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Blood Reviews 23 (2009) 149155

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Blood Reviews
journal homepage: www.elsevier.com/locate/blre

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


for improvement of injury care.
Injury is the most common cause of loss of life in people aged The basic clinical problems that these pioneers rst addressed
144 years in the world and is therefore the most common cause remain important for us today: how to make blood available
of loss of years of productive life.1 Vehicular injury, interpersonal quickly; how to insure its safety; when in the course of clinical care
violence, falls, war, and work-related injury are the major causes to give blood; and how to treat the coagulopathies that often make
of physical injury. Any of these forms of injury are best prevented surgical care futile. Scientic and technical advancement have
through education and social and engineering controls, but when given us better and safer blood products, clinical epidemiology
injury does occur, surgical care that prevents injury from turning provides key insights about when to treat, and social and technical
into death or disability is cost effective.2 Blood transfusion is a crit- developments provide better tools and environments for diagnosis
ical adjunct to the surgical care of injury. and care. Now, massively injured patients, who would have been
The lifesaving role of blood transfusion was rst demonstrated triaged in the past, expect not early death, but sophisticated clini-
in large numbers of casualties from the battleelds of World War cal skill and the deployment of massive resources. This paper will
I.3 The beautifully written papers and books of Roger Lee, Oswald attempt to address these problems from the current state of
Robertson, Walter Cannon, and Harvey Cushing, all of the Harvard knowledge and art.
Medical Unit, remain useful sources about blood transfusion and
care of the injured.49 These men each saw and treated hundreds Making red blood cells available quickly
of casualties a day. Between them, they described citrate as an
anticoagulant for blood, the nal phases of the human coagulation While inspecting a French military hospital in April 1915, Har-
cascade, the rst coagulation test, universal donor blood transfu- vey Cushing saw a young battle casualty with a supercial wound,
sion, the essential elements of modern blood banking, the critical a large subcutaneous hematoma and extreme pallor. He wrote in
timing of transfusion in the injured, the importance of adjunctive his journal that, the man would probably have beneted from a
care of the injured to control the coagulopathies of injury, and blood transfusion if any provision had been made to provide one.9
the integration of modern surgical techniques into emergency care. Provision must be made so that blood for transfusion will be avail-
Their interactions as hematologist, blood banker, physiologist, and 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)
* Corresponding author. Tel.: +410 328 3834; fax: +410 328 6816.
only a few transfusions, there just wasnt time for more. (Robert-
E-mail address: jhess@umm.edu (J.R. Hess). 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- blood use rates are also high because resource planning for the
bility to test blood for ABO type and syphilis, collect whole blood STC incorporates the expectation of simultaneous admission of
anti-coagulated with citrate into one-liter glass bottles and to pack multiple, severely injured casualties. As a result, there is relatively
and ship these bottles packed in ice in old ammunition cases to for- little triage or under-treatment of potentially salvageable injured
ward surgical units. These basic insightssafe collection and stor- patents. Withal, over the 12 month period of the Como study, the
age of blood, testing for potential adverse immunologic and STC admitted only 90 patients who received 10 or more units of
infectious consequences, and the capacity for rapid deployment blood in the rst 24 h of care, thus meeting a common denition
to areas of needremain central to modern blood-banking. of massive transfusion.
In 2004, the most recent year for which the Centers for Disease In this same study, RBC use was greatest early after admission
Control has compiled complete statistics, more than 93,000 Amer- when the largest numbers of patients with uncontrolled hemor-
icans died as a result of physical injuries, 4% of total mortality for rhage were alive. Sixty-one percent of all RBC transfused in the
that year.10 Of these, only about half reached a hospital alive.11,12 course of direct admissions were given in the rst 24 h of care,
On the battleeld, where injuries are generally more severe, almost and 11% of all the RBC units given to these patients were given
80% of the injured die before they reach care.13,14 Uncontrolled in the rst hour of care as un-cross-matched group O universal-do-
hemorrhage is the leading cause of pre-hospital and early death13 nor RBC. Just slightly less than 3% of all admissions, 164 patients,
in civilians and is the primary cause of death in 40% of soldiers who used any RBC in the rst hour of care. Use ranged from 1 to 14 units
die on the battleeld.15 Once patients reach care, treating uncon- and was associated with a 51% overall survival.17 Rate of bleeding,
trolled hemorrhage offers the greatest potential to save lives. as evidenced by the clinical decision to transfuse, was the most
Uncontrolled hemorrhage is rapidly fatal. The exact time to important predictor of survival: 64% of patients who required only
death for any given untreated injured person will be a function 1 or 2 units of uncrossmatched group O RBC in the rst hour sur-
of their underlying health, rate of bleeding, concomitant injuries, vived; 49% of those requiring 3 or 4 units survived; 24% requiring
and other environmental stresses. In a series of 6000 consecutive transfusion of 58 units survived; and 10% of those requiring 9 or
battle deaths in Vietnam, 40% of the injured died instantly, 65% more units survived. Put more simply, the slightly-more-than-half
were dead in 5 min, 80% were dead in 30 min and 90% of all deaths of patients who received only one or two units of uncrossmatched
had occurred within 2 h of injury.14 Thirty years later, and even red cells in the rst hour of care had a 64% survival, whereas those
after arrival at advanced trauma centers, hemorrhagic deaths still who received more than two units had a 70% mortality.
occur quickly. In a review of all deaths over a 10 year period at The STC meets this episodic urgent need for red cells, in con-
our center, the R Adams Cowley Shock Trauma Center (STC) of junction with the blood bank, by maintaining a self-service blood
the University of Maryland Medical System, time to hemorrhagic refrigerator in the Trauma Receiving Unit (TRU). (The blood bank,
death, even among patients who survived for at least 15 min, had while located on the same hospital oor, is more than 300 m
a median of just over 2 h. In this group, 42% were dead in away.) This refrigerator contains 10 units of group O Rh positive
90 min, 63% were dead by 3 h, 82% were dead by 6 h, and 90% were and 2 units of group O Rh negative red cells at all times. (The 2
dead in 12 h. [R Dutton, personal communication] Most of these units of O Rh negative red cells are there to initiate resuscitation
fatal hemorrhagic injuries were truncal, in large part because most in women of childbearing age.) This system works because 75%
severe bleeding from extremity injuries can be controlled with di- of young trauma victims are male, 85% of the US population is
rect pressure. Control of most treatable life-threatening hemor- Rh positive with even higher percentages in ethnic minorities in
rhage requires access to the insides of the chest, abdomen, or whom traumatic injury is more common, and a third of injured
pelvis, and modern trauma care is based on the capacity to achieve women presenting to the trauma center are greater than childbear-
skilled surgical or radiologic intervention in the least possible time. ing age. Thus, of 160 patients a year who receive uncrossmatched
In this setting, prompt blood transfusion replaces blood losses, red cells, only 40 are women, only 6 are Rh negative, only 4 are of
treats shock, and buys time for these interventions to succeed. childbearing age, only two will receive more than two units of red
Over the last 30 years, advanced trauma care in the US and Can- cells, and less than one such patient a year is expected to survive.18
ada has regionalized and become standardized so that there are This risk can be reduced further by training the surgeons and TRU
now 1082 trauma centers in North America accredited by the nurses to call for the early release of additional uncrossmatched
American College of Surgeons.16 These admit more than half of group O Rh negative units when a young female patient with mas-
the 1.2 million people admitted to hospitals for physical injuries sive injury arrives. The net result of this system is that more than
in the US each year.2 The largest proportion of these patients have 500 valuable group O Rh negative red cell units are saved each year
relatively minor injuries and do not require transfusion. Gaining to be given to patients who will benet from them.
useful insights into the transfusion support of those who are criti- The risk of Rh allo-immunization of women of childbearing age
cally injured requires being able to separate the relatively small are further reduced by post-exposure prophylaxis with RhIg given
number of severely and profoundly injured amongst a ood of within three days of exposure and by the immuno-suppression
mildly and moderately injured patients. associated with severe trauma.19 While older data suggested that
In 2004, Como and his colleagues reviewed blood use for pri- 50% of Rh negative women exposed to one unit and 80% of women
mary trauma admissions to the STC in calendar year 2000.17 In that exposed to multiple units of Rh positive red cells became allo-
period, 5649 patients were admitted, only 9% of whom required immunized, the rate appears to be much lower in trauma pa-
any blood products and only 8% of whom required RBC. Overall, tients.20 Dutton et al. found only 10 patients allo-immunized to
5229 units of red cells (RBC) were transfused, giving use rates of any of the common red cell antigens among 76 Rh negative trans-
0.9 units per injured patient and 10.2 units per transfused patient. fused survivors, though it must be admitted that follow-up was not
These rates are probably higher than typical because the STC is the long in many cases.18
primary adult receiving center for the State of Maryland emer- There are several other situations that can occur with the use
gency medical system, and many severely injured trauma patients of uncrossmatched group O red cells that deserve mention
are brought directly to the STC under protocol by the Maryland (Table 1).21 First, there are rare group-O donors who have very high
State Police helicopter evacuation teams while less severely in- titers of anti-A or less commonly anti-B.22 Transfusing such blood
jured patients from the same areas are delivered by ground ambu- can cause acute intravascular hemolytic reactions through passive
lances to local hospital emergency rooms, increasing the transfer of the donor antibodies, which, as IgM, will x comple-
proportion of severely injured patients seen at our center. The 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- The coagulopathies of trauma
tion, across ABO incompatible lines several hundred times each
year and have not seen hemolytic reactions. However, adverse Coagulopathy is common after major trauma and has multiple
reactions and fatalities are reported.2327 The reported incidence causes that can interact synergistically. Common causes include
of adverse reactions to platelet transfusion across ABO lines is loss and dilution of coagulation factors, hypothermia, acidosis,
about one in 9000 group O platelet transfusions given to group A coagulation factor and platelet consumption, and brinolysis (Ta-
individuals, but this incidence may increase now that more people ble 2).30 All of these must be actively anticipated and prevented
are looking for these reactions. The last reported death in the US or treated in patients with ongoing hemorrhage.
from ABO type incompatible platelets was reported four years The principle role of the clotting system is the maintenance of
ago in an infant.24 vascular integrity after minor endothelial disruption, and vascular
A small number of people have preexisting allo-antibodies to integrity is the most important defense against bleeding. However,
minor red cell antigen and are at risk for extravascular hemolysis. vascular integrity is what has most often failed, often dramatically,
This situation will generally be recognized as soon as a blood type in the trauma patient. As an example of the importance of the
and antibody screen are performed. The trauma team needs to be interplay between vascular integrity and the functional capacity
notied about this situation and the potential risk of a falling of the clotting system, leukemia patients undergoing chemother-
hematocrit even after hemostasis is obtained. A similar situation apy tolerate platelet counts of 520  109/L with minimal bleeding
exists with patients who are allo-immunized but do not have if there are no preexisting defects in vascular integrity, but trauma
detectable antibodies. They are at high risk for an anamnestic reap- patients with less than 150  109/L platelets have excess mortality
pearance of their antibody with a delayed hemolytic transfusion after severe and profound injury.31 Similarly, patients on warfarin
reaction 47 days after the transfusion episode. Again, warning for articial heart valves tolerate international normalization ratios
the surgical team of the presence of the recurrent antibody and (INRs) of 5 with a small additional annual risk of bleeding and
the possibility of delayed hemolysis many save the patient invasive hemorrhagic stroke, but trauma patients with INRs greater 1.3
procedures looking for a cause of blood loss. Finally, there are rare have a marked increase in in-hospital mortality following severe
individuals, such as those of the Bombay phenotype, for whom no or profound injury.31
compatible blood may be available. This genetic condition has been With major vascular disruption, the limited power of the clot-
reported in about 1:600,000 people, and these individuals will ting system is easily overwhelmed. The effectors of the clotting
make antibodies against otherwise-universal-donor group O system, platelets and brinogen, are present in small amounts,
blood.28 A handful of units of this rare blood type are stored frozen about 10 grams of each in the circulation of normal individuals.
in rare-donor collections around the world, and if such a patient Occasionally, in profoundly injured patients, the platelet count or
survives the initial injury and resuscitation, type-compatible red brinogen is low at the time of admission as a direct result of con-
cells would be important in carrying such patients through a de- sumption. Much more frequently, depletion of early factors in the
layed hemolytic phase. coagulation system results in prolongation of the plasma coagula-
Once an ABO blood type is available, the use of group 0 uncross- tion times, the prothrombin time (PT) and partial thromboplastin
matched red cells for the resuscitation is converted to the patients time (PTT). Brohi and his colleagues reported that a quarter of se-
biologic blood type. This action both reduces the demand for the verely injured patients brought to the trauma service of the Royal
valuable group O units, and provides a time for the blood bank to London Hospital by helicopter had a prolonged PT at the time of
activate the massive transfusion protocol and begin support with admission, when less than a liter of uids had been administered.32
appropriate ratios of red cells, plasma, and platelets. The historical In these patients, the more severe the injury, the greater was the
concern regarding the potential for hemolysis when biologically proportion with an abnormal PT. For equivalent injury, the pres-
group A or B patients who have been given initial transfusions of ence of an abnormal PT predicted a much greater likelihood of
universal-donor group O RBC are then given type-specic blood in-hospital death. MacLeod and her colleagues reported a similar
are now less as type-specic conversion occurs sooner and blood series of among 19,000 admissions to the Ryder Trauma Center
products are increasing screened for high-titer anti-A and anti-B.29 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 Associated Mechanisms References


Acute 1. Injury multiple endothelial microtears with exposure of tissue Consumption of VII, platelets (There are only 60 nM of VII Armand43
Coagulopathy of factor and collagen and 15 mL of platelets in the body)
Trauma 2. Shock delayed clearance of thrombin Activation of protein C with inactivation of Va, VIIIa, and PAI- Brohi46
1
Dilutional 1. Physiologic vascular rell Hypotension Lundvall35
Coagulopathy 2. Administration of asanguinous uids Tissue swelling, compartment syndromes Rotondo56
3. Administration of plasma-poor RBC in additive solution Critical plasma dilution after 6U RBCs Hirshberg58
Hypothermic 1. Slowing of enzymes 510% slowing for each degree C Wolberg37
Coagulopathy 2. Loss of vWF-GP IbIX mediated platelet activation Death from uncontrolled bleeding at core temperatures Kermode38
<32 C
Coagulopathy of 1. Interference with coagulation factor complex assembly on Loss of coag activity Meng42
Acidosis negatively charged phospholipid surfaces 50% at pH 7.2
70% at pH 7.0
80% at pH 6.8
2. Decreased brinogen synthesis & increased destruction Loss of acute phase increase in brinogen Martini41
Consumption 1. Intravenous tissue factor Brain, fat, or amniotic uid embolization Levi48
2. Massive soft tissue injury Depletion of initiation phase factors across multiple sites of Armand42
injury
Fibrinolysis 1. Release of tPA Reduced vascular ow, injury released ATP Hrafnkelsdottir51
2. Failure to release TAFI Poor local thrombin burst Brohi46
3. Inactivation of PAI-1 Activation of Protein C Brohi46

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 secretion of procoagulants from platelet granules, the development
acute coagulopathy of trauma or, based on Brohis subsequent of active surfaces for coagulation factor assembly through the
work showing that early post-trauma coagulopathy is highly asso- exposure of negatively charged phospholipids, and aggregation
ciated with the coexistence of shock, the acute coagulopathy of with other platelets to form the platelet plug that is the hallmark
trauma and shock (ACoTS).34 The authors group has reviewed of primary hemostasis, this means that cold patients do not clot.
35,322 admissions to the STC over a 7-year period and demon- Jurkovich and his colleagues showed this dramatically in a review
strated a positive correlation between injury severity and the prev- of hypothermic injured patients that demonstrated that the combi-
alence of abnormal results of the PT/INR, PTT, platelets and nation of multifocal bleeding and a core temperature of less than
brinogen.31 Increasingly abnormal results on any of the tests were 32 C was not survivable.39 Again, the importance of keeping the
strongly associated with increased mortality. injured warm cannot be overemphasized. This applies both in
Blood loss is the most obvious result of the disruption of a the eld, where the injured individual is usually unable to move
closed vascular system. Blood loss in severely injured patients will to generate body heat and is exposed to air movement and occa-
be 3040% of the blood volume in stage III shock with, at this de- sionally water, resulting in increased convective loss of body heat,
gree of loss, three obvious consequences. Blood pressure falls, oxy- and in the medical setting, where anesthesia, skin exposure, and
gen delivery decreases, and platelets and plasma proteins are lost. evaporative cooling from open surgical sites can lead to the loss
Osmotic movement of tissue uids into the vascular space is a of 1 C every 40 min.40
physiologic attempt at vascular rell but also dilutes remaining Acidosis is another major cause of coagulopathy in the severely
platelets and coagulation factors.35 Much of the conventional wis- injured. Acidosis occurs when blood ow is reduced by injury and
dom regarding volume resuscitation that emerged from the Viet- normally-aerobic metabolism shifts to anaerobic glycolysis with
nam War era was aimed at avoiding the renal failure and other the production of lactic acid. While acidosis has minor effects on
consequences of severe hypotension. However, asanguinous resus- platelet function and the rate of brinogen catabolism, its major ef-
citation uids further dilute remaining platelets and coagulation fect is on the assembly of plasma coagulation factors into active
factors. In addition, the onset of mild hypotension with blood loss complexes on the negatively-charged surfaces of activated plate-
slows blood loss through the holes in the vascular system and de- lets.41,42 Some of the coagulation factors are enzymes and some
creases pressure on new clots attempting to staunch that loss. are cofactors, but the active enzymes are 10,00010,000,000 times
Bickell and his colleagues showed that civilian patients with pene- more active when assembled with their cofactors in a precise phys-
trating torso trauma had improved survival when they were not ical structure on the negatively charged phospholipid surface. This
volume-resuscitated before surgery.36 The study echoes Walter assembly occurs because the vitamin K dependent coagulation fac-
Cannons work from World War I suggesting that combat casual- tors chelate positively charged calcium ions against the negatively
ties did best when made comfortable, kept warm, and not resusci- charged surface. Higher concentrations of protons associated with
tated until the time of surgery.7 acidosis destabilize these complexes and reduce their activity.
Coldcore temperature hypothermiaalso exacerbates bleed- Meng and her associates have shown that at equivalent concentra-
ing. The enzymes of the plasma coagulation cascade all are less ac- tions, the factor Xa factor Va complex is only a half as enzymat-
tive at lower temperatures, with activities that fall by about 10% for ically active at pH 7.2 as it normally is at pH 7.4. At pH 7.0 it is only
every 1 C decrease in body temperature.37 While these changes 30% as active, and at pH 6.8 it is only 20% as active.42 Because sim-
are important, even more important is the loss of platelet function ilar effects have been demonstrated with the factor VIIatissue fac-
that occurs between 34 and 30 C. In this range, the normal activa- tor complex and probably occur with the factor VIIIafactor IXa
tion of platelets caused by adhesion is lost.38 Since platelet adhe- complex, these effects are probably additive down the coagulation
sion to exposed collagen normally triggers activation with the cascade.42
S.B. Murthi et al. / Blood Reviews 23 (2009) 149155 153

Coagulation factor and platelet concentrations also fall because The end result of all of these mechanisms leading to coagulop-
of consumption. As noted above, the total amounts of all of the athy is that the normally weak coagulation system can be made
coagulation factors and of platelets are small compared to the sur- substantially weaker and slower. It can be overwhelmed by antico-
faces and volumes of injury in severe trauma.43 If all of the plate- agulant and brinolytic mechanisms. Acuity in diagnosis and, ulti-
lets in the circulation were lined up side-by-side, they would mately, prevention of these coagulation abnormalities continues to
cover 5 square meters, but there are enough capillaries in the lung be a major thrust of current research into the coagulation support
to cover half a tennis court and in the body to cover a football of trauma care.
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 Preventing and treating coagulopathy
the most severely injured. Brohi and his colleagues have suggested
that activation of small amounts of thrombin in the initiation For many years, the acute trauma life support (ATLS) course of
phase of coagulation at many small sites of injury leads to the acti- the Committee on Trauma of the American College of Surgeons de-
vation of small amounts of factors V and VIII.46,47 Meanwhile, the ned the way seriously injured patients were resuscitated.54 Fol-
thrombin is carried or diffuses to thrombomodulin on adjacent lowing the ATLS guidelines, when injured patients presented to
normal cells and leads to the activation of anticoagulant protein care, two large-bore IVs were started in peripheral veins. If the pa-
C which inactivates the Va and VIIIa formed in the adjacent injury. tient had a systolic blood pressure of less than 100 mmHg, two li-
This process multiplied across millions of endothelial microtears ters of crystalloid uid were administered. If blood pressure did
has the capacity to consume signicant amounts of factors V and not normalize, if it did normalize but subsequently fell below
VIII while factor VII diffuses through the tears and is bound in tis- 100 mmHg again, or if ongoing bleeding exceeded 100 mL/min,
sue deep to the site of endothelial injury. These processes may ex- then red cell transfusion was to be initiated. This classic advice
plain why the most common forms of the early coagulopathy was based on a report of the resuscitation of 18 patients, from an
present as prolongations of the PT and PTT. era when whole blood was still being used in many centers.55
Consumption can also occur with the classic forms of dissemi- Several major lines of thinking have converged to end the crys-
nated intravascular coagulation associated with brain, fat, and talloid resuscitation era. First, it has become clear that the large
amniotic uid embolization.48 Brain is the richest source of tissue amounts of crystalloid uid given to massively injured patients,
factor in the body. Isolated moderate to severe brain injury was sometimes as much as 1030 l, led to massive tissue swelling,
associated with twice the frequency of a prolonged PT at presenta- sometimes requiring decompressive laparotomy just to prevent
tion to care as isolated injury of equivalent severity at other body abdominal compartment syndrome where the swollen organs com-
sites.31 In their classic form, these injuries typically present with press the inferior vena cava and interfere with blood return to the
low platelets and debrination, distinct from the initiation phase heart.56 Second, the uids used, especially Ringers lactate solution
factor decits seen in the more typical acute coagulopathy of trau- made with racemic lactate, were frankly proinammatory.57 Third,
ma and shock. with the wide use of red cells in additive solution as the primary red
The role of shock in these factor consumptive processes is at cell product, patients received very little plasma in the course of
this point just a clinical association. However, a logical mechanism resuscitation.30 This meant that coagulation factors were progres-
would be to prolong the persistence of thrombin in the circulation. sively diluted in the early phase of resuscitation. Coagulopathic de-
Normally, thrombin free in the circulation is cleared rapidly on rst grees of factor depletion were typically reached after 6 units of red
pass through the lungs.49 Delaying its clearance can give it more cells in additive solution.58,59 Just as standards for crystalloid resus-
time to activate its many substrates. A decade ago the senior citation were being reconsidered based on these insights, the simul-
author described an experiment where 5000 units of a bovine taneous recognition of the existence of an intrinsic coagulopathy of
thrombin highly contaminated with kallikrein was injected into trauma gave added impetus to the perception of the need for new
the femoral vein of a pig.50 The kallikrein led to profound shock approaches to uid use in resuscitation.
and the animals died with a clot from the injection site through If a quarter of seriously injured patients arriving at a trauma
the heart to the lungs. When an equivalent amount of a puried center are coagulopathic on admission, and any others requiring
human thrombin was injected, it caused mild hypotension, but massive transfusion were going to become coagulopathic by the
no signicant clot as the thrombin was still rapidly transported time they received 6 units of red cells, then resuscitation with large
to the lungs and inactivated. This experiment showed the impor- volumes of crystalloid is not going to be helpful in these patients.
tance of reduced ow as a mechanism that gave time for thrombin In fact, simple calculation of the volumes and concentrations in-
to do it work of building a clot and consuming coagulation factors. volved in modern blood components meant that only by giving
Finally, activating brinolysis can have a similar effect, speeding red cells, plasma and platelets at essentially 1:1:1 unit ratios could
the breakdown of clots that have already formed and consuming effective concentrations of all three components be maintained in
the late phase factors of the coagulation cascade. Fibrin is normally the massively transfused patients.43 This recognition led to the use
broken down by plasmin which, in turn, is activated by tissue plas- of thawed plasma as the primary resuscitation uid for the mas-
minogen activator (t-PA), which is released in response to cellular sively injured in the US Army Combat Support Hospital in Baghdad
injury.51 Three inactivators of this system are normally present, the with a dramatic reduction in ventilator times, apparently because
thrombin-activated brinolysis inhibitor (TAFI) which removes of reduced lung water, and seemingly to better hemorrhage control
lysine binding sites for plasmin from brin, alpha-2 anti-plasmin, and better survival. A retrospective review of this experience by
which inactivates plasmin, and plasminogen-activator inhibitor Borgman and his colleagues suggested that the benet in terms
(PAI-1), which inactivates t-PA.52 This system is frequently hyper- of reduced mortality was dramatic, with a mortality of 66% in those
active in shock because t-PA is released in response to injury and receiving greater than 10 units of red cells with a low plasma-to-
low blood pressure, TAFI is not activated without a good thrombin red-cell ratio and only 19% in those resuscitated with a ratio close
burst, anti-plasmin is consumed, and PAI-1 is broken down by to 1:1.60 Holcomb and his colleagues conrmed this nding on a
protein C.52 The experience of watching a surgical team obtain similar retrospective study of massively transfused patients con-
vascular hemorrhage control only to have the entire eld break ducted over a 1 year period at 16 large civilian trauma centers.61
out in diffuse oozing is a reminder of the power of the brinolytic The retrospective data in these studies are confounded by the
system.53 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 sion-related acute lung injury (TRALI), the recognition that
frozen plasma ever got thawed. However, the concept of hemostatic leukemic patients do not need prophylactic platelet transfusions
resuscitation and the data are still impressive. First, these massively above platelet counts of 10  109/L, and the transfusion require-
bleeding patients need to be given volume of some kind, and any- ments in critical care (TRICC) trial have come the recognition that
thing but plasma will only make their coagulopathy worse. Second, many prophylactic uses of blood products are unnecessary and
the benets of avoiding crystalloid uids measured as reduced time dangerous. In the absence of evidence derived from acutely injured
on ventilators and the ability to close abdominal surgery sites pri- patients, many had suggested that trauma patients did not need
marily is an independent demonstration of the utility of the ther- large amounts of plasma and platelets in their initial resuscitation
apy. Finally, the overall mortality of the military casualties is the either. The early data described above suggests that this attempt to
lowest ever reported during warfare, despite the prevalence of mas- apply the data on the prophylactic use of blood products to the
sive wounds caused by improvised explosive devices. treatment of massive hemorrhage may be misleading.
As a result of this work, many groups are now recommending However, only 2% of civilian trauma patients and 8% of military
resuscitation of those who are undergoing massive transfusion with casualties require massive transfusion. Most hemodynamically sta-
a ratio of plasma to red cells of essentially 1:1.62 The US Army Sur- ble injured patients can be spared the risks of blood products. In
geon General issued a eld directive in January 2006 recommending such patients, the lessons of the TRICC trial and the wealth of evi-
the 1:1 ratio in the massively injured. In a review of the published dence about the lack of utility of prophylactic plasma apply.
studies commissioned by the AABB and conducted by the Mayo But only half of civilian injured and 60% of the young military
Clinics Knowledge and Encounter Research Unit, the reviewers con- casualties who receive more than 10 units of red cells in the rst
cluded that the sum of available published information supported 24 h of care survive. If the new information and guidelines on
the idea unambiguously. Clearly, randomized prospective data hemostatic resuscitation are correct and a third of such patients
would be desirable, but this is extremely difcult to obtain in the who presently die are salvageable with better resuscitation, this
trauma setting where none of the patients can give informed con- is important information and can save thousands of lives each year.
sent and the primary events themselves occur rapidly, infrequently, Moreover, we owe it to the patients, the blood donors, and to
and often in the middle of the night. In calendar year 2000, our cen- the citizenry that supports the most advanced trauma and blood
ter saw only 90 patients who required massive transfusion. supply systems in the world, and our colleagues who work in them,
Studies of the same patient groups noted above have also sug- to continue the research that will dene best practice.
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 Conict of interest
of the benet suggests that extra platelets early in resuscitation of
the massively injured help in both hemorrhagic and brain injured One of the authors (J.R.H.) has US Government inventors rights
patients. Obviously, this important clinical suggestion needs fol- in the licensing fees and royalties to patents for advanced red cell
low-up. As noted earlier, admission platelet count is a powerful pre- storage systems and hemorrhage control technologies. He serves as
dictor of in-hospital mortality. Even within the normal range of a consultant to Novo Nordisk, Hemerus, Inc., and Haemostasis, LLC.
platelet counts, 150400  109/L, patients with severe injury with
admission platelet concentrations in the upper half the normal range References
had 50% lower in-hospital mortality than those in the lower half.31
Johansson and his colleagues at the University of Copenhagen 1. Mathers CD, Lopez A, Stein C, Ma Fat D, Rao C, Inoue M, et al. Deaths and disease
burden by cause: Global burden of diseases estimates for 2001 by World Bank
have adopted these new insights most comprehensively. In 2004, Country Groups. Working paper #18, Disease Control Priorities Project,
this group began a blood bank-driven program of identifying pa- Evidence and Information for Policy Group, World Health Organization,
tients who were likely to be massively transfused and issuing red Geneva, Jan 2005.
2. Mackenzie EJ, Rivara FP, Jurkovich GJ, Nathens AB, Frey KP, Egleston BL, et al. The
cells and plasma in a 1:1 ratio with platelets given in even higher national study on costs and outcomes of trauma. J Trauma 2007;63(6 Suppl.):
unit to unit ratios. [Par Johansson personal communication] The S5467.
results of their consecutive series of patients undergoing ruptured 3. Hess JR, Schmidt PJ. The rst blood banker: Oswald Hope Robertson. Transfusion
2000;40(Jan):1103.
abdominal aortic aneurism repair have been published, with all 4. Stansbury LG, Hess JR, Roger I. Lee: the right man at the right time. Transfus Med
cause mortality down from 66% to 44% in the before and after co- Rev 2005;19(Jan):814.
horts.63 In the two years after the change, they used the new 5. Lee RI. A simple and rapid method for the selection of suitable donors for
transfusion by the determination of blood groups. Br Med J 1917;2:6845.
scheme in all 442 massively transfused patients including 231 pa- 6. Robertson OH. A method of citrated blood transfusion. Br Med J 1918;1:4779.
tients undergoing abdominal and vascular surgery, 83 cardio-tho- 7. Cannon WB, Fraser J, Cowell E. The preventive treatment of wound shock. JAMA
racic patients, 60 trauma patients, 38 orthopedic patients, 8 burn 1918;70:61821.
8. Cannon WB. Traumatic shock. New York: Appleton; 1923.
patients, and 22 others. They compared this cohort to the similar
9. Cushing H. From a surgeons journal. Boston: Little Brown; 1936.
cohort of all 390 patients who received ten or more units of red 10. Centers for Disease Control and Prevention. National Center for Health
cells in the rst 24 h in their hospital in calendar years 2002 and Statistics. Injury in the United States: 2007 Chartbook. US Department of
2003 and demonstrated a reduction in mortality at 90 days from Health and Human Services. 2008. http://www.cdc.gov/nchs/data/misc/
injury.pdf. accessed 12 November 2008.
34.6% to 22.4%. This represents a 35% reduction in mortality and 11. Baker CC, Oppenheimer L, Stephens B, Lewis FR, Trunkey DD. Epidemiology of
savings of 50 lives over the two year period at a price of 3 addi- trauma deaths. Am J Surg 1980;140:14450.
tional pools of 4-units of whole blood-derived platelets per patient 12. Potenza BM, Hoyt DB, Coimbra R, Fortlage D, Holbrook T, Hollingsworth-
Fridlund P. Trauma Research and Education Foundation. The epidemiology of
given on the rst hospital day with a concomitant savings of 2 serious and fatal injury in San Diego County over an 11-year period. J Trauma
units of red cells over the course of admission. 2004;56:6875.
13. Bellamy RF. Combat trauma overview. Textbook of military medicine: anesthesia
and pre-operative care of the combat casualty. Washington, DC: Department of
the Army, Ofce of the Surgeon General, Borden Institute; 1994. p. 142.
Who might benet from changing the way we use blood 14. Bellamy RF, Maningas PA, Vayer JS. Epidemiology of trauma: military
products? experience. Ann Emer Med 1986;15:13848.
15. Bellamy RF. The causes of death in conventional land warfare: implicatons for
combat casualty care research. Milat Med 1984;149:5562.
Medical care goes through cycles. With the acquired immuno- 16. Branas CC, MacKenzie EJ, Willians JC, et al. Access to trauma centers in the
deciency syndrome (AIDS) epidemic, the description of transfu- United States. JAMA 2005;293:262633.
S.B. Murthi et al. / Blood Reviews 23 (2009) 149155 155

17. Como JJ, Dutton RP, Scalea TM, Edelman BB, Hess JR. Blood transfusion rates in 41. Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on
the care of acute trauma. Transfusion 2004;44:80913. brinogen synthesis and breakdown in pigs. Ann Surg 2007;246:8315.
18. Dutton RP, Shih D, Edelman BB, Hess J, Scalea TM. Safety of uncrossmatched 42. Meng ZH, Wolberg AS, Monroe 3rd DM, Hoffman M. The effect of temperature
type-O red cells for resuscitation from hemorrhagic shock. J Trauma and pH on the activity of factor VIIa: implications for the efcacy of high-dose
2005;59:14459. factor VIIa in hypothermic and acidotic patients. J Trauma 2003;55(5):88691.
19. Ayache S, Herman JH. Prevention of D sensitization after mismatched 43. Armand R, Hess JR. Treating coagulopathy in trauma patients. Transfus Med Rev
transfusion of blood components: toward optimal use of RhIG. Transfusion 2003;17(July):22331.
2008;48:19909. 44. Crapo JD, Barry BE, Gehr P, Bachofen M, Weibel ER. Cell number and cell
20. Frohn C, Dmbgen L, Brand JM, Grg S, Luhm J, Kirchner H. Probability of anti-D characteristics of the normal human lung. Am Rev Respir Dis 1982;126:3327.
development in D patients receiving D+ RBCs. Transfusion 2003;43:8938. 45. Helenius G, Hagvall SH, Esguerra M, Fink H, Soderberg R, Risberg B. Effect of
21. Stainsby D, Jones H, Asher D, Atterbury C, Boncinelli A, Brant L, et al. SHOT shear stress on the expression of coagulation and brinolytic factors in both
Steering Group. Serious hazards of transfusion: a decade of hemovigilance in smooth muscle and endothelial cells in a co-culture model. Eur Surg Res
the UK. Transfus Med Rev 2006;20:27382. 2008;40:32532.
22. Grove-Rasmussen M, Shaw RS, Marceau E. Hemolytic transfusion reaction in 46. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute
group-A patient receiving group-O blood containing immune anti-A antibodies traumatic coagulopathy: initiated by hypoperfusion: modulated through the
in high titer. Am J Clin Pathol 1953;23:82832. protein C pathway? Ann Surg 2007;245(5):8128.
23. Josephson CD, Mullis NC, Van Demark C, Hillyer CD. Signicant numbers of 47. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, et al. Acute
apheresis-derived group O platelet units have high-titer anti-A/A, B: coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and
implications for transfusion policy. Transfusion 2004;44:8058. hyperbrinolysis. J Trauma 2008;64(5):12117. discussion 1217.
24. Angiolillo A, Luban NL. Hemolysis following an out-of-group platelet 48. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med
transfusion in an 8-month-old with Langerhans cell histiocytosis. J Pediatr 1999;341:58692.
Hematol Oncol 2004;26:2679. 49. Glusa E. Vascular effects of thrombin. Semin Thromb Hemost 1992;18:296304.
25. Janatpour KA, Kalmin ND, Jensen HM, Holland PV. Clinical outcomes of ABO- 50. Pusateri AE, Holcomb JB, Bhattacharyya SN, Harris RA, Gomez RR, MacPhee MJ,
incompatible RBC transfusions. Am J Clin Pathol 2008;129:27681. et al. Different hypotensive responses to intravenous bovine and human
26. Lozano M, Cid J. The clinical implications of platelet transfusions associated thrombin preparations in swine. J Trauma 2001;50(1):8390.
with ABO or Rh(D) incompatibility. Transfus Med Rev 2003;17:5768. 51. Hrafnkelsdottir T, Erlinge D, Jern S. Extracellular nucleotides ATP and UTP
27. McManigal S, Sims KL. Intravascular hemolysis secondary to ABO incompatible induce a marked acute release of tissue-type plasminogen activator in vivo in
platelet products. An underrecognized transfusion reaction. Am J Clin Pathol man. Thromb Haemost 2001;85:87581.
1999;111:2026. 52. Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the
28. Storry JR, Johannesson JS, Poole J, Strindberg J, Rodrigues MJ, Yahalom V, et al. brinolytic system. J Thromb Haemost 2008. Epub ahead of print.
Identication of six new alleles at the FUT1 and FUT2 loci in ethnically diverse 53. Adam DJ, Haggart PC, Ludlam CA, Bradbury AW. Coagulopathy and
individuals with Bombay and Para-Bombay phenotypes. Transfusion hyperbrinolysis in ruptured abdominal aortic aneurysm repair. Ann Vasc
2006;46:214955. Surg 2004;18:5727.
29. Fung MK, Downes KA, Shulman IA. Transfusion of platelets containing ABO- 54. Advanced Trauma Life Support for Doctors. Chicago, IL: 2nd ed.; American
incompatible plasma: a survey of 3156 North American laboratories. Arch College of Surgeons, Chicago, 1997.
Pathol Lab Med 2007;131:90916. 55. Carrico CJ, Canizaro PC, Shires GT. Fluid resuscitation following injury: rationale
30. Hess JR, Lawson J. The coagulopathy of trauma compared to medical for the use of balanced salt solutions. Crit Care Med 1976;4:4654.
disseminated intravascular coagulation. J Trauma 2006;60(6 Suppl.):S129. 56. Rotondo MF, Schwab CW, McGonigal MD. Damage control: an approach for
31. Hess JR, Lindell AL, Stansbury LG, Dutton RP, Scalea TM. The prevalence of improved survival in exsanguinating penetrating abdominal injury. J Trauma
abnormal results of conventional coagulation tests on admission to a trauma 1993;35:37583.
center. Transfusion 2008. Oct 24. Epub ahead of print. 57. Koustova E, Stanton K, Gushchin V, Alam HB, Stegalkina S, Rhee PM. Effects of
32. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma lactated Ringers solutions on human leukocytes. J Trauma 2002;52:8728.
2003;54(6):112730. 58. Hirshberg A, Dugas M, Banez EI, et al. Minimizing dilutional coagulopathy in
33. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy exsanguinating hemorrhage: a computer simulation. J Trauma
predicts mortality in trauma. J Trauma 2003;55(1):3944. 2003;54:45463.
34. Hess JRB, Brohi K, Dutton RP, Hauser CJ, Holcomb JB, Kluger Y, et al. The 59. Ho AM, Karmakar MK, Dion PW. Are we giving enough coagulation factors
coagulopathy of trauma: a review of mechanisms. J Trauma 2008;65:74854. during major trauma resuscitation? Am J Surg 2005;190:47984.
35. Lundvall J, Lnne T. Large capacity in man for effective plasma volume control 60. Borgman M, Spinella PC, Perkins JG, et al. Blood product replacement affects
in hypovolaemia via uid transfer from tissue to blood. Acta Physiol Scand survival in patients receiving massive transfusions at a combat support
1989;137:51320. hospital. J Trauma 2007;63(4):80513.
36. Bickell WH, Wall Jr MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, et al. 61. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA,
Immediate versus delayed uid resuscitation for hypotensive patients with et al. Increased plasma and platelet to red blood cell ratios improves outcome
penetrating torso injuries. N Engl J Med 1994;331(17):11059. in 466 massively transfused civilian trauma patients. Ann Surg
37. Wolberg AS, Meng ZH, Monroe 3rd DM, Hoffman M. A systematic evaluation of 2008;248:44758.
the effect of temperature on coagulation enzyme activity and platelet function. 62. Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Metha S, et al.
J Trauma 2004;56:12218. Damage control resuscitation: directly addressing the early coagulopathy of
38. Kermode JC, Zheng Q, Milner EP. Marked temperature dependence of the trauma. J Trauma 2007;62:30710.
platelet calcium signal induced by human von Willebrand factor. Blood 63. Johansson PI, Stensballe J, Rosenberg I, Hilslv TL, Jrgensen L, Secher NH.
1999;94(1):199207. Proactive administration of platelets and plasma for patients with a ruptured
39. Jurkovich GJ, Greiser WB, Luterman A, Curreri PW. Hypothermia in trauma abdominal aortic aneurysm: evaluating a change in transfusion practice.
victims: an ominous predictor of survival. J Trauma 1987;27(9):101924. Transfusion 2007;47:5938.
40. Hirshberg A, Sheffer N, Barnea O. Computer simulation of hypothermia during
damage control laparotomy. World J Surg 1999;23(9):9605.