Mechanisms of Trauma Coagulopathy

Dr B M Schyma

Changi General Hospital

Singapore

A continued cause of PREVENTABLE death.

24% of trauma patients are coagulopathic on arrival1

• 56% of severe trauma patients have coagulation abnormalities at 25min (samples taken on scene)

Time to Definitive Haemorrhage Control is a key determinant of outcome 3.

HAEMORRHAGE

1) Brohi, J Trauma (2003) 2) Floccard et al, Injury (2012) 3) Macleod, J Trauma (2003)

Coagulopathy is the Harbinger of Mortality

1) Frith et al, J Throm Haemost (2010)

• Pooled data from 5693 patients in 5 countries

• Samples taken on admission

Number of Units in 24hrs

The Triad of Death – The Complete Story?

HYPOTHERMIA

ACIDAEMIA COAGULOPATHY

CLOTTING FACTOR DYSFUNCTION

CLOTTING FACTOR LOSS DILUTION

CONSUMPTION

BUT…..of 701,491 patients:

• Only 11,026 (1.57%) had an admission temperature < 35°C1

Hypothermia

1) Martin et al, Shock (2005)

ROTEM

• CT: Time to initiation of fibrin formation • Alpha Angle: Rapidity of Fibrin Build up and Cross Linking • CFT: Clot Kinetics (2mm to 20mm) • MCF: Clot strength

ROTEM

p < 0.00001, r = 0.85 p < 0.00001, r = 0.89

Clot Strength

pH

MC

F (m

m)

Dilution

1. Maegele, World Journal of Emergency Medicine (2010)

71 Patients, ISS > 15

Stratified to degree of hypoperfusion by base deficit

Similar volume of crystalloid

Venous sample taken on admission

• Factor assay

Clotting factor DEFICIENCY?

1) Jansen et al , J Trauma (2011)

Base Deficit Vs. Factor Activity

1) Jansen et al , J Trauma (2011)

76% factor activity remained in the normal range

42% of patients had no deficiency

Factor 5 behaves differently

• Significant association between BD and factor activity for 2,7,9,10 &,11

• No association between BD and Factor 5 Activity

• Lowest level of activity of all factors

• 54% had a level below normal range

However…

A significant number of our trauma patients arrive with significant coagulopathy.

Mechanisms traditionally thought to cause coagulopathy appear to only occur in extremes.

An interesting juxtaposition…

Is There Something Else?

This Next Slide May Contain The Sexiest Graph You Will See Today

1) Frith et al, J Throm Haemost (2010)

Similar Pattern with Mortality

1) Frith et al, J Throm Haemost (2010)

Protein C • Activated by Thrombin-Thrombomodulin Complex

• Inhibits Factors 5 & 8

• Promotes Fibrinolysis

Cohen et al • 206 patients

• Serial Blood Samples at 6,12, and 24 hrs

• Stratified by Base Deficit and ISS

Potential Mechanism?

1. Cohen et al, Ann Surg (2012)

Increased Activation of Protein C

*p < 0.05

Activated Protein C Levels Protein C Levels

Associated with Decreased Factor 5 & 8

*p < 0.05

Factor Va Level Factor VIIIa Level

Fibrinolysis

FIBRINOGEN

CROSS LINKED FIBRIN

Thrombin

FIBRIN DEGRADATION

PRODUCTS

PLASMIN

PLASMINOGEN

tPA

APC Associated with De-Repression of Fibrinolysis

*p < 0.05

The Thrombin Switch

SHOCK

THROMBOMODULIN

THROMBIN-THROMBOMODULIN

THROMBIN

PROTEIN C

ACTIVATED PROTEIN C

Fibrinolysis

Fibrinogen concentration falls quickly

Low fibrinogen predictor of mortality at 24hrs and 28 days1

Degree of fibrinolysis related to mortality2

Fibrinogen & Fibrinolysis

1. Rourke et al, J Thromb Haemost (2012) 2. Tauber et al, Br J Anaesth (2011)

Platelets

• Limited knowledge of the role of platelets in Trauma Induced Coagulopathy

Endothelial Dysfunction

What have we not talked about…

‘Imbalance of the Dynamic Equilibrium Between Procoagulant Factors, Anti-coagulant Factors, Platelets, Endothelium and

Fibrinolysis’1

Multi-Factorial • Acute Coagulopathy of Trauma

• Hyperfibrinolysis

• Factor Deficiency • (Dilutional) • (Acidaemia) • (Hypothermia)

Trauma Induced Coagulopaty (TIC)

1. Frith and Brohi, Curr Opin Crit Care (2012)

Remember • Identify the bleeding coagulopathic patient early.

• Classical tests of coagulation may not detect TIC

Instigate Damage Control Resuscitation • Haemostatic Resuscitation

• Haemostatic Packaging

• Minimal, Targeted, Crystalloid Administration

• Early High Ratio Component Therapy

• Address Fibrinolysis

• Point of care coagulation testing

Managing TIC

Khan et al 2014

106 patients

• Median ISS 35 (25-41)

INTERN (International Trauma Research Network)

Lactate and ROTEM analysed at 4, 8 and 12 units PRBC

FFP:PRBC 2:3

Platelets & Cryoprecipitate at 6 PRBC

FULL CIRCLE…

*versus time zero

4 Unit Transfusions 8 Unit Transfusions 12 Unit Transfusions

ROTEM 5min Clot Amplitude (CA5) ROTEM Mean Clot Firmness (MCF)

ROTEM Clotting Time (CT)

Resuscitation is not an end-point, it is a means to

facilitating definitive management.

Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54:1127-1130.

Floccard B, Rugeri L, Faure A et al. Early coagulopathy in trauma patients: an on-scene and hospital admission

study. Injury. 2012;43:26-32.

MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J

Trauma. 2003;55:39-44.

Frith D, Goslings JC, Gaarder C et al. Definition and drivers of acute traumatic coagulopathy: clinical and

experimental investigations. J Thromb Haemost. 2010;8:1919-1925.

Martin RS, Kilgo PD, Miller PR, Hoth JJ, Meredith JW, Chang MC. Injury-associated hypothermia: an analysis of

the 2004 National Trauma Data Bank. Shock. 2005;24:114-118.

Engstrom M, Schott U, Romner B, Reinstrup P. Acidosis impairs the coagulation: A thromboelastographic

study. J Trauma. 2006;61:624-628.

Maegele M. Acute traumatic coagulopathy: Incidence, risk stratification and therapeutic options. World J

Emerg Med. 2010;1:12-21.

References (1)

Jansen JO, Scarpelini S, Pinto R, Tien HC, Callum J, Rizoli SB. Hypoperfusion in severely injured trauma patients

is associated with reduced coagulation factor activity. J Trauma. 2011;71:S435-S440.

Cohen MJ, Call M, Nelson M et al. Critical role of activated protein C in early coagulopathy and later organ

failure, infection and death in trauma patients. Ann Surg. 2012;255:379-385.

Rourke C, Curry N, Khan S et al. Fibrinogen levels during trauma hemorrhage, response to replacement

therapy, and association with patient outcomes. J Thromb Haemost. 2012;10:1342-1351.

Tauber H, Innerhofer P, Breitkopf R et al. Prevalence and impact of abnormal ROTEM(R) assays in severe blunt

trauma: results of the ‘Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study’. Br J

Anaesth. 2011;107:378-387.

Frith D, Brohi K. The pathophysiology of trauma-induced coagulopathy. Curr Opin Crit Care. 2012;18:631-636.

Khan S, Brohi K, Chana M et al. Hemostatic resuscitation is neither hemostatic nor resuscitative in trauma

hemorrhage. J Trauma Acute Care Surg. 2014;76:561-7; discussion 567.

References (2)