Transfusion and

Coagulopathy
Anthony Holley
Intensivist
Royal Brisbane & Womens Hospital

Exsanguination
Haemorrhage remains a major and
potentially reversible cause of all trauma
deaths.
More pronounced in the setting of
penetrating trauma.
Mortality in this group is 20-50%

Rev Gonsky
@coolholdenv8R

The Mission

On arrival in ED
Groom HR 123, BP 118/60, Extensive
pelvic #. INR 1.3
Bride HR 100, BP 110/80, bilateral femur
fractures. INR1.2
Driver HR 140, BP 80/35, pelvic #,
moderate severity head injury, bilateral
tib/fib compound #. INR1.7
Front passenger HR 100 BP 80/46, +FAST.
INR 1.1

Coagulopathy is present at
admission in 25% of trauma
patients.
Associated with a 5-fold increase
in mortality.

Early coagulopathy in trauma patients: an

on-scene and hospital admission study.
Prospective, observational study
investigating the on-scene coagulation
profile and its time course.
N = 45 patients
At the scene of the accident, before fluid
administration.
to hypoperfusion.

Measured
Prothrombin time
Activated partial thromboplastin time
Fibrinogen concentration
Factors II, V and VII activity,
Fibrin degradation products
Antithrombin and protein C activities
Platelet counts and base deficit.

On-scene coagulation status was abnormal

in 56% of patients.
Protein C activities were decreased
Factor V levels decreased significantly
with the severity of the trauma.

Why?

Acute Coagulopathy of Trauma

Syndrome of non-surgical bleeding from mucosal

lesions, serosal surfaces, wound and vascular access
sites associated with serious injury
INR > 1.5 reliably predicts those who will require
massive transfusion
Seen in most severely injured upon admission to ED
Coagulopathy correlates with ISS
Also associated with:
Hypothermia (temp < 35oC)
Acidosis (pH < 7.2 or BD > 6)
Haemodilution

A Time to Consider
Mechanism of coagulopathy
Strategies to best manage patients
Best modality to assess coagulopathy

Classically Trauma-induced
Coagulopathy

Bleeding

Acidosis

Coagulopathy

Hypothermia

Kashuk JL, Moore EE, Millikan JS, Moore JB. Major abdominal vascular
traumaa unified approach. J Trauma 1982; 22:672-679.

Time to Challenge the

Dogma?
None of these appears to be responsible for
acute coagulopathy, and it appears that
shock is the prime initiator of the process!"
Trauma-induced coagulopathy can develop in
24.4% of patients independent of acidosis and
hypothermia but secondary to trauma by itself
J Trauma, Aug 08, p272

Bleeding

Acidosis

Hypothermia

yr u j n I

Classically Trauma-induced
Coagulopathy

Hy p er f i b r i nol y si
Coagulopathy
AP C

Dilution?

Little or no dilutional effect of crystalloid therapy on

the standard tests of coagulation either in vitro or in
healthy volunteers
London study ~ median fluid 500 ml
German study ~ median fluid 2.2 L
Colloid vs Crystalloid
Coagulopathy was present in 10% of patients who
received less than 500 ml of fluid
? Alternative mechanism

Hypothermia?

Moderate/severe hypothermia present < 9% of trauma

patients
Relationship between hypothermia, shock and injury
severity a weak independent predictor of mortality (OR
1.19)
Very little effect of moderate hypothermia on coagulation
proteases.
Significant effects on function and clinical bleeding only at
temperatures < 33C.

Acidaemia?

Effects of IV HCL acid on human volunteers.

Definite doseresponse of acidaemia on clotting function
by thromboelastometry.
Little clinically significant effect on protease function down
to a pH of 7.2 in in-vitro studies
Animal studies: pH of 7.1 produces only a 20%
prolongation of the PT & APTT.

Consumption?

Consumption regarded as a primary cause of traumatic

coagulopathy
Little evidence for consumption of clotting factors as a
relevant mechanism
In patients without shock coagulation times are never
prolonged, regardless of the amount of thrombin generated

Drivers of Traumatic
Coagulopathy?
Shock and systemic hypoperfusion?
Dose-dependent prolongation of clotting
times with increasing systemic
hypoperfusion.
Base deficit (BD) as a surrogate for
perfusion
2% of patients with a BD < 6 mEq/l had
prolonged clotting times
20% of patients with a BD > 6 mEq/l.

Mechanism of Acute
Traumatic Coagulopathy

Acute coagulopathy in massive transfusion

appears to be due to activation of
anticoagulant and fibrinolytic pathways.
Thrombomodulinprotein C pathway is
implicated.

Procoagulant

Antifibrinolytic
activity

Activity

Thrombus

Normal
Haemostasis

fibrinolytic
activity

Bleeding

Anticoagulant
Activity

Protein C Activation

With tissue hypoperfusion the endothelium

expresses thrombomodulin which complexes
with thrombin.
Less thrombin is available to cleave fibrinogen
Thrombin complexed to thrombomodulin
activates protein C, which inhibits cofactors V
and VIII

Protein C Anticoagulant Pathway

.
Brohi et al. Acute traumatic coagulopathy: initiated by hypoperfusion:
modulated through the protein C pathway? Ann Surg 2007 May. 2007
May;245(5):812-8
,

Biological Response Pathological

in Shock
Tissues subjected to low-flow states
generate an anticoagulant milieu
Avoids thrombosis of vascular beds.

Hyperfibrinolysis

Trauma is associated with increased

fibrinolytic activity.
Tissue plasminogen activator (tPA) is released
from the endothelium following injury and
ischaemia.
Local control mechanism to reduce
propagation of clot to normal vasculature

Hyperfibrinolysis

APC

Reduction in plasminogen activator inhibitor-1 (PAI-1) levels

in tissue hypoperfusion

Tranexamic acid

Effects of tranexamic acid on death,

vascular occlusive events, and blood
transfusion in trauma patients with
significant haemorrhage (CRASH-2): a
randomised, placebo-controlled trial
CRASH-2 trial collaborators. The Lancet. 2010;376:23-32

Tranexamic Acid
Tranexamic Acid

ACEM ASM 2010

Plasminoge
n activator

Plasminoge
n

Plasmin

Fibrinolysis

Blockade

Blockade

The Study
Prospective

double blind
274 hospitals
40 countries
n=20211
Tranexamic (n=10 060) acid vs placebo
(10115)
1 g over 10 minutes then 1 g over 8 hours
Primary outcome: in hospital four week
mortality

Tranexamic Acid

Tranexamic Acid

But............
Entrance

criteria soft (HR>110 bpm, SBP<90

mmHg)
70% of patients SBP > 90 mmHg
Only 16% of patients SBP <75 mmHg
No reduction in blood transfusion observed
Median no. of RBC units transfused = 3 in
both groups
Needs to be given within three hours of
injury

MATTERs
Arch Surg. 2012;147(2):113-119. 2011

Study profi le illustrating the overall cohort and study groups.

MATTERs

Arch Surg. 2012;147(2):113-119.2011

MATTERs
From: Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study
Arch Surg. 2012;147(2):113-119.

Percentage of patients with hypocoagulopathy on admission to the emergency department (ED) and then the intensive care unit
(ICU) following the initial operation. Coagulation data were available for 462 patients in the overall cohort and 155 patients in the
groups that received massive transfusion. TXA indicates tranexamic acid. * P < .05.

MATTERs
Arch Surg. 2012;147(2):113-119.

Kaplan-Meier survival curve of the overall cohort, including patients receiving tranexamic acid (TXA) vs no TXA. P = .006, MantelCox log-rank test.

MATTERs
From: Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study
Arch Surg. 2012;147(2):113-119.

Kaplan-Meier survival curve of the massive transfusion group receiving tranexamic acid (TXA) or no TXA. P = .004, Mantel-Cox logrank test.

Tranexamic acid safely reduces the

risk of death in bleeding trauma
patients!

The Old Question of Ratios?

Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, Gonzalez EA,
Pomper GJ, Perkins JG, Spinella PC, Williams KL, Park MS. Increased plasma and platelet to red
blood cell ratios improves outcome in 466
massively transfused civilian trauma patients. Ann Surg 2008; 248:447-458.

Product Ratios

Massive data base ~ 25 000

16% transfused
11.4% received massive transfusions
Logistic regression identified the ratio of FFP to PRBC
use as an independent predictor of survival.
With a higher the ratio of FFP:PRBC, a greater
probability of survival was noted.
The optimal ratio in this analysis was an FFP:PRBC ratio
of 1:3 or less.

Teixeira PG, Inaba K, Shulman I, Salim A, Demetriades D, Brown C,

Browder T, Green D, Rhee P. Impact of plasma transfusion in massively
transfusedtrauma patients. J Trauma 2009; 66:693-697.

Increased platelet:RBC ratios are associated

with improved survival after massive
transfusion.
n =2312
Massive transfusion in n = 643
To mitigate survival bias, 25 patients who died within 60 minutes of
arrival were excluded from analysis.
Increased platelet ratios were associated with improved survival at
24 hours and 30 days (p < 0.001 for both)
Holcombe and everybody et al. Everybody. J Trauma 2011 Aug;71(2
Suppl 3):

J Trauma. 2009;66:358364.

Retrospective data demonstrate a

relationship between higher cumulative
FFP:PRBC ratios and lower mortality at a
specific point in time
Ratio calculated at 24 hours after
admission in most studies.
Actual temporal relationship between the
administration of specific components
and mortality has not been elucidated

http://www.nba.gov.au/guidelines/order/index.html
http://www.nba.gov.au/guidelines/review.html

National Blood
Authority
2001 National Health and Medical Research Council/
Australasian Society of Blood Transfusion
(NHMRC/ASBT)
Clinical practice guidelines on the use of blood components
Now replaced by NBA:
Patient Blood Management Guidelines: Modules 1-6

Patient blood Management

Guidelines

Patient blood management aims to improve clinical

outcomes by avoiding unnecessary exposure to blood
components
It includes the three pillars of:

1.

2.
3.

Optimisation of blood
volume and red cell
mass
Minimisation of blood
loss
Optimisation of the
patients tolerance of
anaemia.

Crash 2
In trauma patients with or at risk of
significant haemorrhage, tranexamic acid
(loading dose 1 g over 10 minutes,
followed by infusion of 1 g over 8 hours)
should be considered.
No systematic review was conducted on
tranexamic acid in critical bleeding/massive
transfusion. The study population was not
restricted to critical bleeding requiring
massive transfusion.

So in patients with critical bleeding

requiring massive transfusion, which
parameters should be measured early
and frequently?

Practice Point
In patients with critical bleeding requiring
massive transfusion, the following parameters
should be measured early and frequently:
Temperature
2.
Acidbase status
3.
Ionised calcium
4.
Haemoglobin
5.
Platelet count
6.
PT/INR
7.
APTT
8.
Fibrinogen level.
With successful treatment, values should trend towards normal.
1.

Practice Point
Values indicative of critical physiologic
derangement include:
1.
2.
3.
4.
5.
6.
7.
8.

Temperature < 35C

pH < 7.2, base excess > 6, lactate > 4 mmol/L
ionised calcium < 1.1 mmol/L
platelet count < 50 109/L
PT > 1.5 normal
INR > 1.5
APTT > 1.5 normal
fibrinogen level < 1.0 g/L.

Activated Factor VII

301 trauma patients were enrolled. 143 blunt, 137 penetrating.

Randomized prospective trial

573 patients
No effect on mortality
No effect on thrombotic events
Trial stopped early for lack of efficacy!

Hauser et al. J Trauma. 2010 Sep;69(3):489-500

Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated

factor VII in randomized clinical trials. N Engl J Med 2010;363:1791-1800.

What of the Post Trauma Period

5% of war casualties from Iraq/Afghanistan
developed PE
The more we bleed the more we clot
The more tissue damage we sustain the
more we clot.

Suggested criteria for activation of MTP

Actual or anticipated 4 units RBC in < 4 hrs, + haemodynamically unstable, +/ anticipated ongoing bleeding
Severe thoracic, abdominal, pelvic or multiple long bone trauma
Major obstetric, gastrointestinal or surgical bleeding

Initial management of bleeding

Resuscitation
Avoid hypothermia, institute active warming
Avoid excessive crystalloid
Tolerate permissive hypotension (BP 80100 mmHg systolic)
until active bleeding controlled
Do not use haemoglobin alone as a transfusion trigger

Identify cause
Initial measures:
- compression
- tourniquet
- packing
Surgical assessment:
- early surgery or angiography to stop bleeding

Special clinical situations

Warfarin:
add vitamin K, prothrombinex/FFP
Obstetric haemorrhage:
early DIC often present; consider cryoprecipitate
Head injury:
aim for platelet count > 100 109/L
permissive hypotension contraindicated

Specific surgical considerations

If significant physiological derangement, consider
damage control surgery or angiography

Cell salvage
Consider use of cell salvage where appropriate

Considerations for use of rFVIIa b

Dosage

The routine use of rFVIIa in trauma patients is not recommended due to

its lack of effect on mortality (Grade B) and variable effect on morbidity
(Grade C). Institutions may choose to develop a process for the use of
rFVIIa where there is:
uncontrolled haemorrhage in salvageable patient, and

Platelet count < 50 x 109/L

1 adult therapeutic dose

INR > 1.5

FFP 15 mL/kga

Fibrinogen < 1.0 g/L

cryoprecipitate 34 ga

Tranexamic acid

loading dose 1 g over 10 min,

then infusion of 1 g over 8 hrs

failed surgical or radiological measures to control bleeding, and

adequate blood component replacement, and
pH > 7.2, temperature > 340C.
Discuss dose with haematologist/transfusion specialist

a Local transfusion laboratory to advise on number of units

needed to provide this dose

ABG
INR
DIC
RBC

arterial blood gas

international normalised ratio
disseminated intravascular coagulation
red blood cell

FFP
BP
PT
rFVlla

rFVIIa is not licensed for use in this situation; all use must be part of practice review.

fresh frozen plasma

blood pressure
prothrombin time
activated recombinant factor VII

APTT
MTP
FBC

activated partial thromboplastin time

massive transfusion protocol
full blood count

Thank You