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Preconditions of Hemostasis in Trauma: A Review.
The Influence of Acidosis, Hypocalcemia, Anemia,
and Hypothermia on Functional Hemostasis in Trauma
Heiko Lier, MD, Henning Krep, MD, PhD, Stefan Schroeder, MD, PhD, and Frank Stuber, MD, PhD
Background:
Beside the often dis-
cussed topics of consumption and dilution
coagulopathy, additional perioperative im-
pairments of coagulation are caused by acido-
sis, hypocalcemia, anemia, hypothermia, and
combinations.
Methods:
Reviewing current literature,
cutoff values of these parameters become ob-
vious at which therapy should commence.
Results:
A notable impairment of he-
mostasis arises at a pH <7.1. Similar ef-
fects are caused by a BE of ⴚ12.5 or less.
Thus, in case of severe bleeding, buffering
toward physiologic pH values is recom-
mended, especially with massive transfu-
sions of older RBCCs displaying exhausted
red blood cell buffer systems. It completes
the optimization of the volume homeostasis
to ensure an adequate tissue perfusion.
Combining beneficial cardiovascular
and coagulation effects, the level for ion-
ized calcium concentration should be held
>0.9 mmol/L.
From the hemostatic point of view,
the optimal Hct is higher than the one
required for oxygenation. Even without a
“classical” transfusion trigger, the ther-
apy of acute, persistent bleeding should
aim at reaching an Hct >30%.
A core temperature of <34°C causes
a decisive impairment of hemostasis. A
controlled hypotensive fluid resuscitation
should aim at reaching a mean arterial
pressure of >65 mm Hg (possibly higher
for cerebral trauma). Prevention and later
aggressive therapy of hypothermia by ex-
clusive infusion of warmed fluids and the
use of warming devices are prerequisites
for the cure of traumatic coagulopathy.
Combined appearance of single pre-
conditions cause additive impairments of
the coagulation system.
Conclusions:
The prevention and
timely correction, especially of the combi-
nation acidosis plus hypothermia, is cru-
cial for the treatment of hemorrhagic
coagulopathy.
Key Words:
Blood coagulation, Co-
agulopathy, Acidosis, Hypocalcemia, Ane-
mia, Hypothermia.
J Trauma. 2008;65:951–960.
In the first four decades of life, trauma is the leading cause
of death and remains a significant cause in later life.
1
Exsanguination accounts for 40% to 45% of total fatalities
in the trauma setting.
2,3
It is the second most common reason
for acute and early deaths within the first days in hospitals,
only central nervous system injuries are more frequent.
4
More
than 80% of trauma deaths that occur in the operating room
do so as a result of hemorrhage.
3
Traumatic hemorrhage may
occur as a result of direct injury to blood vessels, with
massive bleeding, or as a result of diffuse bleeding secondary
to coagulopathy in vessels too small and too numerous for
surgical management. Impaired hemostasis in these patients
is often caused by a combination of dilution and consumption
of clotting factors and hyperfibrinolysis. The goal of therapy
lies in the stabilization of the clotting process.
However, despite the application of apparently sufficient
quantities of fresh frozen plasma, coagulation factors and plate-
lets, this goal is not met in many instances. The major reason for
inefficacy of this therapy is given by the fact that optimal
coagulation requires specific preconditions concerning acid-
base-balance, calcium, hematocrit (Hct), and temperature. In
case these prerequisites are not fulfilled, all procoagulants may
have been applied in vain as stable clotting does not occur.
The standard clinical clotting assays, i.e., activated partial
thromboplastin time and prothrombin time (PT) are performed
in buffered plasma or serum with calcium excess but without
any erythrocytes and at 37°C. These tests are not sensitive
indices of coagulation function in clinical practice,
5
neither can
prolonged PT or elevated international normalized ratio predict
excessive bleeding in patients undergoing invasive procedures at
all.
6
Thus, routine coagulation tests are not reliable in cases of
impaired preconditions of traumatic hemostasis.
7,8
Awareness of perioperative impairments of coagula-
tion’s preconditions is essential for their prevention and a
reduction in perioperative morbidity and mortality. Parame-
ters to be considered are:
A. Acidosis: Decreased tissue perfusion represents the main
reason for blood acidosis. Lactic acidosis directly reduces
the activity of the coagulation.
9
Nevertheless, the serum
Submitted for publication September 24, 2007.
Accepted for publication July 24, 2008.
Copyright © 2008 by Lippincott Williams & Wilkins
From the Department of Anaesthesiology and Intensive Care Medicine
(H.L., H.K.), University of Cologne, Cologne, Germany; Department of
Anaesthesiology and Intensive Care Medicine (S.S.), Westkuestenklinikum
Heide, Heide, Germany; and Department of Anaesthesiology and Pain Ther-
apy (F.S.), University of Bern, Bern, Switzerland.
Address for reprints: Dr. Heiko Lier, Department of Anaesthesiology
and Intensive Care Medicine, University of Cologne, Kerpener Street 62,
D-50924 Ko¨ln, Germany; email: heiko.lier@uk-koeln.de.
DOI: 10.1097/TA.0b013e318187e15b
Review Article The Journal of TRAUMA威Injury, Infection, and Critical Care
Volume 65 •Number 4 951
pH does not necessarily reflect the pH in hypoxic, injured
tissue. It may remain acidotic although the blood pH is in
the normal range.
10
Most of the coagulation proteases
have an optimum pH value between 8.0 and 8.5.
10
B. Hypocalcemia: In extracellular plasma, Calcium
(Ca
⫹⫹
⫽Factor [F] IV) is in a free ionized state as well
as bound to other molecules. About 55% are biologically
inert and bound to proteins. The majority of protein-
bound Ca
⫹⫹
associates with albumin (80%). Therefore,
changes in albumin alter total calcium concentrations sig-
nificantly. Forty-five percent of the total Ca
⫹⫹
is biolog-
ically active and exists in the ionized form (Ca
i
⫹⫹
), with
a normal concentration of 1.1 mmol/L to 1.3 mmol/L.
11
There is an inverse relation between Ca
i
⫹⫹
and the
blood’s pH: an increase in pH of 0.1 will decrease Ca
i
⫹⫹
by 0.036 mmol/L
12
to 0.05 mmol/L.
13
In states of hy-
pocalcemia, it is also important to anticipate decreased
magnesium serum concentrations.
11
C. Hemoglobin/Hematocrit: Platelets play a major role in
localizing clotting reactions to the site of injury because
they adhere and aggregate at the sites of injury where
tissue factor is exposed.
14
They flow primarily at the
vascular margin.
15
The number and size of the red blood
cells, the Hct, are the determining factors of platelets’
radial transport and their adhesion to damaged sites of the
endothelium.
16
D. Hypothermia: According to the equations of van’t Hoff
and Arrhenius, a decrease in temperature of 1°C or 1°K
will theoretically cause a decrease in the coagulation
proteases’ activity of 4% to 10%.
17,18
The standard coag-
ulation tests, PT and activated partial thromboplastin
time, are prolonged by hypothermia when they are per-
formed at the patient’s actual core temperature.
19
But
even then, these assays still underestimate the magnitude
of the coagulopathy as they do not reflect the in vivo
process occurring on cell membranes.
20
Reviewing current literature, cutoff values of these
parameters become obvious at which therapy should
commence.
Acidosis
Nonsurvivors of trauma are more likely to have a lower
pH than survivors.
21
Acidosis impairs almost all essential
parts of the coagulation process: At a pH lower than 7.4,
normal human platelets change their internal structure and
their shape, becoming spheres deprived of pseudopodia.
22
Different coagulation factors are differently influenced by
acidosis.
2,18,23
Additionally, the factors’ Ca
⫹⫹
-binding sites
have a unique pH-dependent affinity that is reduced consid-
erably under acidic conditions.
24
Impaired thrombin generation is the main cause of co-
agulopathic bleeding.
2
In Martini’s experiments thrombin
generation in the propagation phase was inhibited by a pH of
7.1 by as much as 50%, with no changes in the initiation
phase. A pH of 7.1 caused a 35% reduction of fibrinogen
most likely caused by altered sequestration or degradation.
Additionally, the platelet count was reduced to 50%.
23
A thrombelastographic (TEG) survey
25
found a pH of
7.1 to significantly affect each platelet receptor examined.
Such a low pH seemed to have a more deleterious effect on
coagulation than hypothermia which is consistent with other
publications.
10
Another TEG study showed that the rate at
which the clot is formed and polymerized is impaired in a
progressive manner by acidosis.
26
The base excess (BE) was characterized as an expedient
and sensitive measure of both the degree and the duration of
inadequate perfusion
27
and correlated with mortality.
28
As
the BE refers to the amount of acid required to return the
blood pH of an individual to normal (pH 7.4, assuming
normal physiologic values of PaO
2
,PaCO
2
, and temperature),
there is also an influence of BE on coagulation factors,
29
favor-
ing a BE above ⫺12.5.
30
Transforming Meng’s findings
18
for
pH values to negative BE (postulating a nonrespiratory aci-
dosis) shows: a BE of ⫺15 mmol/L reduces the activity of
different coagulation factors by 50%
31
(Fig. 1).
Even in industrialized countries, more than 30% of red
blood cell concentrates (RBCCs) are stored longer than 3
weeks.
32
Although the storage’s effect on oxygen capacity is
still discussed controversially, a massive transfusion of older
RBCCs can boost a patient’s acidosis.
33
Hyperkaliemia is
increased when blood is held in storage, as 2,3-diphospho-
glycerate levels decrease, pH is reduced, supernatant potas-
sium levels increase, and intracellular potassium levels
decrease.
10
Fresh RBCCs have a BE of ⫺20 mmol/L, after 6
weeks it is ⫺50 mmol/L.
34
These findings indicate the adverse effects of acidosis
lower than 7.1 on the activity of coagulation factors and
platelets. High concentrations of hydrogen lead to an im-
paired ionic interaction between the coagulation factors and
negatively charged phospholipids.
17
For this reason, correc-
tion of acidosis using sodium bicarbonate (NaHCO
3
) or trishy-
droxymethylaminomethane (THAM) should be beneficial.
2,18,26
Other findings suggest that NaHCO
3
may inhibit the conversion
of fibrinogen to fibrin.
35
Although bicarbonate infusion suc-
Fig. 1. Conclusive correlation between the activity respectively ac-
tivation of different coagulation factors and a negative base excess
(BE) (postulating a nonrespiratoric acidosis): 〫generation of FXa,
⌬generation of FIIa, Eactivation of FVIIa (data according to
Meng
18
, adapted from Zander
31
, with kind permission).
The Journal of TRAUMA威Injury, Infection, and Critical Care
952 October 2008
cessfully reversed pH and BE, neither the reduced fibrinogen
concentration nor the impaired thrombin generation were
reversed by buffering.
23
Albeit, NaHCO
3
buffering effect is
dependent on normal respiratory function.
36
Testing
THAM,
37
the neutralization of arterial pH did not alter the
loss of fibrinogen, but the inhibition in thrombin generation
was not observed and thrombin generation kinetics returned
to baseline levels. The addition of the buffer THAM also
reversed the coagulation’s impairment at lower pH values in
TEG studies.
26,36
Like Martinowitz demanded for rFVIIa,
2
cor-
rection of the pH to ⱖ7.2 is recommended before the adminis-
tration of any hemotherapeutics.
26
Future studies will need to
address the question which buffering agent should be used.
Because conversion of fibrin to thrombin will only be
accomplished if enough platelets and fibrinogen are avail-
able, data support a possible need for fibrinogen and platelets
supplementation in treating acute trauma patients with aci-
dotic coagulopathy.
2,23
Conclusion
A notable impairment of hemostasis arises at a pH ⱕ7.1.
Similar effects are caused by a BE of ⫺12.5 or less. Thus, in
case of severe bleeding, buffering toward physiologic pH
values is recommended, especially with massive transfusions
of older RBCCs displaying exhausted red blood cell buffer
systems. It completes the optimization of the volume ho-
meostasis to ensure an adequate tissue perfusion.
Hypocalcemia
Ionized hypocalcemia is common among critically ill
adults and is associated with increased mortality. Hazard
ratios of 5.1 for severe (⬍0.90 mmol/L) and 1.8 for mild
ionized hypocalcemia (0.90 –1.15 mmol/L) at admission on
the intensive care unit were published.
38
Adverse cardiac
effects of hypocalcemia have been reported to commence at
or below 0.8 mmol/L to 0.9 mmol/L.
39,40
In a cohort of 212
consecutive severe trauma patients admitted to a trauma cen-
ter, significant correlations between Ca
i
⫹⫹
within 77 minutes
after trauma and the amount of infused colloid and arterial pH
but not with the amount of infused crystalloid were noted.
41
Analyzing severely traumatized patients with a hypocalcemia
⬍0.9 mmol/L
41
strongly suggested that colloid-induced he-
modilution is an important causative factor of early hypocal-
cemia in severe trauma patients and is further amplified by
shock and ischemia-reperfusion.
42
The vitamin K-dependent factors FII, FVII, FIX, and FX
as well as protein C and S are negatively charged. The same
is true for the phospholipids. Positively charged Ca
i
⫹⫹
acts as
a “bridge” between these surfaces and serves the enhance-
ment of coagulation factors at the damaged endothelium. Its
role in the conversion of fibrin to thrombin was noted as early
as 1892.
43
The binding of Ca
⫹⫹
to fibrinogen exerts a pro-
tective effect on the molecule, decreasing its susceptibility to
denaturation by heat, acids, or plasmin proteolysis.
44
It is
essential for the timely formation and stabilization of fibrin
polymerization sites at all successive stages of the fibrin
polymerization.
45
A reduction of cytosolic calcium concen-
tration causes a decrease in all platelet-related activities
46
and
the modification of their shape during activation.
47
Intracel-
lular Ca
⫹⫹
mobilization is required for stable platelet incor-
poration into the developing thrombus.
48
This mobilization
acts on the platelets via the same surface ADP-receptors that
are responsible for the platelets’ morphologic changes and the
beginning of their aggregation.
49
Inhibitory pathways, partic-
ularly the activation of protein C
50
and fibrinolysis
51
are also
calcium dependent.
Infusions of the citrate anticoagulant in blood compo-
nents may worsen hypocalcemia.
10
Excess amounts of citrate
anticoagulant are present in fresh frozen plasma.
33
The more
rapid the infusion is, the stronger the temporary decrease of
Ca
⫹⫹
will be
52
(Fig. 2).
Very few studies analyze the dose-response effects of
calcium on coagulation. The search for this relationship
of calcium and thrombin generation identified an upper limit
of 0.5 mmol/L above which thrombin generation was not
further enhanced.
53
By using heparinized blood, the authors
53
may have underestimated the true Ca
i
⫹⫹
by up to 9%.
54
Accordingly, coagulation defects can be attributed to hy-
pocalcemia if the Ca
i
⫹⫹
is ⬍0.6 mmol/L to 0.7 mmol/L.
Two distinct pharmacologic compounds are usable for
substitution of Ca
i
⫹⫹
: One milliliter of calcium gluconate
provides 9.3 mg of elemental calcium whereas 1 mL of
calcium chloride yields 27 mg.
11
Conclusion
Combining beneficial cardiovascular and coagulation ef-
fects, the level for ionized calcium concentration should be
held ⱖ0.9 mmol/L.
Anemia/Hemoglobin/Hematocrit
Platelets are expelled toward the red blood cell-depleted
marginal layer near the tube wall by mutual interaction with
erythrocytes: the near-wall concentration of platelets is sig-
nificantly enhanced up to about seven times the average
concentration, practically independent of the tube diameter in
the range of 100
mto500
m.
55
Therefore, rheologic
displacement of platelets toward the vessel’s area with max-
imum shear-stress
56
is dependent on the amount of red blood
cells and is called margination.
57
The number and size of the
red blood cells, the Hct, are the determining factors of plate-
lets’ radial transport and their adhesion to endothelial
damage
16
: Under flow conditions platelet adhesion increases
fivefold as Hct values increase from 10% to 40% but under-
goes no further increase from 40% to 70%, implying a satu-
ration of the transport-enhancing capabilities of red cells. For
flow conditions in which platelet-surface reactivity is more
dominant, platelet adhesion and thrombus formation increase
monotonically as Hct values increase from 10% to 70%.
16
Activation of platelets is dependent on red blood cells’
provision of ADP.
58
The presence of erythrocytes induced a
Preconditions of Hemostasis in Trauma
Volume 65 •Number 4 953
twofold increase in platelet thromboxane B2 synthesis upon
collagen stimulation, indicating that erythrocytes modulated
platelet eicosanoid formation. Stimulated platelet-erythrocyte
suspensions contained 6.9-fold more ADP and 4.9-fold more
ATP than stimulated platelets alone. Metabolically active
erythrocytes amplify platelet reactivity as expressed by in-
creased recruiting capacity, production of thromboxane B2,
and release of ADP and P-thromboglobulin.
59
Erythrocytes
promoted significant increases in cyclo-oxygenase and li-
poxygenase metabolites upon platelet stimulation with colla-
gen or thrombin.
60
Thromboxane A2 and arachidonic acid
derived from activated platelets, induce a prothrombotic phe-
notype on erythrocytes in proximity. So, erythrocytes can
actively contribute to platelet-driven thrombogenesis and mi-
crovascular occlusion.
61
Normal RBC participate in the he-
mostatic process of thrombin generation through exposure of
procoagulant phospholipids.
62
A significant inverse correlation was noted between the
bleeding time and Hct
63,64
and an inverse correlation of Hct
and platelet count.
65
This fact must be taken into account in
the assessment of anemic patients, particularly those who
may have an associated hemostatic disorder.
64
A normaliza-
tion of both platelet count and Hct are required to achieve
optimum hemostasis. A reduced Hct inhibits the platelet
aggregation and adhesion.
66
Significant abnormalities in laboratory measures of
blood clotting develop before compromise of tissue oxygen-
ation (assessed by mixed venous oxygen saturation and total
body oxygen consumption) in swine and in healthy
adolescents.
67
Especially, in patients with severe trauma who
received large volumes of colloids, the hemodilution had
important effects on Hct levels and hemostasis.
41
Removal of
two units of RBCs in healthy volunteers produced a 60%
increase in the bleeding time associated with a 15% reduction
in the peripheral venous Hct and a 9% reduction in the
platelet count. The platelet dysfunction observed with the
reduction in Hct was due in part to a reduction in shed blood
thromboxane B2.
68
A decrease of the platelet count by
50,000/
L could be compensated for by a 10% increase in
Hct.
69
The endogenous thrombin potential increased as the
Fig. 2. Present model of “cell-based” coagulation according to Hoffman
14,20
and the target location of ionized calcium. The coagulation
factors are characterized by their Latin numbers. Ca
⫹⫹
: ionized calcium; GP: glycoprotein receptor on the platelets’ surface; PAR1⫹4:
protease-activated receptor 1 and 4 ⫽thrombin’s bonding side on platelets, essential for the activation of platelets; TF: tissue factor; TFPI:
tissue factor pathway inhibitor ⫽blocks (like ATIII) Xa, if Xa is not on the surface of TF-bearing cells; vWF: von Willebrand factor.
The Journal of TRAUMA威Injury, Infection, and Critical Care
954 October 2008
Hct was elevated from 10% to 40%; the maximal thrombin
concentration achieved increased linearly over the range from
0% to 60%. The effect of red cells on thrombin generation is
probably due to the presence of exposed phosphatidylserine
on their membranes.
70
Initial therapy of traumatic blood loss is the replacement
of the lost volume by crystalloid and colloidal solutions.
Volume replacement, and not oxygen-carrying capacity,
plays the most important role in initial treatment of hemor-
rhagic shock.
71
Yet concerning the preconditions of hemo-
stasis, current military experience in Iraq and Afghanistan
point to a possible usefulness of damage control resuscitation
with minimal colloid use and early application of thawed
plasma and RBCC.
72
Nevertheless, sole compensation of the
lost blood by crystalloids and colloids and later by RBCCs
will worsen the consumption coagulopathy by adding a dilu-
tion effect.
73
The decrease of almost all procoagulant and
anticoagulant factors will closely follow that of the Hct.
74
The formation of fibrin from its precursor fibrinogen is
the essence of the coagulation process.
23,75
Only 10 g of
fibrinogen exist in the normal circulation at any given time.
17
The decline of fibrinogen levels have been considered as one
of the two most sensitive measures of clinical coagulopathy
(the other being platelet counts).
76
Maintaining fibrinogen
concentrations is essential when continuing blood loss is
bridged by colloid infusion until transfusion triggers are
reached, especially in patients already exhibiting borderline
fibrinogen levels at baseline.
77
In diluted blood, “primary”
hemostasis, i.e., the interaction of platelets and the damaged
endothelium seems to be influenced by lower blood viscosity
and altered rheology. Hydroxy-ethyl-starch (HES) caused
changes which mainly corresponded to hypocoagulability:
TEG parameters, which predominantly are influenced by
platelet function (
␣
-angle, maximal amplitude) were always
reduced with HES.
78
The reduction of fibrinogen levels was
significantly worse in patients substituted with HES.
79
So, the
first coagulation factor decreasing to pathologically low lev-
els in trauma and hemodilution is usually fibrinogen.
67,80
It
apparently is the factor most closely linked to the clot’s
quality in normal individuals.
81
This drop cannot be ex-
plained solely by blood loss and resuscitation fluids
75
and
often is reached earlier than expected.
77
Fries et al. withdrew
60% of the estimated total blood volume from pigs and
replaced the loss with gelatin solution. Compensation exclu-
sively with fibrinogen concentrate normalized the impaired
clot strength and led to statistically significant less blood loss
after a liver stab wound.
82
Even moderate dilution with col-
loids reduced the clot’s firmness and impaired especially the
polymerization of FI.
80
In fact, this interference also held true
for low molecular weight HES (6% HES 130/0.4).
80
Therefore, optimal hemostasis in severely bleeding
trauma patients requires a fairly high Hct
83
which exceeds
Hct values needed for adequate oxygenation
67
: Depending on
the patient’s clinical status, RBC transfusion is recommended
if acute anemia reduces hemoglobin (Hb)-values to 6 g/dL
84
and 9 g/dL.
85
A liberal transfusion strategy even seems to
have possible negative effects on patients’ survival.
86
Nev-
ertheless, these values are not sufficient for the improvement
of hemostasis in persistent hemorrhage requiring massive
transfusions
84
: sometimes continued massive bleeding re-
quires a increase in Hct possibly as high as 35%
83
oraHbup
to 10 g/dL to 11 g/dL.
83,87
Conclusion
From the hemostatic point of view, the optimal Hct is
higher than the one required for oxygenation. Even without a
“classical” transfusion trigger, the therapy of acute, persistent
bleeding should aim at reaching an Hct ⱖ30%.
Hypothermia
The impact of body core hypothermia on outcome in 71
adult trauma patients with Injury Severity Scores (ISS)
greater than or equal to 25 was analyzed
88
: Although mor-
tality was 7% if body core temperature was ⱖ34°C, it was
40% at ⬍34°C, 69% at ⬍33°C, and 100% at ⬍32°C. Within
each subgroup (i.e., greater ISS, massive fluid administration,
shock) the mortality of hypothermic patients was signifi-
cantly higher than those who remained warm.
88
Analyzing
more than 38,000 patients of the Pennsylvania Trauma Out-
come Study registry, admission hypothermia defined as
ⱕ35°C measured within 30 minutes after arrival in the
trauma center noted a threefold-increased odds of death, even
when adjusted for the confounding effects of age, injury
severity and mechanism, admission systolic blood pressure,
and temperature measurement route.
89
High risk for persis-
tent coagulopathy was qualified as temperature ⬍35°C in the
patient with medical bleeding.
29
A strong correlation between
perioperative temperature and blood loss independent of de-
gree of physiologic or anatomic injury was also noted.
90
In
hypothermic (35.0°C ⫾0.5°C) patients intraoperative and
postoperative blood loss were significantly greater.
91
Temperature-related coagulation disorders are caused by
clotting factor enzyme function, platelet function, and fi-
brinolytic activity.
92
The series of enzymatic reactions of the
coagulation cascade are strongly inhibited by hypothermia.
19
Thirty-four degree celsius was the critical point at which
enzyme activity in trauma patients slowed significantly, and
at which significant alteration in platelet activity was seen.
93
It has been recommended to quickly obtain a temperature of
ⱖ34°C
21
or 36°C,
30
respectively. Clotting time prolongation
appeared proportional to the number of enzymatic steps
involved
94
: clotting time correlated significantly with assay
temperature in a negative exponential fashion. This data
showed that hypothermia-induced coagulopathy is, at least in
part, independent of the clotting factor levels. In a follow-up
study the same group suggested that clotting times were more
severely prolonged when test temperatures were hypothermic
than when body temperatures were hypothermic.
8
Despite the
presence of normal clotting factor levels, at temperatures
below 33°C hypothermia produces a coagulopathy that is
Preconditions of Hemostasis in Trauma
Volume 65 •Number 4 955
functionally equivalent to significant, i.e., ⬍50% of nor-
mal activity, factor-deficiency states under normothermic
conditions.
95
So the avoidance or correction of hypothermia
may be critical in preventing or correcting coagulopathy in
the patient receiving massive transfusion.
21
Therefore, the
appropriate treatment for hypothermia-induced coagulopathy
is rewarming rather than administration of clotting factors.
Interestingly, in Martinowitz’ study the recombinant FVIIa
retained its activity at the patients’ mean temperature of
34.1°C ⫾2.5°C.
2
Nonetheless, the authors recommended that
body temperature should be restored to physiologic values.
In addition to the negative influence of hypothermia on
clotting factors, there is also an impairment of platelets’
function. Hypothermia has been shown to induce morpho-
logic changes in the platelet structure during activation
96
and
results in coagulopathy by reducing the availability of platelet
activators.
92
In vitro, hypothermia inhibited thrombin- and
up-regulation of GMP-140 complex, down-regulation of the
GPIb-IX complex, platelet aggregation, thromboxane B2
generation and in vivo platelet activation. These inhibitory
effects of hypothermia were all completely reversed by re-
warming the blood.
97
Measuring local skin temperature of the
forearm cooled with ice, isolated local hypothermia produced
an increased bleeding time and a significant reduction in the
thromboxane B2 level at the bleeding time site.
98
Each 1°C
decrease in temperature resulted in a 15% decrease in the
rate of thromboxane B2 production and thus in platelet
aggregation.
99
In platelets, the intracellular concentration of
Ca
⫹⫹
and the three catalytic steps of the metabolism of
arachidonic acid to thromboxane A2 by the cyclo-oxygenase
pathway are strongly temperature dependent.
100
Thus, hypo-
thermia acts on platelet activation and adhesion by inhibiting
the interaction between vonWillebrand factor with the plate-
let GPIb-IX-V complex.
100
Measured with TEG, core temperature ⱕ34°C caused a
significant slowing of enzyme activity of about 10% per
degree celsius and decreased platelet activity without signif-
icantly altered fibrinolysis.
93
A systematic evaluation of the
effect of temperature on coagulation enzyme activity and
platelet function showed
101
: Factor Xa generation was re-
duced by 13% at 33°C compared with 37°C, which is almost
consistent with an expected twofold increase in rate for every
10°C increase in reaction temperature for a typical enzyme.
Prothrombinase (FXa/Va) activity decreased in a temperature-
dependent fashion from 37°C to 33°C and thrombin genera-
tion was reduced by 25% at 33°C. At that temperature,
platelet aggregation and adhesion are significantly impaired.
Below 33°C reduced enzymatic reaction rate significantly
blocked the factors’ activity.
Thus, between 37°C and 33°C hemostatic defects
primary result from a defect in platelet adhesion and aggre-
gation, but below 33°C altered enzymatic activity is an ad-
ditional factor. In a porcine model, hypothermia of 32°C
resulted in decreased platelet count but increased receptor
densities.
25
Systemic hypothermia between 31°C and 34°C
accelerated microvascular thrombosis, which was mediated
by increased GPIIb-IIIa activation on platelets.
102
The au-
thors speculated, fibrinogen may possibly “bridge” the acti-
vated GPIIb-IIIa receptors, so the consumption of fibrinogen
may cause the coagulopathy. Additionally, another reason
seems to be a reduction in the availability of platelet activa-
tors, like the observed reduction in thrombin generation.
103
So, the net result of hypothermia in vivo is still considered to
be anticoagulant, even a superficial cooling of an arm with
preserved core temperature resulted in a significantly pro-
longed bleeding time.
104
Perioperative heat loss in the trauma setting is primarily
caused by fluid resuscitation and is proportional to the mass
of fluid used and the temperature gradient from the patient to
the fluid.
105
The energy needed by the body to warm2Lof
colloidal fluids infused at room temperature of 25°C within 1
hour exceeds the energy that can be delivered by conven-
tional warming methods in 1 hour.
106
Therefore, the amount
of infused fluids should be limited to ensure the delicate
balance between oxygen delivery and the tissue’s metabolic
demands. As proposed by the concept of “low-volume fluid
resuscitation”
107
and “goal-directed therapy”,
108
this equilib-
rium should be reached with an mean arterial pressure of ⱖ65
mm Hg
109
or systolic pressure at approximately 90 mm
Hg.
72,81
The effects of hypothermia-induced coagulopathy
can be limited by early and sole infusion of warmed fluids,
106
use of warm fluids via rapid infusion systems,
30
more effec-
tive, efficient, possibly aggressive and invasive (i.e., contin-
uous arteriovenous)
110
rewarming techniques,
111
the use of
adjunctive warming devices
30
such as warm air blankets,
30
and an increased ambient or operation room temperature.
112
Conclusion
A core temperature of ⱕ34°C causes a decisive impair-
ment of hemostasis. A controlled hypotensive fluid resusci-
tation should aim at reaching a mean arterial pressure of ⱖ65
mm Hg (possibly higher for cerebral trauma). Prevention and
later aggressive therapy of hypothermia by exclusive infusion
of warmed fluids and the use of warming devices are prereq-
uisites for the cure of traumatic coagulopathy.
Combinations
Although studies determining the influences of single
preconditions to traumatic coagulopathy are interesting for
scientific purposes, in the clinical setting, the deterioration of
hemostasis in trauma is always caused by multiple and con-
curring ones.
The terms “lethal triad ” or “bloody vicious circle” are
used by many authors for the combination of hypothermia,
acidosis, and coagulopathy.
21,109
Of 45 trauma patients re-
quiring massive transfusions with a mean ISS of 55 ⫾6, a
mean transfusion of 22.5 ⫾5 units of blood, and a mortality
of 33%, nonsurvivors had a higher incidence of clinical
coagulopathy (73% vs. 23%), had lower pH (pH 7.04 ⫾0.06
vs. 7.18 ⫾0.02), received more transfusions (26.5 ⫾9 vs.
The Journal of TRAUMA威Injury, Infection, and Critical Care
956 October 2008
18.6 ⫾1), and had lower core temperature (31 ⫾1°C vs.
34 ⫾1°C).
21
Despite adequate blood, plasma, and platelet
replacement, patients who were hypothermic and acidotic
developed clinically significant bleeding. Hypothermia
⬍35°C and dilution acted additively on coagulation times and
platelet function.
113
Analyzing 58 injured patients without
severe head injury and preexisting coagulation dysfunction
who received ⬎10 units RBCC per 24 hour, a model was
developed to identify patients at risk for early life-threatening
coagulopathy.
109
The four risk factors were: pH ⬍7.1, core
temperature ⬍34°C, ISS ⬎25, and systolic blood pressure
⬍70 mm Hg. With all four risk factors the incidence of
coagulopathy was 98%. Comparing hypothermia and acidosis
regarding the development of coagulopathy found the effects
of lowering pH from 7.4 to 7.15 to be almost identical to the
effects of decreasing the temperature from 36°C to 32°C.
26
In a porcine model of hemorrhagic shock when shock and
hypothermia occurred simultaneously, their deleterious ef-
fect on hemodynamic and coagulation parameters were
additive.
114
The effects of hypothermia persisted despite the
arrest of hemorrhage and volume replacement. In 212 severe
trauma patients, a study showed hemodilution by colloids and
acidosis are highly correlated with hypocalcemia.
41
Acidosis
plus hypothermia led to a 72% increase in splenic bleeding
time in a pig model.
5
Both acidosis and hypothermia altered
circulating platelet status in swine.
25
In the same setting, pH
of 7.1 and temperature of 32°C led to significantly delayed
thrombin generation and platelet granule release, and reduced
thromboxane B production rate.
115
Although in this model
the effects of 32°C on clot initiation (r time) suggested re-
duced enzymatic rates, the pH of 7.1 slowed clot initiation
primarily by altered cellular response. Nevertheless, the com-
bined effects of acidosis plus hypothermia were greater than
the individual ones.
116
The fact that high infusion rates of blood
products containing citrate will decrease Ca
⫹⫹
is particularly
true in combination with hypothermia.
112
As proven by Martini
et al.,
37
the kinetics of fibrinogen activation and thrombin gen-
eration are inhibited by acidosis and hypothermia via different
mechanisms: thrombin generation is impaired by hypothermia in
the initiation phase and by acidosis in the propagation phase.
5
Although fibrinogen generation is reduced by hypothermia,
37
acidosis impairs its degradation.
5
Recently, in a rabbit model
employing 50% hemodilution and 4°C temperature reduction,
all the clotting proteins as well as RBC and platelets were diluted
by at least 40%.
117
The excessive bleeding was caused by a slow
clotting process and a decrease in platelet count and fibrinogen
concentration in the blood.
Conclusion
Combined appearance of single preconditions cause ad-
ditive impairments of the coagulation system. The prevention
and timely correction, especially of the combination acidosis
plus hypothermia, is crucial for the treatment of hemorrhagic
coagulopathy.
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bleeding time and in vitro thrombelastography measurements are
better indicators of dilutional hypothermic coagulopathy than
prothrombin time. J Trauma. 2007;62:1352–1359.
Errata
In the article, “Blunt Abdominal Trauma Leading to Traumatic Transection of the Liver Without Massive Hemorrhage,”
which appeared as an online only article in volume 65, number 2 of The Journal of Trauma, two author’s names were
misspelled. The author listing should have read: Martijn Hommes, MD, J. Carel Goslings, MD, and Thomas M. van
Gulik, MD.
This error has been corrected in the online version of the article available at www.jtrauma.com.
REFERENCE
Hommes M, Goslings C, van Gulik TM. Blunt abdominal trauma leading to traumatic transaction of the liver without massive hemorrhage.
J Trauma 2008;65:E21–3.
In volume 65, number 2 of The Journal of Trauma, the Letters to the Editor from Dr. Dirnhofer and Dr. Rutty were
incorrectly published under the heading of “The Authors’ Reply.” These letters should have appeared under the heading
“To the Editor.”
These errors have been corrected in the online version of the article available at www.jtrauma.com.
REFERENCES
Dirnhofer R, Ranner G, Yen K. CT scanning as a detection tool for forensic pathologists. J Trauma 2008;65:494.
Rutty GN, Morgan B, O’Donnell C, Leth PM, Thali M. Forensic institutes across the world place CT or MRI scanners or both into their
mortuaries. J Trauma 2008;65:493– 4.
The Journal of TRAUMA威Injury, Infection, and Critical Care
960 October 2008
