Holley analyses the cascade of events in bleeding trauma patients leading to Australia's latest evidenced-based guidelines on transfusion protocols in critical bleeding.

1. Transfusion andTransfusion and
CoagulopathyCoagulopathy
Anthony Holley
Intensivist
Royal Brisbane & Women’s Hospital

2. ExsanguinationExsanguination
 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%

5. Rev Gonsky
@coolholdenv8R

7. The MissionThe Mission

8. On arrival in EDOn 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

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

10. Early coagulopathy in trauma patients: anEarly coagulopathy in trauma patients: an
on-scene and hospital admission study.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.

11. MeasuredMeasured
 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.

12.  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.

13. Why?Why?

14. Acute Coagulopathy ofTraumaAcute Coagulopathy ofTrauma
 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 < 35o
C)
◦ Acidosis (pH < 7.2 or BD > 6)
◦ Haemodilution

15. A Time to ConsiderA Time to Consider
 Mechanism of coagulopathy
 Strategies to best manage patients
 Best modality to assess coagulopathy

16. Coagulopathy
Acidosis Hypothermia
Bleeding
Kashuk JL, Moore EE, Millikan JS, Moore JB. Major abdominal vascular
trauma—a unified approach. J Trauma 1982; 22:672-679.
Classically Trauma-induced
Coagulopathy

17. Time to Challenge theTime to Challenge the
Dogma?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”
– JTrauma,Aug 08, p272

18. Coagulopathy
Acidosis Hypothermia
Bleeding
Injury
Hy p er f i b r i nol y si
Classically Trauma-induced
Coagulopathy
AP C

19. Dilution?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

20.  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 < 33°C.
Hypothermia?

21.  Effects of IV HCL acid on human volunteers.
 Definite dose–response 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.
Acidaemia?

22.  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
Consumption?

23.  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.
Drivers of Traumatic
Coagulopathy?

24.  Acute coagulopathy in massive transfusion
appears to be due to activation of
anticoagulant and fibrinolytic pathways.
 Thrombomodulin–protein C pathway is
implicated.
Mechanism of Acute
Traumatic Coagulopathy

25. Normal
Haemostasis
Procoagulant
Activity
Antifibrinolytic
activity
Anticoagulant
Activity
fibrinolytic
activity
Thrombus
Bleeding

26.  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 cofactorsV
andVIII
Protein C Activation

27. Protein C Anticoagulant PathwayProtein C Anticoagulant Pathway

28. .
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
,

29. Biological Response PathologicalBiological Response Pathological
in Shockin Shock
 Tissues subjected to low-flow states
generate an anticoagulant milieu
 Avoids thrombosis of vascular beds.

30.  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

31. HyperfibrinolysisHyperfibrinolysis
Reduction in plasminogen activator inhibitor-1 (PAI-1) levels
in tissue hypoperfusion
APC

33. CRASH-2 trial collaborators. The Lancet. 2010;376:23-32
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
Tranexamic acid

34. ACEM ASM 2010
Plasminoge
n activator
Plasmin
Plasminoge
n
Blockade Blockade
Tranexamic AcidTranexamic Acid
Tranexamic AcidTranexamic Acid
Fibrinolysis

35. The StudyThe 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

37. Tranexamic AcidTranexamic Acid

38. Tranexamic AcidTranexamic Acid

39. But............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

40. Arch Surg. 2012;147(2):113-119. 2011
Study profi le illustrating the overall cohort and study groups.
MATTERs

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

42. 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

43. 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, Mantel-
Cox log-rank test.
MATTERs

44. 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 log-
rank test.
MATTERs

45. Tranexamic acid safely reduces the
risk of death in bleeding trauma
patients!

46. The Old Question of Ratios?The Old Question of Ratios?

47. 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.

48. Product RatiosProduct 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.

50. 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):
Increased platelet:RBC ratios are associatedIncreased platelet:RBC ratios are associated
with improved survival after massivewith improved survival after massive
transfusiontransfusion..

51. J Trauma. 2009;66:358–364.

52.  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

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

56. National BloodNational Blood
AuthorityAuthority
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

57. Patient blood ManagementPatient blood Management
GuidelinesGuidelines

58. Patient blood management aims to improve clinicalPatient blood management aims to improve clinical
outcomes by avoiding unnecessary exposure to bloodoutcomes by avoiding unnecessary exposure to blood
componentscomponents
It includes the three pillars of:It includes the three pillars of:
1. Optimisation of blood
volume and red cell
mass
2. Minimisation of blood
loss
3. Optimisation of the
patient’s tolerance of
anaemia.

59. Crash 2Crash 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.

60. So in patients with critical bleedingSo in patients with critical bleeding
requiring massive transfusion, whichrequiring massive transfusion, which
parameters should be measured earlyparameters should be measured early
and frequently?and frequently?

61. In patients with critical bleeding requiringIn patients with critical bleeding requiring
massive transfusion, the following parametersmassive transfusion, the following parameters
should be measured early and frequently:should be measured early and frequently:
1. Temperature
2. Acid–base 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.
Practice Point

62. Values indicative of critical physiologicValues indicative of critical physiologic
derangement include:derangement include:
1. Temperature < 35°C
2. pH < 7.2, base excess > –6, lactate > 4 mmol/L
3. ionised calcium < 1.1 mmol/L
4. platelet count < 50 × 109/L
5. PT > 1.5 × normal
6. INR > 1.5
7. APTT > 1.5 × normal
8. fibrinogen level < 1.0 g/L.
Practice Point

64. Activated Factor VIIActivated Factor VII
301 trauma patients were enrolled. 143 blunt, 137 penetrating.

65. Hauser et al. J Trauma. 2010 Sep;69(3):489-500Hauser et al. J Trauma. 2010 Sep;69(3):489-500
 Randomized prospective trial
 573 patients
 No effect on mortality
 No effect on thrombotic events
 Trial stopped early for lack of efficacy!

67. 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.

69. What of the Post Trauma PeriodWhat 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.

70. 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
• failed surgical or radiological measures to control bleeding, and
• adequate blood component replacement, and
• pH > 7.2, temperature > 340
C.
Discuss dose with haematologist/transfusion specialist
b
rFVIIa is not licensed for use in this situation; all use must be part of practice review.
• 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
• Avoid hypothermia, institute active warming
• Avoid excessive crystalloid
• Tolerate permissive hypotension (BP 80–100 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
• If significant physiological derangement, consider
damage control surgery or angiography
• Consider use of cell salvage where appropriate
• 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
Specific surgical considerations
ResuscitationInitial management of bleeding
Dosage
Cell salvage
Considerations for use of rFVIIab
Special clinical situations
Suggested criteria for activation of MTP
ABG arterial blood gas FFP fresh frozen plasma APTT activated partial thromboplastin time
INR international normalised ratio BP blood pressure MTP massive transfusion protocol
DIC disseminated intravascular coagulation PT prothrombin time FBC full blood count
RBC red blood cell rFVlla activated recombinant factor VII
Platelet count < 50 x 109
/L 1 adult therapeutic dose
INR > 1.5 FFP 15 mL/kga
Fibrinogen < 1.0 g/L cryoprecipitate 3–4 ga
Tranexamic acid loading dose 1 g over 10 min,
then infusion of 1 g over 8 hrs
a Local transfusion laboratory to advise on number of units
needed to provide this dose

71. Thank YouThank You