Massive traumatic bleeding: The multi-factorial complex nature of

1
Massive traumatic bleeding The multi-factorial
complex nature of
Uri Martinowitz MD

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

Member, Hemorrhage Control Steering Committee ,
The U.S. Army Medical Research and Materiel
Command USAMARC, The Combat Casualty Care
Research Program CCRP
2
Trauma Is the leading cause of death in the
young Hemorrhage is a major cause of death in
trauma
MILITARY TRAUMA
CIVILIAN TRAUMA 289 FATALITIES 49 PENETRATING,
48 BLUNT
CNS-DOW 5
MULTI-KIA 13
MOF 7
MOF-DOW 4
CNS 42
Other 6
SHOCK-DOW 3
EXSANG 39
CNS EXSANG 6
CNS-KIA 31
EXSANG-KIA 44
KIA killed in action DOW died of wound MOF
multiple organ failure. WDMET Vietnam war
19671969 8000 CASUALTIES.
Sauaia A et al. J Trauma. 1995 38185-193.
140,000 deaths/year in the US
3
Massive Hemorrhage in Trauma (and controlled
trauma.)
Surgical bleed
Massive combined bleed
Trauma induced coagulopathy (TIC)
Early coagulopathy (10 min.) Hypoperfusion?
acidosis, hyperfibrinolysis ,Prot. C pathway
activation by thrombin with systemic
anticoagulation ??? Brohi K. J. Trauma 2008
64 1211
Late coagulopathy Activation?
consumption hemodilution, anemia, metabolic,
hypothermia
4
Incidence of coagulopathy correlates with
ISSin civil trauma
Brohi K J. Trauma (2003) 551127
(Kaufman CR,J. trauma 1997,Cosgriff N. J. Trauma
1997) ISS-injury Severity score. gt15 severe
injury
5
Coagulopathy is associated with increased
mortality in civil trauma 4-6 times beyond
expected from the injury severity
Brohi K J. Trauma (2003) 551127
(n1088)
Similar results

• The German Trauma Registry (n8724)

Maegele M. Injury 2007 38298

• US Army in Iraq

. Niles S. J. Trauma. 2008641459.
6
Severity of early ICU coagulopathy is predictive
of mortality in civil trauma
E. Gonzalez J. Trauma 2007
7
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. 2008641459 1465.
8
Incidence of coagulopathy depends on its
definition (expressed by PT and PTT)
K. Brohi Curr Opin Crit Care 13680685. 2007
Niles 2008 INRgt.1.5 391
38 17 4
24
Gonzalez 2007 INRgt1.2 (most 1.8) 97
70 ) INR2 mortalitygt50(
Military
9
Traumatic induced coagulopathy(TIC)

• Blood loss, hypoperfusion?acidosis
• Activation of coagulation?Consumption
• ?Hyperfibrinolysis
• Dilution
• Fluids rescusitation
• Inbalanced massive transfusions
• Fibrinogen reduction and polimerization defects
• Severe anemia -platelets dysfunction
• Hypothermia

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Hypothermia

• Platelets
• Thrombocytopenia
• Sequestration in liver and spleen
• Villalobos T J Cin Invest (1958) 371
• Platelet dysfunction
• Adhesion and aggregation
• Kermode J Blood (1999) 94199
• Coagulation factors
• Reduction of the enzymatic activity
• not impaired gt 33 C
• Increased fibrinolytic activity
• PAI 1 reduced
• a2-Antiplasmin reduced ? hyperfibrinolysis

37 C
33 C
Wolberg A J Trauma (2004) 561221
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Admission hypothermia and outcome after major
trauma

• 5 (1921 pts) ? CT 35C
• increased mortality
• for the full cohort
• (OR 3,03 95 CI 2,623,51)
• group with brain injury
• (OR 2,21CI 1,623,03)
• independent
• age
• ISS and mechanism of injury
• route of temperature measurement

Mortality in
50
40
30
20
10
lt 32
32.0 1 33
330 1 34
Wang H Crit Care Med 2005331296
340 1 35
350 1 36
360 1 37
12
Acidosis compromises coagulation
500 400 300 200 100

• Platelets
• Thrombocytopenia
• Platelet dysfunction
• Marumo M Thromb Res (2001) 104353
• Coagulation factors
• Reduce fibrinogen and
• Decreased MCF
• Engstrom M J. Trauma (2006) 61624

Platelets
107/µl
pH 7,4
pH 7,1
300 200 100 50
Fibrinogen
mg/dl
pH 7,4
pH 7,1
Martini W J Trauma (2006) 61 99
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Acidosis compromises coagulation
Effect of pH on Thrombin Generation on
phospholipid vesicles
Inhibition of 70 at pH 7.0 as
compared to 7.4
Meng ZH et al, J Trauma. 200355886-891.
14
Coagulopathic effect of combined hypothermia and
acidosis
Martini WJ J. Trauma 2005
15
Anemia compromises coagulation

• 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.

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Effect of Hct on platelet deposition on damaged
arterial segments
Hct 40, PLTs 200,000/mcL
1
Normal
Hct 20, PLTs 200,000/mcL
2
Anemia
Hct 20, PLTs 50,000/mcL
3
Anemia thrombocytopenia
Transfusion 1994 34542-9
17
Hemodilution by PRBC and fluids effects of
fluids on coagulation
Starch based fluids (HES solutions) Dextran
? Interfere with the measurement of
fibrinogen - false high levels ? Impairs
fibrin polymerization ? Impaired Platelet
function
Hiippala ST. Blood Coagul Fibrinolysis 1995
,Trieb J, TH 1997Jamnicki M, Anesthesia. 1999
Undiluted blood clot
Contribution to acidosis ? Saline 0.9
pH 4.5 - 7 ? Ringer Lactate pH 6 - 7.5
Prough DS , Anesthesiol. 1999
65 dilution with gelatin
Fries D, Br J Anaesth. 2005
18
Fibrinogen level (Claus) in hemodilution does
not discriminate functional from nonfunctional
proteins
Fibrinogen (Claus) 2.03g/L
H. Schochl, Salzburg unpublished
May explain increased bleeding at fibrinogen
levels above 2 g/L Blome M et al., Thromb
Haemost 2005931101-1107
19
Interference to fibrin polymerization
55 dilution
Fenger-Eriksen C., Br J Anaesth. 2005
20
Hyperfibrinolysis according to ISS and organ of
injury

• Hyperfibrinolysis
• Underestimatedno routine tests (Except TEG)
• Common in trauma? severe form in20 of patients
  with ISSgt15
• May develop early-within minutes (TBI)

M.Vorweg M.Doehn,unpublished,with
permissionon
H. Schockle ,unpublished, with permission
21
High mortality (84) increases with sevirity of
fibrinolysis
Thromboelastography

• Complete lysis lt 30min
• ER 11
• ICU 3
• Survivor 0
• Complete lysis 30 60 min
• ER 3
• ICU 4
• Survivor 0
• Complete lysis gt 60 min
• EM 0
• ICU 5
• Survivor 5

H. Schochl, trauma hospital , Zalzburg, Austria
unpublished
22
Fibrinogen level on admission to ER
n 180
H. Schochl, trauma hospital , Zalzburg, Austria
unpublished
23
Coagulopathy is underestimated -we only see the
tip of the iceberg
Lag time of 45-60 min. to results
Consumption
Hemodilution
fibrinolysis
platelets dysfunction
hypothermia
Fibrinogen dysfunction
Anemia
Acidosis
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Hypothermic coagulopathy is underestimated
Coagulation tests are performed in test tubes at
37C
Effect of temp. on PT and PTT
Rohrer MJ, Crit Care Med 1992.
Coagulation process is taking place on cell
membranes in body temperature of the patient
The effect of temp. on platelets function is not
assessed
25
Standard coagulation test are of limited value
they only detect initiation of clot formation
Fluid
Clot
Fluid
PT/PTT TT,ACT
Clot formation
Benni Sorensen 2008 with permission
26
Thromboelastography -real time clot analysis
Continuous registration of clot firmness
Fibrinogen function
Platelets function
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Thrombin Generation measurement
2
3
1
Routine coagulation tests
1.Lag time 2.Pick height 3.ETP-Endogenous
thrombin potential (area under curve)
Research tool ,not a real time test, commercial
kits are developed
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Hemostatic resuscitation of traumatic coagulopathy
fibrinogen (goal gt1g/L ? gt4g/L
Surgical hemostasis
Avoidance of massive Fluid resuscitation

1111
Hemostaticbandages and glues
Platelets (goal gt100,000)
rFVIIa
Inhibition of fibrinolysis
Early FFP 11 RBCFFP Instead 1-4/6
Prevention and correction of hypothermia (not a
limiting factor for rFVIIa)
Reversal of acidosis ?. Inhibition of rVIIa.
Platelets and Fib. may be needed
Threshold of Hb? Age of blood?
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The blood bank from (problematic) provider to
partner in massively bleeding patientsPär I.
Johansson, Transfusion 2007 Aug. 47176-181s
(Anesth.transfus
Early hemostatic rescusitation
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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)

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Conclusion

• Coagulopathy is common in major trauma, its
  severity correlates with bleeding and mortality
• Hypothermia , acidosis, hemodilution are
  important confounders of the coagulation process
• Hyperfibrinolysis is underestimated
• Fibrinogen depletes early in severe trauma
• Standard coagulation test are of limited value
• Thrombelastography could be helpful in detecting
  coagulopathy and monitor treatment

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Thank you for your participation,I hope it was
usefull

• Overview of rFVIIa