Massive traumatic bleeding:

The multi-factorial complex nature of

Institute of Thrombosis Hemostasis and The National Hemophilia Center, Sheba medical Center, Tel Hashomer,

Uri Martinowitz MDUri Martinowitz MD

Member, Hemorrhage Control Steering Committee , The U.S. Army Medical Research and Materiel Command USAMARC, The Combat Casualty Care

Research Program CCRP

MILITARY TRAUMA

CNS-KIA31%

MULTI-KIA13% MOF-DOW 4%

CNS-DOW5%

SHOCK-DOW 3%

EXSANG-KIAEXSANG-KIA44%44%

KIA – killed in action; DOW KIA – killed in action; DOW – died of wound; MOF – – died of wound; MOF – multiple organ failure.multiple organ failure.

WDMET Vietnam war WDMET Vietnam war 1967–1969; 8000 1967–1969; 8000 CASUALTIESCASUALTIES. .

CNS 42%

EXSANGEXSANG39%39%

CNS + EXSANG6%

MOF 7%Other 6%

Sauaia A et al. Sauaia A et al. J Trauma.J Trauma. 1995; 1995;38:185-19338:185-193.

Trauma Is the leading cause of death in the young

Hemorrhage is a major cause of death in trauma

CIVILIAN TRAUMA289 FATALITIES: 49% PENETRATING, 48%

BLUNT

140,000 deaths/year in the US140,000 deaths/year in the US

Massive Hemorrhage in Trauma Massive Hemorrhage in Trauma

(and “controlled” trauma.)(and “controlled” trauma.)

“Surgical”

bleed

Massive

” combined”

bleed

“Late” coagulopathy

Activation consumption

hemodilution, anemia,

metabolic, hypothermia

Early coagulopathy (10 min.)

Hypoperfusion acidosis,

hyperfibrinolysis ,Prot. C

pathway activation by

thrombin with” systemic

anticoagulation” ??? Brohi K. J. Trauma 2008: 64 :1211

Trauma induced coagulopathy (TIC)

0

10

20

30

40

50

60

70

80

% Coagulopathy

0- 14 15 - 29 30 - 44 45 - 59 60 - 75

ISS

Brohi K: J. Trauma (2003) 55:1127

Incidence of coagulopathy correlates with ISSin civil trauma

(Kaufman CR,J. trauma 1997,Cosgriff N. J. Trauma 1997) (Kaufman CR,J. trauma 1997,Cosgriff N. J. Trauma 1997)

ISS-injury Severity score. >15 =severe injury

0102030405060708090

100

% mortality

0- 14 15 - 29 30 - 44 45 - 59 60 - 75

ISS

normalCoagulopathy

Coagulopathy is associated with increased mortality in civil trauma

4-6 times beyond expected from the injury severity

Brohi K: J. Trauma (2003) 55:1127

The German Trauma Registry (n=8724);

(n=1088)

Maegele M. Injury 2007 38:298

. Niles S. J. Trauma. 2008;64:1459. US Army in Iraq

Similar results:

E. Gonzalez J. Trauma 2007

Severity of early ICU coagulopathy is predictive

of mortality in civil trauma

Early Coagulopathy of Trauma in Combat Casualties

The trend of INR associated with mortality with 95% CI by univariate analysis

S. Niles, D. McLaughlin, J. Perkins et al J. Trauma. 2008;64:1459 –1465.

K. Brohi ;Curr Opin Crit Care 13:680–685. 2007

Gonzalez 2007 INR>1.2 (most 1.8) 97 70% ) INR≥2 mortality>50%(

Incidence of coagulopathy depends on its definition (expressed by PT and PTT)

Niles 2008# INR>.1.5 391 38% 17 4% 24%

# Military

Traumatic induced coagulopathy(TIC)

Blood loss, hypoperfusionacidosis

Activation of coagulationConsumption

Hyperfibrinolysis

DilutionFluids rescusitationInbalanced massive transfusions

Fibrinogen reduction and polimerization defects

Severe anemia -platelets dysfunction

Hypothermia

HypothermiaPlatelets

ThrombocytopeniaSequestration in liver and spleen

Villalobos T: J Cin Invest (1958) 37:1

Platelet dysfunctionAdhesion and aggregation

Kermode J: Blood (1999) 94:199

Coagulation factorsReduction of the enzymatic activity

not impaired > 33° C

Increased fibrinolytic activityPAI 1 reduced2-Antiplasmin reduced hyperfibrinolysis

Wolberg A: J Trauma (2004) 56:1221

37° C

33° C

Admission hypothermia and outcome after major trauma

5% (1921 pts) CT ≤35°C increased mortality

for the full cohort

(OR 3,03; 95% CI 2,62–3,51)

group with brain injury (OR 2,21;CI 1,62–3,03)

independent

age

ISS and mechanism of injury

route of temperature measurement

Wang H: Crit Care Med 2005;33:1296 < 3

2

32.0

1 –

33

330

1 –

3434

0 1

– 35

350

1 –

3636

0 1

– 37

50%

40%

30%

20%

10%

Mortality in %

Acidosis compromises coagulation

PlateletsThrombocytopeniaPlatelet dysfunction

Marumo M: Thromb Res (2001) 104:353

Coagulation factorsReduce fibrinogen andDecreased MCF

Engstrom M: J. Trauma (2006) 61:624

PlateletsThrombocytopeniaPlatelet dysfunction

Marumo M: Thromb Res (2001) 104:353

Coagulation factorsReduce fibrinogen andDecreased MCF

Engstrom M: J. Trauma (2006) 61:624

Fibrinogen

Platelets

mg/

dl10

7 /µ

l

300

200

100

50

500

400

300

200

100

pH 7,4 pH 7,1

pH 7,4 pH 7,1

Martini W: J Trauma (2006) 61: 99

0

0.5

1

1.5

2

2.5

3

6.2 6.6 7 7.4 7.8 8.2 8.6 9 pHRela

tive

Rate

of I

Ia G

ener

atio

n

Inhibition of 70% at pH 7.0 as compared to 7.4

Effect of pH on Thrombin Generation on phospholipid vesicles

Meng ZH et al, J Trauma. 2003;55:886-891.

Acidosis compromises coagulation

TEG Velocity at Target Conditions (Thromboplastin)

0

5

10

15

20

25

30

0 30 60 90 120

150

180

210

240

270

300

330

360

390

420

450

480

510

540

570

600

Time (sec)

Ve

loc

ity

(m

m/m

in) A

H

HA

N

Martini WJ J. Trauma 2005

Coagulopathic effect of combined hypothermia and acidosis

• Anemic patients tend to bleed more in surgery

• Ht 35 vs. 31 at end of CPB =blood loss X4-5

• Patients with bleeding diathesis (uremia, Glanzmans’ , irradiation colitis, angiodisplasia etc.) bleed less with correction of Hb (EPO).

• RBC transfusion is an important hemostatic treatment .In massive bleedings the goal is to achieve Ht 30-35,Hb 10-11.

Anemia compromises coagulation

Effect of Hct on platelet deposition on damaged arterial segments

Hct = 40%, PLTs = 200,000/mcL

Hct = 20%, PLTs = 200,000/mcL

Hct = 20%, PLTs = 50,000/mcL

Transfusion 1994; 34:542-9

1

2

3

Anemia

Anemia +

thrombocytopenia

Normal

• Starch based fluids (HES solutions) & Dextran

► Interfere with the measurement of fibrinogen - ”false” high levels

► Impairs fibrin polymerization

► Impaired Platelet function

• Contribution to acidosis

► Saline 0.9% pH 4.5 - 7

► Ringer Lactate pH 6 - 7.5

Hemodilution by PRBC and fluids :effects of fluids on coagulation

Prough DS &, Anesthesiol. 1999

Hiippala ST. Blood Coagul Fibrinolysis

1995 ,Trieb J, T&H 1997Jamnicki M,

Anesthesia. 1999 Undiluted blood clot

65% dilution with gelatinFries D, Br J Anaesth. 2005

May explain increased bleeding at fibrinogen levels above 2 g/LBlome M et al., Thromb Haemost 2005;93:1101-1107

Fibrinogen level (Claus) in hemodilution does not

discriminate functional from nonfunctional proteinsFibrinogen (Claus) 2.03g/L

H. Schochl, Salzburg ;unpublished

Time [sec]

0 200 400 600 800 1000 1200 1400

Ve

loc

ity [

mm

*10

0 / s

ec

]

0

2

4

6

8

10

12

14

16

Isotonic saline / controlHES 130/0.4Dextran 70HES 205/0.5Undiluted whole blood

Fenger-Eriksen C., Br J Anaesth. 2005

Interference to fibrin polymerization 55% dilution

0 2 4 6 8 10 12 14 16 18

limp fr

abd

pelvis

brain injury

thoracic trauma

H. Schockle ,unpublished, with permission

Hyperfibrinolysis

• Underestimated–no routine tests (Except TEG)

• Common in trauma? severe form in~20% of patients with

ISS>15

• May develop early-within minutes (TBI) M.Vorweg & M.Doehn,unpublished,with permissiononM.Vorweg & M.Doehn,unpublished,with permissionon

01

13 13

4

0

2

4

6

8

10

12

14

0 - 14 15 - 29 30 - 44 45 - 59 60 - 75

ISS

Hyperfibrinolysis according to ISS and organ of injury

• Complete lysis < 30min– ER: 11– ICU: 3– Survivor: 0

• Complete lysis 30 – 60 min– ER: 3– ICU: 4– Survivor: 0

• Complete lysis > 60 min– EM: 0– ICU: 5– Survivor: 5

High mortality (84%) increases with sevirity of fibrinolysis

H. Schochl, trauma hospital , Zalzburg, Austria; unpublishedH. Schochl, trauma hospital , Zalzburg, Austria; unpublished

Thromboelastography

Fibrinogen level on admission to ER

0

50

100

150

200

250

0 - 14 15 - 29 30 - 44 45 - 59 60 - 75ISS

Fibrinogen in mg/ dl

H. Schochl, trauma hospital , Zalzburg, Austria; unpublishedH. Schochl, trauma hospital , Zalzburg, Austria; unpublished

n = 180

Coagulopathy is underestimated -we only see the tip of the iceberg

Acidosis

hypothermia

platelets dysfunction

fibrinolysis

Hemodilutio

n

Anemia

Consumption

Lag time of 45-60 min. to results

Fibrinogen dysfunction

1111

1212

1313

1414

1515

1616

1717

2626 2828 3030 3232 3434 3636 3838 4040 4242

Temperature (°C)Temperature (Temperature (°°CC))

PT (S

ec)

PT (S

ec)

PT (S

ec)

3434

3939

4444

4949

5454

5959

2626 2828 3030 3232 3434 3636 3838 4040 4242

Temperature (°C)Temperature (Temperature (°°C)C)PT

T (Se

c)

PTT (

Sec

PTT (

Sec

))Rohrer MJ, Crit Care Med 1992Rohrer MJ, Crit Care Med 1992..Rohrer MJ, Crit Care Med 1992Rohrer MJ, Crit Care Med 1992..

Hypothermic coagulopathy is underestimated

Coagulation tests are performed in test tubes at 37°C

Coagulation process is taking place on cell membranes

in body temperature of the patient

Effect of temp. on PT and PTT

The effect of temp. on platelets function is not assessed

Time [sec]

0 1000 2000 3000 4000 5000 6000

Coagulation

Fluid

Time [sec]

0 1000 2000 3000 4000 5000 6000

Clot

Time [sec]

0 1000 2000 3000 4000 5000 6000

FluidFibrinolysis

Time [sec]

0 1000 2000 3000 4000 5000 6000

Clo

t fo

rma

tion

Benni Sorensen 2008 with permission

Standard coagulation test are of limited valueStandard coagulation test are of limited value

they only detect initiation of clot formation

PT/PTT

TT,ACT

Thromboelastography -real time clot analysis

clotting time [sec]clot formation time [sec]

ma

xim

um

clo

t firm

ne

ss

fibrinolysis

clo

t fi

rmn

ess

time

blood activators

Continuous registration of clot firmness

Fibrinogen function

Platelets function

Thrombin Generation measurement

1.Lag time

2.Pick height

3.ETP-Endogenous thrombin potential (area under curve)

1

3

2

Research tool ,not a real time test, commercial kits are developed

Routine coagulation tests

Surgicalhemostasis

Reversal ofacidosis ?. Inhibition of

rVIIa. Platelets and Fib. may be

needed

Inhibitionof

fibrinolysis

Avoidanceof massive

Fluidresuscitatio

n

Hemostaticbandage

sand glues

Preventionand correction

of hypothermia

(not a limitingfactor for

rFVIIa)

Threshold of Hb? Age of blood?

Early FFP 1:1 RBC:FFP

Instead 1-4/6

Platelets(goal:

>100,000)rFVIIa

Hemostatic resuscitation of traumatic coagulopathy

1:1:1:1

fibrinogen(goal >1g/L

? >4g/L

The blood bank: from (problematic) provider to partner in massively bleeding patients

Pär I. Johansson, Transfusion 2007 Aug. 47:176-181s (Anesth.+transfus

Early hemostatic rescusitation

Pro-hemostatic agents :

Extra-vascular (surgical):

● Fibrin glues ● New hemostatic polymers Intravascular - ● Fibrinolytic / proteolytic inhibitors ● Coagulation factors (cryo, FFP) and platelets ● Coagulation factor concentrates PCC, APCC, fibrinogrn FXIII , platelets substitutes ● DDAVP … ● New generation of Injury-specific hemostatic agents . (rFVIIa, Xa / PL, pdVIIa/Xa ,mutants rFVIIa)

ConclusionCoagulopathy is common in major trauma, its Coagulopathy is common in major trauma, its severity correlates with bleeding and mortalityseverity correlates with bleeding and mortality

Hypothermia , acidosis, hemodilution are Hypothermia , acidosis, hemodilution are important confounders of the coagulation important confounders of the coagulation processprocess

Hyperfibrinolysis is underestimatedHyperfibrinolysis is underestimated

Fibrinogen depletes early in severe trauma Fibrinogen depletes early in severe trauma

Standard coagulation test are of limited valueStandard coagulation test are of limited value

Thrombelastography could be helpful in Thrombelastography could be helpful in detecting coagulopathy and monitor treatmentdetecting coagulopathy and monitor treatment

• Overview of rFVIIa

Thank you for your participation,I hope it was usefull