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Crit Care Clin 20 (2004) 13 – 24

Coagulation defects in trauma patients:


etiology, recognition, and therapy
Thomas G. DeLoughery, MD
Divisions of Medical Oncology/Hematology and Laboratory Medicine, L586 Oregon Health &
Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA

Hemostatic complications are common in trauma patients. These coagulation


defects may be related to many processes, ranging from pre-existing disease to
complications of therapy. This article reviews the causes of hemostasis defects,
how to recognize them, and how to treat them.

Etiology
The coagulation defects that occur in trauma patients are complex in origin
(Box 1). Often, these abnormalities are caused by many interrelated factors. The
most common reasons for abnormal coagulation laboratory test results in these
patients are dilution of hemostatic factors by fluid or blood resuscitation, severe
hypothermia, tissue damage from trauma, and effects of underlying diseases.

Dilution
Simplistically, it seems obvious that if large amounts of fluid and packed red
cells are given to patients, their plasma proteins (including coagulation factors) will
be diluted [1]. In trauma patients, however, the situation is more complex. Fluid can
shift to extravascular spaces; plasma proteins continue to be produced, and factors
are being consumed. Studies have shown that dilution is often not an issue until
over one blood volume (10 to 12 units of red cells) is given to a patient [2,3]. It is
impossible to predict how an individual patient will respond to transfusions.
Several studies have demonstrated poor correlation between the amount of blood
products given and coagulation defects [4– 7]. In Counts’ study [5], a very low
correlation was seen with the amount of blood given and decreases in specific

E-mail address: delought@ohsu.edu

0749-0704/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S0749-0704(03)00089-7
14 T.G. DeLoughery / Crit Care Clin 20 (2004) 13–24

Box 1. Coagulation defects: etiologies


Dilution of coagulation factors
Hypothermia

Slowing down coagulation factor enzyme function


Platelet dysfunction
Enhanced Fibrinolysis

Trauma

Head trauma—disseminated intravascular coagulation

Underlying disease

Hemophilia
von Willebrand disease
Liver disease
Warfarin

factor levels, with the r2 ranging from 0.02 to 0.17. Giving prophylactic platelets
has been shown not to be an effective strategy for preventing defects [8]. Patients
with disseminated intravascular coagulation caused by trauma may have severe
coagulation defects even before the first transfusion. For these reasons, one needs
to use specific monitoring of coagulation status and not rely on simplistic formulas
for predicting factor deficiencies.

Hypothermia
Trauma patients are prone to hypothermia [9,10]. Patients may be out ‘‘in the
field’’ for a prolonged period of time and be hypothermic on arrival [11]. Packed
red cells are stored at 4C, and the infusion of one unit can lower the body
temperature by 0.25C [12]. Infusion of fluids at room temperature can lower the
temperature by 0.5C for every liter infused. Exposure of viscera during surgery
can result in profound cooling of the patient.
Hypothermia has profound effects on the coagulation system that are associated
with clinical bleeding [9,13,14]. Coagulation occurs because of enzyme reactions
that are temperature dependent. Even modest cooling slows these reactions,
rendering the patient coagulopathic. For example, the Rohrer study showed that
the activated partial thromboplastin time (aPTT) lengthened from 36 seconds at
37C to 39 seconds at 34C and to 46 seconds at 31C [15]. In addition, all facets of
platelet function decline with modest hypothermia [13,16]. Finally, hypothermia
stimulates fibrinolysis, which can provoke more diffuse bleeding. Thus, even
modest hypothermia can augment bleeding greatly.
T.G. DeLoughery / Crit Care Clin 20 (2004) 13–24 15

Trauma
The key stimulus for coagulation is tissue trauma. The most profound example
is head trauma [17,18]. Patients with severe brain injuries often have severe
defibrination caused by exposure of the thromboplastin-rich brain tissue to flowing
blood. These patients may present with severely deranged hemostasis characterized
by fibrinogens below 50 mg/dL. They have severe consumptive coagulopathies
and may require large amounts of blood products. Because the liver is the source of
most coagulation proteins, severe liver injury or significant shock results in failure
of the body to compensate for consumption of coagulation factors.
Although not as spectacular as brain injuries, any type of severe trauma that is
associated with extensive tissue damage results in disseminated intravascular
coagulation (DIC). There is also evidence that fibrinolysis may be activated in
trauma patients, further amplifying the propensity for bleeding [19,20].

Underlying disease
Trauma is not restricted to previously healthy people. Patients with underlying
coagulation defects often enter trauma systems and tend to do worse. Hemophiliacs
may have impressive bleeding with their injuries. A rapidly emerging problem is
the growing number of the population taking oral anticoagulants. The indications
for long-term anticoagulation are increasing, and these patients are being seen more
frequently in the trauma setting.
Patients with liver disease are particularly problematic and have a significantly
higher mortality with trauma, in part because of their underlying hemostatic defects
[21,22]. Patients with severe liver disease have multiple coagulation defects [23].
All major coagulation factors and inhibitors are synthesized solely in the liver,
except factor VIII and von Willebrand factor. Patients with liver disease are
thrombocytopenic and have evidence of platelet dysfunction. Liver disease is the
most common cause of primary fibrinolysis because of a drop in plasma levels of
fibrinolytic inhibitors and delayed clearance of plasmin. Evidence of fibrinolysis
can be found in 30% of patients with end-stage liver disease.
As many as 1 in 100 patients have inherited coagulation defects. Most common
is von Willebrand disease, which is associated with excessive persistent bleeding
after trauma [24]. Most patients with von Willebrand disease have a history of
excessive bleeding with minor procedures and a propensity for bruising. If not
recognized, patients with von Willebrand disease can have on-going bleeding
despite surgical management. One in 10,000 male patients has hemophilia [25].
These patients may exsanguinate with trauma unless specific factor replacement
is provided.
Over 1% of the population takes warfarin. Several studies have shown that
patients taking warfarin have higher morbidity and mortality when they present
with intracranial hemorrhage [26,27]. It has been difficult to show that anti-
coagulated patients do worse with trauma, however, perhaps because these patients
are identified early and receive plasma [28].
16 T.G. DeLoughery / Crit Care Clin 20 (2004) 13–24

Recognition
Patients who bleed from coagulation defects have generalized bleeding from
multiple sites. These patients have diffuse oozing in the surgical field, bleeding
from intravenous (IV) sites, and ongoing blood loss into drains. A bleeding
diathesis is confirmed by laboratory testing, but in emergency situations, therapy
should be given while awaiting the results of testing.

Specific testing
The basic tests of coagulation are the platelet count, prothrombin time (PT –
INR), the aPTT, and the fibrinogen level (Box 2).
Platelets are essential for initial hemostasis in that they form the platelet plug.
Thrombocytopenia is the largest determinant of microvascular bleeding in mas-
sively transfused patients. In massively transfused patients, maintenance of the
platelet count at 50,000/mL or higher results in less microvascular bleeding [5,19].
Platelet dysfunction also has been reported with trauma. There still is not a simple
method for reliably measuring platelet function, however. Bleeding times are
difficult to perform and not predictive of bleeding [29,30]. Recently, a rapid
automatic test for platelet function, the PFA – 100, was introduced [31]. It is
unknown, however, whether measuring platelet function is helpful for the man-
agement of coagulation defects in trauma patients.
The PT – INR is a measure of the tissue factor VII pathway. It is sensitive to low
levels of factor VII and is often mildly prolonged (1.3 to 2.0) in the trauma setting.
Isolated elevations of the PT –INR reflect isolated factor VII deficiency and are not
indicative of severe coagulation defects. It appears that INR elevations are not

Box 2. Specific testing

Key hemostatic tests


Platelet count
Hematocrit
INR
Activated partial thromboplastin time
Fibrinogen
Tests for more complex situations
Thromboelastography
Platelet function analysis
Euglobulin clot lysis time
Specific factor levels
T.G. DeLoughery / Crit Care Clin 20 (2004) 13–24 17

indicative of the risk of generalized bleeding unless they are over 1.8 and are
associated with an elevated aPTT [6].
The aPTT reflects multiple steps in the coagulation cascade. Elevated levels
of the aPTT in the trauma setting indicate multiple and severe defects. aPTTs over
1.8 times controls have been associated with bleeding in several studies [5,6]. One
common error is to draw coagulation laboratory tests through intravenous access
lines. This commonly results in falsely elevated aPTT and can lead to therapeutic
misadventures [32].
Fibrinogen is often the forgotten factor. Fibrinogen is important for forming the
fibrin clot. Excessive bleeding has been reported with fibrinogen levels under
50 mg/dL [6]. Fibrinogen is also essential for the proper analysis of coagulation
assays. The endpoints of both the PT-INR and aPTT are time to formation of the
fibrin clot. When plasma levels of fibrinogen fall below 80 mg/dL, the clot may be
small and undetectable. This results in a very prolonged PT – INR and aPTT.
Thromboelastogram (TEG) is a unique laboratory test that examines whole
blood thrombus formation and lysis [33]. TEG is performed by placing 0.35mL of
whole blood into an oscillating container with a pin that measures the force of
thrombus formation. TEG measures five parameters:

1. r time: time from starting TEG until clot formation, correlated with coagu-
lation factor activity
2. K time: time between tracing going from 2mm to 20 mm, correlated with
speed of clot formation
3. alpha angle: slope of tracing between r and K time, correlated with fi-
brin formation
4. MA: greatest amplitude of TEG tracing, a marker of platelet function
5. Whole blood lysis index: amplitude of tracing 60 minutes after MA

Most modern TEG machines automatically calculate these parameters. TEG


allows rapid point-of-care testing of coagulation, and it is particularly useful in
assessing fibrinolysis. Research is underway to assess the role of TEG in the
trauma setting.

Therapy
Therapy of the bleeding trauma patient is directed at correcting the coagulation
defects, treatment of related problems such as underlying coagulation defects, and
therapy of complications such as hypothermia.

Massive transfusion
Trauma patients can require large amounts of transfusions. Early data showed
high mortality rates with transfusion of over 20 units of blood [3], but with modern
blood banking techniques and improved laboratory testing, this rate has decreased
18 T.G. DeLoughery / Crit Care Clin 20 (2004) 13–24

dramatically. Recent studies showed a survival rate of 43% to 70% in patients


transfused with over 50 units of blood [34 – 36].
The approach to massive transfusion involves measuring five laboratory tests
that reflect the basic parameters essential for both blood volume and hemostasis.
The tests are: hematocrit, platelet count, INR, activated partial thromboplastin time,
and fibrinogen level.
The clinical laboratory should be able to perform these tests rapidly and re-
port them to the trauma team. Replacement therapy is based on the results of
these laboratories.
Hematocrit goals vary with the clinical situation. For the rapidly bleeding
patient, blood is given until the patient is stable. For patients who are suffer-
ing mainly from derangements in coagulation, a lower hematocrit goal may be
more appropriate.
For a platelet count less than 50 to 75,000/mL, a plateletpheresis concentrate or
6 – 8 pack of single-donor platelet concentrate is given to the patient. Because the
platelets are suspended in plasma, this transfusion also provides plasma to the
patient. As a key determinant of primary hemostasis, platelets should be monitored
aggressively and replaced.
For a fibrinogen level less than 100 mg/dL, 10 units of cryoprecipitate should be
given. This should raise the fibrinogen by 100 mg/dL. In certain clinical situations,
such as brain injuries, hepatic trauma, or limb reperfusion, severe fibrinolysis may
occur, and large amounts of cryoprecipitate may be required.
For INR over 2.0 with an abnormal aPTT, two to four units of FFP are given.
As noted previously, isolated elevation of the INR does not require replace-
ment therapy.
For an aPTT greater than 1.5 times normal, two to four units of plasma are given.
If the aPTT is markedly elevated ( > 80 seconds) one should make sure the sample
is not contaminated by heparin. If both the PT –INR and aPTT are increased, then
the fibrinogen may be low.
One should repeat the basic five laboratory tests after administering the blood
products. This allows one to ensure adequate replacement therapy was given for the
abnormal laboratories. Frequent checks of the coagulation laboratories also allow
rapid identification and therapy of new coagulation defects before they become
severe. A flow chart of the laboratories and the blood products administered also
should be kept. Best results for massive transfusions are obtained when a multi-
disciplinary approach is used that involves the trauma team, transfusion medicine,
anesthesia, and hematology.
Occasionally, empiric therapy of the severely bleeding patient is required. One
should start with platelet products, since they also provide plasma. In patients likely
to have DIC also (ie, head trauma patients), empiric administration of 10 units of
cryoprecipitate is indicated.
There are many reports on the use of recombinant activated factor VIIa (rVIIa)
for the massively bleeding trauma patient [37 – 39]. rVIIa binds to the tissue factor
exposed at the site of injury and stimulates coagulation. Dosing has ranged from
90 to 270 mg/kg. Definite recommendations on use await completion of clinical
T.G. DeLoughery / Crit Care Clin 20 (2004) 13–24 19

trials. The use of rVIIa, however, may be reasonable in a patient who continues to
have diffuse bleeding despite maximal replacement of blood products or in trauma
patients on warfarin.

Complications of transfusions
One of the major complications of transfusing the trauma patient is hypother-
mia. This can be prevented by several measures. One is to transfuse the blood
through blood warmers. Devices are available that can warm a unit of blood in
1 minute. An increasingly popular technique is to perform damage control sur-
gery. Patients initially are stabilized with control of damaged vessels and packing
of oozing sites [40]. Then the patient is taken to the ICU to be warmed and have
coagulation defects corrected. This is discussed extensively in another article in
this issue.
Although much feared, electrolyte abnormalities are unusual even in the
massively transfused patient [41]. Platelet and plasma contain citrate, which can
chelate calcium. However, the citrate is metabolized rapidly, however, and it is rare
to see clinically significant hypocalcemia. Although empiric calcium replacement
often is recommended, one study suggests this is associated with a worse outcome
and should not be done [42]. If hypocalcemia is a clinical concern, levels should be
drawn to guide therapy.
Although potassium leaks out of stored red cells, even old units of blood only
contain a total of 8 mEq, so hyperkalemia is usually not a concern. There are rare
reports of sodium bicarbonate or other incompatible fluids being added to cell saver
blood, leading to massive hemolysis and fatal hyperkalemia. It is important to
remember that fluids such as Ringer’s lactate and glucose solutions cannot be given
with blood.
Stored blood is acidic, with a pH of 6.5 to 6.9. Acidosis attributed solely to
transfused blood is rare, however. Empirical bicarbonate replacement has been
associated with severe alkalosis and is not recommended [43,44].
Blood salvage is used frequently in trauma patients to help lessen red cell
transfusions. With blood washing, reports of coagulopathies have lessened [45].
Coagulopathy can occur, however, both due to dilution and infusion of thrombo-
genic substances [45,46]. Patients receiving large amounts of cell saver blood
(> 10 to 15 units) should have their coagulation status carefully monitored.

Adjunctive therapy
Trauma patients with liver disease require very close monitoring. These patients
may develop dramatic coagulation defects with only minor trauma. For a summary
of adjunctive therapy, see Box 3.
Abnormal fibrinolysis is an often overlooked cause of bleeding in patients with
liver disease. Bleeding in these patients tends to be characterized by diffuse oozing
from sites of minor trauma. Often these patients are treated futilely with massive
amounts of fresh frozen plasma before the fibrinolytic defect is discovered.
20 T.G. DeLoughery / Crit Care Clin 20 (2004) 13–24

Box 3. Adjunctive therapy

Liver disease: fibrinolysis


Amicar 5 grams bolus then 1 g/h for 8 hours

Hemophilia
Factor VIII deficiency: 50 Mg/kg of factor VIII concentrate
Factor IX deficiency: 120 units/kg of factor IX concentrate

von Willebrand disease


Humate– P 3000 factor VIII units

Warfarin

INR 1.5 – 3.0


Fresh plasma, 7.5mg/kg
Vitamin K, 1 mg IV or by mouth

INR 3.0 – 4.5


Fresh plasma, 15 mg/kg
Vitamin K, 2.5 mg IV or by mouth

INR 4.5 – 10
Fresh plasma, 15 mg/kg
Vitamin K, 5 mg IV or by mouth
INR > 10
Fresh plasma, 15 mg/kg
Vitamin K, 10 mg IV or by mouth

Diagnosis is made either clinically or, if available, by demonstrating a shortened


euglobulin clot lysis time in the setting of excessive bleeding.
In the patient who is bleeding from fibrinolysis, a trial of antifibrinolytic therapy
is warranted. The patient should be screened for DIC and significant urinary tract
bleeding. The dose of epsilon – aminocaproic acid is a bolus of 4 to 5 g given over
1 hour, followed by a continuous infusion of 1 g per hour for 8 hours [47 – 49].
Patients with inherited coagulation defects should receive specific therapy.
Severely injured patients with von Willebrand disease should receive Humate –P to
replace missing factor. If the injuries are modest, desmopressin (0.3 mg/kg) can be
given to the patients instead of Humate –P. Because 20% of patients with von
Willebrand disease do not respond to desmopressin, however, this should never be
given empirically to patients, unless their disease type is known. Hemophiliacs
T.G. DeLoughery / Crit Care Clin 20 (2004) 13–24 21

Box 4. Therapy of coagulation defects


Platelets < 50– 75,000/ML, give platelet concentrates or 6– 8
pack of single donor platelets
Fibrinogen < 125 mg/dL, give 10 units of cryoprecipitate
Hematocrit below 30%, give red cells
Protime > INR 2.0 and aPTT abnormal, give two to four units
of FFP

should receive doses of concentrate to raise their levels to over 100%. Arrange-
ments should be made to monitor factor levels to guide therapy precisely.
Trauma patients on warfarin require immediate reversal. The short-term risk of
thrombosis is outweighed by the need to control hemostasis. Patients should
receive vitamin K to reverse the warfarin with dosing guided by the INR. This
should be supplemented by plasma at 15 mL/kg. Patients with intracranial
hemorrhage also should receive either prothrombin complex concentrates 50 to
75 units/kg or rVIIa 40 mg/kg.

Correcting coagulation defects before procedures


Procedures such as central venous line placement very frequently are performed
successfully on patients with coagulopathies (Box 4) [50 – 53]. One study found the
risk was not related to the degree of hemostatic defects [54]. In this study, the risk of
hemorrhage was higher when inexperienced operators attempted line placement.
For urgent line placement, experience of the operator is more important than
waiting for transfusion therapy [54]. In a nonurgent situation, raising the platelet
count to 30 to 50,000/mL and attempting to lower the aPTT to less than 1.5 times
normal may be reasonable goals, but one should not delay a necessary procedure by
trying to achieve arbitrary targets for laboratory values.

Summary
Trauma patients have many reasons to have defects in coagulation. These can be
caused by the trauma or because of pre-existing disorders. Trauma patients who are
at risk for coagulation defects should be screened with the basic tests (aPTT, INR/
PT, platelet counts, hematocrit, and fibrinogen), with therapy based on the results.
Attention also should be paid to any other correctable factors such as hypothermia.
Finally, pre-existing disorders can influence the patient’s hemostasis greatly and
may require specific therapies.

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