Transfusion and Transfusion and Coagulopathy Coagulopathy

Anthony HolleyIntensivistRoyal Brisbane & Women’s Hospital

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%

Rev Gonsky@coolholdenv8R

The MissionThe Mission

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

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

Early coagulopathy in trauma patients: an Early 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.

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.

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?Why?

Acute Coagulopathy of TraumaAcute 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 ConsiderA Time to Consider

Mechanism of coagulopathy Strategies to best manage patients Best modality to assess coagulopathy

Coagulopathy

Acidosis Hypothermia

Bleeding

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

Classically Trauma-induced Coagulopathy

Time to Challenge the Time 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”

– J Trauma, Aug 08, p272

Coagulopathy

Acidosis Hypothermia

Bleeding

In

ju

ry

Hy p er f i b r i nol y si s

Classically Trauma-induced Coagulopathy

AP C

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

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?

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?

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?

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?

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

Normal

Haemostasis

Procoagulant

Activity

Antifibrinolytic activity

AnticoagulantActivity

fibrinolytic activity

Thrombus

Bleeding

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 Activation

Protein C Anticoagulant PathwayProtein 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 Biological Response Pathological in Shockin Shock

Tissues subjected to low-flow states generate an anticoagulant milieu

Avoids thrombosis of vascular beds.

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

HyperfibrinolysisHyperfibrinolysis

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

APC

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

ACEM ASM 2010

Plasminogen activator

PlasminPlasminoge

n

Blockade Blockade

Tranexamic AcidTranexamic AcidTranexamic AcidTranexamic AcidF

ibrin

olysis

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

Tranexamic AcidTranexamic Acid

Tranexamic AcidTranexamic Acid

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

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) StudyArch 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, Mantel-Cox log-rank test.

MATTERs

From: Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) StudyArch 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

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

The Old Question of Ratios?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 466massively transfused civilian trauma patients. Ann Surg 2008; 248:447-458.

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.

n =2312Massive 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 associated Increased platelet:RBC ratios are associated with improved survival after massive with improved survival after massive

transfusiontransfusion..

J Trauma. 2009;66:358–364.

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.htmlhttp://www.nba.gov.au/guidelines/review.html

National Blood National 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

Patient blood Management Patient blood Management GuidelinesGuidelines

Patient blood management aims to improve clinical Patient blood management aims to improve clinical outcomes by avoiding unnecessary exposure to blood outcomes 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.

Crash 2Crash 2In 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 So in patients with critical bleeding requiring massive transfusion, which requiring massive transfusion, which parameters should be measured early parameters should be measured early and frequently?and frequently?

In patients with critical bleeding requiring In patients with critical bleeding requiring massive transfusion, the following parameters massive 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

Values indicative of critical physiologic Values 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

Activated Factor VIIActivated Factor VII

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

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!

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 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.

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 > 340C.

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 timeINR international normalised ratio BP blood pressure MTP massive transfusion protocolDIC disseminated intravascular coagulation PT prothrombin time FBC full blood countRBC 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

Thank YouThank You