Associate Professor Samuel Galvagno: My bloody head: Diagnosis and management of coagulopathy and traumatic brain injury. From CICM ASM PROGRAM 2019.

1. R ADAMS COWLEY SHOCK TRAUMA CENTER
My Bloody Head!
Diagnosis and Management of
Coagulopathy and Traumatic Brain
Injury
Sam Galvagno, DO, PhD, FCCM
Col, USAF, MC, SFS
Associate Professor
Medical Director, Lung Rescue Unit (LRU)
University of Maryland School of Medicine
R Adams Cowley Shock Trauma Center
Baltimore, MD, USA

2. R ADAMS COWLEY SHOCK TRAUMA CENTER
Disclosures
• United States Air
Force Reserve
• UpToDate®
Author
• One time
honorarium from
Haemonetics ®
• Department of
Defense Funding

3. R ADAMS COWLEY SHOCK TRAUMA CENTER
maryland.ccproject.com

4. R ADAMS COWLEY SHOCK TRAUMA CENTER
Objectives
• Review the pathophysiology of traumatic
brain injury and acute traumatic
coagulopathy
• List pros and cons of conventional tests
versus viscoelastic monitoring
• Describe management strategies for
reversal of anticoagulants

6. R ADAMS COWLEY SHOCK TRAUMA CENTER
Not a chance!
Look at the
TEG!You must give
more FFP now!

7. R ADAMS COWLEY SHOCK TRAUMA CENTER
Epidemiology
• Prevalence of acute traumatic coagulopathy in TBI:
20-30%
• Highly variable due to definitions
• Higher mortality with severe TBI (>40%)
• Strongly associated with progressive hemorrhagic
injury and intracranial hemorrhage
• Warfarin: doubles the risk of poor outcomes
• Not necessarily so with antiplatelets
Epstein DS. Injury 2014.
Harhangi BS. Acta Neuroshir 2008.
Talving P J Trauma 2009.
Abdelmalik PA. Neurocrit Care 2016.
Albert V. Hematol Oncol Stem Cell Ther 2019.
Lustenberger T. Injury 2010.

8. R ADAMS COWLEY SHOCK TRAUMA CENTER
The risk of dying with TBI and
coagulopathy is 10x higher than in
patients without coagulopathy
Harhangi BS. Acta Neurochir 2008.

9. Meagle M. Lancet Neurol 2017.

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Pathophysiology
• Tissue factor hypothesis
• Intravascular vs.
extravascular?
• Maladaptive Protein C
response
• Depletion 
Hypercoagulability
• Activation 
Hyperfibrinolysis
Albert V. Hematol Oncol Stem Cell ther 2019.
Giesen PL. Semin Thromb Hemost 2000.
Cohen MJ. J Trauma 2007.
Wu X. J Trauma Acute Care Surg 2014.
Halpern CH. J Neurotrauma 2008.
Gando J. Trauma 1999.
• Hyperfibrinolysis
• Low incidence (2.5-7%)
• High mortality
• tPA release, ↓ factor VII
activity

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Platelet Dysfunction
“Exhaustion”

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Defending the Glycocalyx
Kozar RA. Anesth Analg 2011.
Pati S. J Trauma 2010.
Albert V. Med Sci 2018.

13. Hypoperfusion
Lustenberger T. J Trauma 2010.

14. R ADAMS COWLEY SHOCK TRAUMA CENTER
PROPPR Secondary Analysis
Lower
SBP
Higher
HR
Lower Plt
Higher PT
TBI + HS
Other Groups
Galvagno SM. J Trauma Acute Care Surg 2017.

15. R ADAMS COWLEY SHOCK TRAUMA CENTER
Transfusions
Galvagno SM. J Trauma Acute Care Surg 2017.

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Adjusted Analysis: Mortality
Group Odds Ratio 95% Conf. Interval
TBI+HS 10.6 4.8-23.2
HS only 2.6 1.2-5.4
TBI only 8.2 3.4-19.5
Age
Treatment Group
Blunt Injury
Total Products Received
Time to Randomization
Galvagno SM. J Trauma Acute Care Surg 2017.

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Diagnosis

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Lab Tests
Meagle M. Transfusion 2013.

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Acquired coagulopathy of traumatic brain injury defined by routine
laboratory tests: which laboratory values matter?
Joseph B, Aziz H, Znagbar B, et al.al.
University of Arizona, Tucson, AZ, USA
J Trauma Acute Care Surg. 2014; 76.
• Platelet count < 100K
• OR 4 (1.7-10)
• INR 1.5
• OR 2 (1.1-4.3)
Predictors of Progression on Head CT

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INR Superior?
• INR > 1.25 associated with in-hospital
mortality
• INR superior to TEG for detecting warfarin
• INR > 1.3 found more frequently in TBI
patients
• Normalization of INR associated with improved
mortality
Yuan YY. Scand J Trauma Resusc Emerg Med 2018.
Gozal YM. Surg Neurol Int 2017.
Zehtababchi S. Resuscitation 2008.
Epstein DS. J Clin Neuroscience 2016.

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Coagulation parameters and risk of progressive hemorrhagic injury after
traumatic brain injury: A systematic review and meta-analysis
Zhang D, Gong S, Jin H, et al. t al.
Changzheng Hospital, Shanghai, China
BioMed Research International 2015; 1-10.
• Standard lab tests are not great
• Positive associations for risk of
progression:
• PT, D-dimer, INR
• Higher fibrinogen and platelets associated
with lower risk for progression
• INR > D-dimer > fibrinogen > platelets

23. VIIa
XII
XI
IX XI
IXa VIII
X V
Va
VIIIa
XIa
IX
IXa Xa
IXa VIIIa Va
Prothrombinase Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombin + Ca +
Acidic Phospholipids
2+
Prothrombin
Thrombin
Activated Platelet
Initial Phase Amplification Propagation
Tissue Factor
TEG Parameter
Replacement
r time
CT- clotting time
Alpha angle / k (kinetics)
CFT- clot formation time
FFP / PCC Cryoprecipitate / Fibrinogen
MA- Maximum Amplitude
MCF - Maximum clot firmness
Platelets / DDAVP
LY (x) - Estimated % lysis (at x min)
CL (x) - clot lysis (at x min)
Antifibrinolytic
ROTEM Parameter
TEG and the Cell Based Model for Coagulation
Hoffman and Cichon. Transfusion 2013.

24. R ADAMS COWLEY SHOCK TRAUMA CENTER
Severe traumatic brain injury is associated with a unique coagulopathy
phenotype
Samuels JM, Moore EE, Silliman CC, et al.t al.
University of Colorado, USA
J Trauma Acute Care Surg. 2019; 86.
• Low angle (<65o)
• (RR 2.22; 95% CI 1.38-3.56)
• Abnormal ACT
• (RR 1.53; 95% CI 1.08-2.16)
• Decreased functional fibrinogen (FFLEV)
• (RR 1.67; 95% CI 1.16-2.39)
• Hyperfibrinolysis rare
• INR not informative

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Other TEG Studies
• Folkerson et al., 2018
• ↑ ACT (r-time), MA < 55 mm, angle < 65o, LY30 > 30%, Platelets <
150,000
• Odds of death: 2.2 (1.1-4.4)
• Gozal et al., 2017
• r-time ↑ in 43% with CT progression
• Davis et al., 2013
• ↑ ADP and arachidonic acid receptor inhibition
• Level of inhibition correlated with severity
• Kunio et al., 2012
• ↑ mortality with ↑ r-time, ↓MA
• Martin et al., 2018
• More abnormalities found on TEG in penetrating TBI

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TEG Limitations
• Insensitive to warfarin effect
• Can’t detect DOAC effect
• TEG6s ® NOAC assay in development
• Obesity
• Acidosis
• Alcohol
• Normal tests seen with:
• Mechanical bleeding
• Hypothermia
• Platelet inhibitors
• Platelet dysfunction
• Von Willebrand’s disease
• DOACS

27. Cochrane Review: Conclusion
“ No evidence on the accuracy of TEG and
very little evidence on the accuracy of
ROTEM…Undermined by small number of
included studies…concerns about risk of bias
relating to the index test…”
Hunt H. Cochrane Database Syst Rev 2015.

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ADP Receptor Inhibition
Severe TBI
Uninjured
Control
Castellino FJ. J Trauma Acute Care Surg 2014.

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Multiple Electrode
Aggregometry (MEA)
Multiplate ®
Lindblad C. Frontiers Neurology 2018.
COX Inhibitor
Effect
Platelet
Transfusion
Response

30. Treatment

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33. VIIa
XII
XI
IX XI
IXa VIII
X V
Va
VIIIa
XIa
IX
IXa Xa
IXa VIIIa Va
Prothrombinase Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombin + Ca +
Acidic Phospholipids
2+
Prothrombin
Thrombin
Activated Platelet
Initial Phase Amplification Propagation
Tissue Factor
TEG Parameter
Replacement
r time
CT- clotting time
Alpha angle / k (kinetics)
CFT- clot formation time
FFP / PCC Cryoprecipitate / Fibrinogen
MA- Maximum Amplitude
MCF - Maximum clot firmness
Platelets / DDAVP
LY (x) - Estimated % lysis (at x min)
CL (x) - clot lysis (at x min)
Antifibrinolytic
ROTEM Parameter
TEG Based Treatment

34. Brandy
Tumbler
Wine
Glass
Champagne
Flute
Test
Tube
Upside Down
Martini Glass
Do Nothing FFP Cryo Platelets TXA

35. R ADAMS COWLEY SHOCK TRAUMA CENTER
Plasma Resuscitation
• Both FFP and LP decrease
brain lesion size and improve
neurological recovery
 FFP associated with
downregulation of
inflammatory pathway genes
• Pathogen-reduced FFP may
decrease brain edema
• Early prehospital use of plasma
associated with improved
neurological / functional
outcome
Georgoff PE. J Neurotrauma 2017.
Silleson M. J Am Coll Surg 2017.
Halaweish I. J Am Coll Surg 2015.
Halaweish I. J Trauma Acute Care Surg 2016.
Genet GF. J Neurotrauma 2017.
Hernandez MC. J Trauma Acute Care Surg 2017.
Leeper CM. J Trauma Acute Care Surg 2018.
Zhang LM. World Neurosurg 2017.
• Over-resuscitation associated
with fibrinolysis shutdown in
pediatric TBI
 Poor prognosis
• Increased FFP independently
associated with ARDS,
pneumonia, mortality in TBI
PROCON

36. R ADAMS COWLEY SHOCK TRAUMA CENTER
• PAMPer trial: multicenter, cluster-
randomized
• 2 units thawed plasma
• 23 vs. 33% mortality
 Adjusted risk of death 39% lower in
plasma group
• No differences in secondary outcomes
except fewer transfusions needed and
lower PT in plasma group

37. R ADAMS COWLEY SHOCK TRAUMA CENTER
PCCs
• Warfarin
• Time to reversal significantly shorter
• Time delay to operations decreased
• In Conjunction with FFP
• 25 U/kg corrected INR faster
• ↓ red cell transfusion requirement
• ↓ time to craniotomy
Yanamadala V. J Clin Neuroscience 2014.
Joseph B. Neurosurgery 2015.
Allison TA. J Intensive Care Med 2018.
• DOAC Reversal
• 35 U/kg
• Only 13 patients
• Hemostasis achieved in 80%
• FFP vs. PCC for Traumatic ICH
• Shorter time to reversal
• No difference in mortality or
thrombosis

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Marino & Galvagno. The Little ICU Book 2017.

39. R ADAMS COWLEY SHOCK TRAUMA CENTER
Antiplatelet Reversal
• Discontinue the agent (!)
• No procedure? No platelet transfusion!
• Transfuse if on ADP inhibitor or aspirin
• Testing:
• Platelet mapping, MEA
• Empirically treat if specialized testing not
available
• Initial dose: 1 x 6-pack of apheresis platelets
• Single dose of ddAVP (0.4 mg/kg IV)

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Thank you!
sgalvagno@som.umaryland.edu

43. R ADAMS COWLEY SHOCK TRAUMA CENTER
Other Tests
 ROTEM
 Less studies in trauma
 VN-ASA test
 Detects ASA use
 Gozal YM, Sur Neurol Int 2017
 Platelet Function Analyzer (PFA-100)
 SYND-1 (Albert, 2018)

44. Viscoelastic Fibrinolytic Spectrum
Walsh M. Semin Thromb Hemost 2017
Moore EB. J Trauma Acute Care Surg 2014, 2015.
Moore HB. Fibrinolysis. In: Gonzalez E et al. Trauma Induced Coagulopathy 2016.

45. R ADAMS COWLEY SHOCK TRAUMA CENTER
• R-time normal in 45.5% of subjects with INR 2.9
• Sensitivity for warfarin effect: 54.5%
• False negative rate: 45.5%
• Similar results for RapidTEG
TEG is insensitive to warfarin effects
Dunham CM. Thrombosis Journal 2014.
Nascimento B. Transfusion 2012.

46. R ADAMS COWLEY SHOCK TRAUMA CENTER
Non-vitamin K Oral Anticoagulants
(NOACs)
• No standardized point-of-care test available to
evaluate anticoagulant effects of NOACs
• New automated TEG®6s NOAC assay
 Direct thrombin inhibitor / Anti-Factor Xa assay
• >92% sensitivity, > 95% specificity for detecting
NOAC therapy
• May be an effective tool for identifying NOAC
therapy
Bliden KP. J Thromb Thrombolysis 2017.

47. R ADAMS COWLEY SHOCK TRAUMA CENTER
Obesity
• Clot strength (MA) higher on admission for obese patients
• For every 5 kg/m2 increase BMI, 85% greater odds of
thromobembolic complication
Obese trauma patients are often
HYPERcoagulable
Kornblith LZ J Trauma Acute Care Surg 2015.
Branco BC. Shock 2014.

48. R ADAMS COWLEY SHOCK TRAUMA CENTER
Acidosis
• Acidemia-induced coagulopathy is worse at the level of the
capillary (microcirculation)
• pH in injured tissue ≅ 6.2
• Coagulation activity is altered in acidic environments
• All 5 TEG ® variables affected
TEG may not reflect what is
going on at microcirculatory level
Campbell JE. J Trauma Acute Care Surg 2015.
Lv X. Am J Emerg Med 2017.

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Howard BM. J Trauma Acute Care Surg 2014.
Howard BM. J Trauma Acute Care Surg 2018.
Karamanos E. Eur J Trauma Emerg Surg 2013.
Lustenberger T. J Neurotrauma 2011.
Rao AJ. World Neurosurgery 2018.
R time increased by 3.8 seconds
for every 10 mg/dL increase in alcohol!