma coagulation cascade all are less ac-
tive at lower temperatures, with activities that fall by about 10% for
every 1 C decrease in body temperature.37 While these changes
are important, even more important is the loss of platelet function
that occurs between 34 and 30 C. In this range, the normal activa-
tion of platelets caused by adhesion is lost.38 Since platelet adhe-
sion to exposed collagen normally triggers activation with the
Associated Mechanisms References
Consumption of VII, platelets (There are only 60 nM of VII Armand43
and 15 mL of platelets in the body)
Activation of protein C with inactivation of Va, VIIIa, and PAI- Brohi46
1
Hypotension Lundvall35
Tissue swelling, compartment syndromes Rotondo56
Critical plasma dilution after 6U RBCs Hirshberg58
510% slowing for each degree C Wolberg37
Death from uncontrolled bleeding at core temperatures Kermode38
<32 C
Loss of coag activity Meng42
50% at pH 7.2
70% at pH 7.0
80% at pH 6.8
Loss of acute phase increase in brinogen Martini41
Brain, fat, or amniotic uid embolization Levi48
Depletion of initiation phase factors across multiple sites of Armand42
injury
Reduced vascular ow, injury released ATP Hrafnkelsdottir51
Poor local thrombin burst Brohi46
Activation of Protein C Brohi46
secretion of procoagulants from platelet granules, the development
of active surfaces for coagulation factor assembly through the
exposure of negatively charged phospholipids, and aggregation
with other platelets to form the platelet plug that is the hallmark
of primary hemostasis, this means that cold patients do not clot.
Jurkovich and his colleagues showed this dramatically in a review
of hypothermic injured patients that demonstrated that the combi-
nation of multifocal bleeding and a core temperature of less than
32 C was not survivable.39 Again, the importance of keeping the
injured warm cannot be overemphasized. This applies both in
the eld, where the injured individual is usually unable to move
to generate body heat and is exposed to air movement and occa-
sionally water, resulting in increased convective loss of body heat,
and in the medical setting, where anesthesia, skin exposure, and
evaporative cooling from open surgical sites can lead to the loss
of 1 C every 40 min.40
Acidosis is another major cause of coagulopathy in the severely
injured. Acidosis occurs when blood ow is reduced by injury and
normally-aerobic metabolism shifts to anaerobic glycolysis with
the production of lactic acid. While acidosis has minor effects on
platelet function and the rate of brinogen catabolism, its major ef-
fect is on the assembly of plasma coagulation factors into active
complexes on the negatively-charged surfaces of activated plate-
lets.41,42 Some of the coagulation factors are enzymes and some
are cofactors, but the active enzymes are 10,00010,000,000 times
more active when assembled with their cofactors in a precise phys-
ical structure on the negatively charged phospholipid surface. This
assembly occurs because the vitamin K dependent coagulation fac-
tors chelate positively charged calcium ions against the negatively
charged surface. Higher concentrations of protons associated with
acidosis destabilize these complexes and reduce their activity.
Meng and her associates have shown that at equivalent concentra-
tions, the factor Xa factor Va complex is only a half as enzymat-
ically active at pH 7.2 as it normally is at pH 7.4. At pH 7.0 it is only
30% as active, and at pH 6.8 it is only 20% as active.42 Because sim-
ilar effects have been demonstrated with the factor VIIatissue fac-
tor complex and probably occur with the factor VIIIafactor IXa
complex, these effects are probably additive down the coagulation
cascade.42
 S.B. Murthi et al. / Blood Reviews 23 (2009) 149155
Coagulation factor and platelet concentrations also fall because
of consumption. As noted above, the total amounts of all of the
coagulation factors and of platelets are small compared to the sur-
faces and volumes of injury in severe trauma.43 If all of the plate-
lets in the circulation were lined up side-by-side, they would
cover 5 square meters, but there are enough capillaries in the lung
to cover half a tennis court and in the body to cover a football
eld.44 There is enough tissue factor exposed on 300 g of muscle
cells to bind all of the factor VII in the body.45 Despite these dispar-
ities, reduced platelet counts are unusual at presentation in all but
the most severely injured. Brohi and his colleagues have suggested
that activation of small amounts of thrombin in the initiation
phase of coagulation at many small sites of injury leads to the acti-
vation of small amounts of factors V and VIII.46,47 Meanwhile, the
thrombin is carried or diffuses to thrombomodulin on adjacent
normal cells and leads to the activation of anticoagulant protein
C which inactivates the Va and VIIIa formed in the adjacent injury.
This process multiplied across millions of endothelial microtears
has the capacity to consume signicant amounts of factors V and
VIII while factor VII diffuses through the tears and is bound in tis-
sue deep to the site of endothelial injury. These processes may ex-
plain why the most common forms of the early coagulopathy
present as prolongations of the PT and PTT.
Consumption can also occur with the classic forms of dissemi-
nated intravascular coagulation associated with brain, fat, and
amniotic uid embolization.48 Brain is the richest source of tissue
factor in the body. Isolated moderate to severe brain injury was
associated with twice the frequency of a prolonged PT at presenta-
tion to care as isolated injury of equivalent severity at other body
sites.31 In their classic form, these injuries typically present with
low platelets and debrination, distinct from the initiation phase
factor decits seen in the more typical acute coagulopathy of trau-
ma and shock.
The role of shock in these factor consumptive processes is at
this point just a clinical association. However, a logical mechanism
would be to prolong the persistence of thrombin in the circulation.
Normally, thrombin free in the circulation is cleared rapidly on rst
pass through the lungs.49 Delaying its clearance can give it more
time to activate its many substrates. A decade ago the senior
author described an experiment where 5000 units of a bovine
thrombin highly contaminated with kallikrein was injected into
the femoral vein of a pig.50 The kallikrein led to profound shock
and the animals died with a clot from the injection site through
the heart to the lungs. When an equivalent amount of a puried
human thrombin was injected, it caused mild hypotension, but
no signicant clot as the thrombin was still rapidly transported
to the lungs and inactivated. This experiment showed the impor-
tance of reduced ow as a mechanism that gave time for thrombin
to do it work of building a clot and consuming coagulation factors.
Finally, activating brinolysis can have a similar effect, speeding
the breakdown of clots that have already formed and consuming
the late phase factors of the coagulation cascade. Fibrin is normally
broken down by plasmin which, in turn, is activated by tissue plas-
minogen activator (t-PA), which is released in response to cellular
injury.51 Three inactivators of this system are normally present, the
thrombin-activated brinolysis inhibitor (TAFI) which removes
lysine binding sites for plasmin from brin, alpha-2 anti-plasmin,
which inactivates plasmin, and plasminogen-activator inhibitor
(PAI-1), which inactivates t-PA.52 This system is frequently hyper-
active in shock because t-PA is released in response to injury and
low blood pressure, TAFI is not activated without a good thrombin
burst, anti-plasmin is consumed, and PAI-1 is broken down by
protein C.52 The experience of watching a surgical team obtain
vascular hemorrhage control only to have the entire eld break
out in diffuse oozing is a reminder of the power of the brinolytic
system.53
153
The end result of all of these mechanisms leading to coagulop-
athy is that the normally weak coagulation system can be made
substantially weaker and slower. It can be overwhelmed by antico-
agulant and brinolytic mechanisms. Acuity in diagnosis and, ulti-
mately, prevention of these coagulation abnormalities continues to
be a major thrust of current research into the coagulation support
of trauma care.
Preventing and treating coagulopathy
For many years, the acute trauma life support (ATLS) course of
the Committee on Trauma of the American College of Surgeons de-
ned the way seriously injured patients were resuscitated.54 Fol-
lowing the ATLS guidelines, when injured patients presented to
care, two large-bore IVs were started in peripheral veins. If the pa-
tient had a systolic blood pressure of less than 100 mmHg, two li-
ters of crystalloid uid were administered. If blood pressure did
not normalize, if it did normalize but subsequently fell below
100 mmHg again, or if ongoing bleeding exceeded 100 mL/min,
then red cell transfusion was to be initiated. This classic advice
was based on a report of the resuscitation of 18 patients, from an
era when whole blood was still being used in many centers.55
Several major lines of thinking have converged to end the crys-
talloid resuscitation era. First, it has become clear that the large
amounts of crystalloid uid given to massively injured patients,
sometimes as much as 1030 l, led to massive tissue swelling,
sometimes requiring decompressive laparotomy just to prevent
abdominal compartment syndrome where the swollen organs com-
press the inferior vena cava and interfere with blood return to the
heart.56 Second, the uids used, especially Ringers lactate solution
made with racemic lactate, were frankly proinammatory.57 Third,
with the wide use of red cells in additive solution as the primary red
cell product, patients received very little plasma in the course of
resuscitation.30 This meant that coagulation factors were progres-
sively diluted in the early phase of resuscitation. Coagulopathic de-
grees of factor depletion were typically reached after 6 units of red
cells in additive solution.58,59 Just as standards for crystalloid resus-
citation were being reconsidered based on these insights, the simul-
taneous recognition of the existence of an intrinsic coagulopathy of
trauma gave added impetus to the perception of the need for new
approaches to uid use in resuscitation.
If a quarter of seriously injured patients arriving at a trauma
center are coagulopathic on admission, and any others requiring
massive transfusion were going to become coagulopathic by the
time they received 6 units of red cells, then resuscitation with large
volumes of crystalloid is not going to be helpful in these patients.
In fact, simple calculation of the volumes and concentrations in-
volved in modern blood components meant that only by giving
red cells, plasma and platelets at essentially 1:1:1 unit ratios could
effective concentrations of all three components be maintained in
the massively transfused patients.43 This recognition led to the use
of thawed plasma as the primary resuscitation uid for the mas-
sively injured in the US Army Combat Support Hospital in Baghdad
with a dramatic reduction in ventilator times, apparently because
of reduced lung water, and seemingly to better hemorrhage control
and better survival. A retrospective review of this experience by
Borgman and his colleagues suggested that the benet in terms
of reduced mortality was dramatic, with a mortality of 66% in those
receiving greater than 10 units of red cells with a low plasma-to-
red-cell ratio and only 19% in those resuscitated with a ratio close
to 1:1.60 Holcomb and his colleagues conrmed this nding on a
similar retrospective study of massively transfused patients con-
ducted over a 1 year period at 16 large civilian trauma centers.61
The retrospective data in these studies are confounded by the
counting as low-ratio failures, patients who presented for care, re-
154 S.B. Murthi et al. / Blood Reviews 23 (2009) 149155
ceived rapid infusion of 10 units of red cells but then died before the
frozen plasma ever got thawed. However, the concept of hemostatic
resuscitation and the data are still impressive. First, these massively
bleeding patients need to be given volume of some kind, and any-
thing but plasma will only make their coagulopathy worse. Second,
the benets of avoiding crystalloid uids measured as reduced time
on ventilators and the ability to close abdominal surgery sites pri-
marily is an independent demonstration of the utility of the ther-
apy. Finally, the overall mortality of the military casualties is the
lowest ever reported during warfare, despite the prevalence of mas-
sive wounds caused by improvised explosive devices.
As a result of this work, many groups are now recommending
resuscitation of those who are undergoing massive transfusion with
a ratio of plasma to red cells of essentially 1:1.62 The US Army Sur-
geon General issued a eld directive in January 2006 recommending
the 1:1 ratio in the massively injured. In a review of the published
studies commissioned by the AABB and conducted by the Mayo
Clinics Knowledge and Encounter Research Unit, the reviewers con-
cluded that the sum of available published information supported
the idea unambiguously. Clearly, randomized prospective data
would be desirable, but this is extremely difcult to obtain in the
trauma setting where none of the patients can give informed con-
sent and the primary events themselves occur rapidly, infrequently,
and often in the middle of the night. In calendar year 2000, our cen-
ter saw only 90 patients who required massive transfusion.
Studies of the same patient groups noted above have also sug-
gested a survival benet for early use of platelets in massive resusci-
tation.61 Again, the data are retrospective and further confounded by
the fact that platelets in the US are platelets in plasma, but the timing
of the benet suggests that extra platelets early in resuscitation of
the massively injured help in both hemorrhagic and brain injured
patients. Obviously, this important clinical suggestion needs fol-
low-up. As noted earlier, admission platelet count is a powerful pre-
dictor of in-hospital mortality. Even within the normal range of
platelet counts, 150400  109/L, patients with severe injury with
admission platelet concentrations in the upper half the normal range
had 50% lower in-hospital mortality than those in the lower half.31
Johansson and his colleagues at the University of Copenhagen
have adopted these new insights most comprehensively. In 2004,
this group began a blood bank-driven program of identifying pa-
tients who were likely to be massively transfused and issuing red
cells and plasma in a 1:1 ratio with platelets given in even higher
unit to unit ratios. [Par Johansson personal communication] The
results of their consecutive series of patients undergoing ruptured
abdominal aortic aneurism repair have been published, with all
cause mortality down from 66% to 44% in the before and after co-
horts.63 In the two years after the change, they used the new
scheme in all 442 massively transfused patients including 231 pa-
tients undergoing abdominal and vascular surgery, 83 cardio-tho-
racic patients, 60 trauma patients, 38 orthopedic patients, 8 burn
patients, and 22 others. They compared this cohort to the similar
cohort of all 390 patients who received ten or more units of red
cells in the rst 24 h in their hospital in calendar years 2002 and
2003 and demonstrated a reduction in mortality at 90 days from
34.6% to 22.4%. This represents a 35% reduction in mortality and
savings of 50 lives over the two year period at a price of 3 addi-
tional pools of 4-units of whole blood-derived platelets per patient
given on the rst hospital day with a concomitant savings of 2
units of red cells over the course of admission.
Who might benet from changing the way we use blood
products?
Medical care goes through cycles. With the acquired immuno-
deciency syndrome (AIDS) epidemic, the description of transfu-
sion-related acute lung injury (TRALI), the recognition that
leukemic patients do not need prophylactic platelet transfusions
above platelet counts of 10  109/L, and the transfusion require-
ments in critical care (TRICC) trial have come the recognition that
many prophylactic uses of blood products are unnecessary and
dangerous. In the absence of evidence derived from acutely injured
patients, many had suggested that trauma patients did not need
large amounts of plasma and platelets in their initial resuscitation
either. The early data described above suggests that this attempt to
apply the data on the prophylactic use of blood products to the
treatment of massive hemorrhage may be misleading.
However, only 2% of civilian trauma patients and 8% of military
casualties require massive transfusion. Most hemodynamically sta-
ble injured patients can be spared the risks of blood products. In
such patients, the lessons of the TRICC trial and the wealth of evi-
dence about the lack of utility of prophylactic plasma apply.
But only half of civilian injured and 60% of the young military
casualties who receive more than 10 units of red cells in the rst
24 h of care survive. If the new information and guidelines on
hemostatic resuscitation are correct and a third of such patients
who presently die are salvageable with better resuscitation, this
is important information and can save thousands of lives each year.
Moreover, we owe it to the patients, the blood donors, and to
the citizenry that supports the most advanced trauma and blood
supply systems in the world, and our colleagues who work in them,
to continue the research that will dene best practice.
Conict of interest
One of the authors (J.R.H.) has US Government inventors rights
in the licensing fees and royalties to patents for advanced red cell
storage systems and hemorrhage control technologies. He serves as
a consultant to Novo Nordisk, Hemerus, Inc., and Haemostasis, LLC.
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