Coagulation dysfunctions in severe trauma

D. Săndesc “V. Babes” University of Medicine and Pharmacy Timisoara, Romania

1

საღამო მშვიდობისა! saghamo mshvidobisa! მადლობა ! Madloba !

2

3

Prevention of upper gastrointestinal bleeding (UGIB) and gastric stress ulcers (GSU) in the critically ill and postop patients

D. Săndesc “V. Babes” University of Medicine and Pharmacology Timisoara , Romania 4

5

6

7

8

9

10

11

Coagulation dysfunctions in severe trauma

Main topic: what is the acute coagulopathy of severe trauma:

1.A primary phenomenon or a secondary one (dilution, hypotermia, acidosis)?

2. A form of DIC(Disseminated Intravascular

Coagulation) or a totally different syndrome?

12

Coagulation dysfunctions in severe trauma

Main topic : what is the acute coagulopathy in severe trauma ? •a form of DIC? •a different syndrome?

The crucifixion of Jesus: Review of hypothesized mechanisms of death and implications of shock and trauma-induced coagulopathy

“Trauma-induced coagulopathy may have been a contributing factor, if not the primary factor, in Jesus’ death.

It would explain how Jesus’ death could occur so rapidly, namely 6 hrs, rather than several days. It would also explain how blood could flow from Jesus’ corpse when his chest was impaled by the spear.”

Joseph W. Bergeron MD. Available online 12 July 2011

15

Hess JR, Lawson JH. The Coagulopathy of Frida Kahlo Trauma J Trauma 2006; 60: S12-S19

Acute coagulopathy of trauma – clinical definition

“ … a syndrome of non-surgical bleeding from mucosal lesions, serosal surfaces, wounds and vascular access sites that continues after identifiable vascular bleeding has been controlled” *

16

17

1. CDC: Web-based Injury Statistics Query and Reporting System, 2002

2. Acosta JA, Yang JC, Winchell RJ, et al. J Ann Coll Surg 1998; 186: 528-533

Bleeding in trauma – epidemiology (1)

Trauma leading cause of death 1-44 years leading cause of years of potential

life lost1

Coagulopathy affects at least 1 in 4 seriously

injured trauma patients2 largest proportion of deaths in the

first hour of trauma center over 80% of operating room deaths almost 50% of deaths in the first 24

hours

18

Bleeding in trauma – epidemiology (2)

Journal of Trauma-Injury Infection & Critical Care. Early Massive Trauma Transfusion: Current State of the Art. 60(6) Supplement:S3-S11, June

Journal of Trauma-Injury Infection &Critical Care.) Supplement:S3S11, June 2006 2006

Frida Kahlo, “The broken column”

.” 19

Frida Kahlo

Bleeding in trauma – epidemiology (3)

Acute Traumatic Coagulopathy.. Journal of Trauma Injury Infection & Critical Care. 54(6):1127-1130, June 2003

.

Incidence of coagulopathy. ISS, Injury Severity Score.

20

Bleeding in trauma – epidemiology (4)

Journal of Trauma-InjuryInfection & Critical

Care 54(6):1127-1130 June 2003

21

Coagulation dysfunctions in severe trauma

Main topic: what is the acute coagulopathy of severe trauma:

A primary phenomenon or a secondary one (dilution, hypotermia, acidosis)?

22

The classical paradigm:Acute coagulopathy of trauma –a secondary phenomenom

Acidosis Hypothermia

Hemodilution

Coagulopathy

Death

Brohi, K, et al. J Trauma, 2003.

1. Brazil EV, Coats TJ. Sonoclot coagulation analysis of in-vitro haemodilution with resuscitation solutions. J R Soc Med 2000; 93:507–510. 2. Brohi K, Singh J, Heron M, et al. Acute traumatic coagulopathy. J Trauma 2003; 54:1127–1130.

Instigators of the coagulopathy in trauma: hemodilution Bleeding, volume therapy,

transfusions German study:

coagulopathy present in 50% of patients that received> 3 l in prehospital

role of the type of solutions in coagulopathy(HES)1

London study:2 simillar incidence of

coagulopathy with german study minimal prehospital fluid

administration (500 ml media) Hemodilution: contributor, not

instigator factor

24

1. Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting life-threatening coagulopathy in the massively transfused trauma patient: Hypothermia and acidoses revisited. J Trauma. 1997;42:857–861. 2. Shafi S, Elliott AC, Gentilello L. Is hypothermia simply a marker of shock and injury severity or an independent risk factor for mortality in trauma patients? Analysis of a large national trauma registry. J Trauma 2005; 59:1081–1085.

Instigators of the coagulopathy in trauma: hypotermia Influence on coagulation

factor’s activity Influence on platelet’s

function1

Significant effects on coagulation: only at temperatures bellow 330C 2

Severe hypotermia: only in 9% of trauma patients

25

1. Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M. . J Trauma. 1997;42:857–861.

Instigators of the coagulopathy in trauma: acidosis Considered “clasically”

the most important instigator of the coagulopathy in trauma

Hydrogen ions: interface with ionic interactions of coagulation factors and activated plateletes1

But it is difficult to separate the effects of acidemia per se from the effects of shock

26

A new paradigm: Acute coagulopathy of trauma- a primary phenomenon

Main instigator of the acute coagulopathy of trauma : Shock/hypoperfusion

27

Acute coagulopathy in trauma –new paradigm: Anticoagulation

Acute coagulopathy of trauma:mechanism, identification and effect.Brohi, Karim; Cohen, Mitchell; Davenport, Ross Current Opinion in Critical Care. 13(6):680-685, December 2007.

28

Acute coagulopathy of trauma: mechanism, identification and effect.Brohi, Karim; Cohen, Mitchell; Davenport, RossCurrent Opinion in Critical Care. 13(6):680-685, December 2007.

Acute coagulopathy in trauma –new paradigm: Hyperfibrinolysis

29

Endothelium as an organ

Approximately 1013 endothelial cells 1 1kg, 4000-7000 m2 !(SIZE DOES MATTER…) HIGHLY ACTIVE, sensing and responding to alterations of

local/general homeostasis (bacteriemia, trauma, ischemia etc.)

Wide variety of functions2,3: Vasomotor tone Cellular and nutrient trafficking Inflammatory response Blood fluidity/coagulation Generation of new blood vessels Programmed cell death etc.

1. Fisher CJJr, Agosti JM, Opal SM, et al. NEJM 1996. 2. Cines DB, Pollak ES, Buck CA, et al. Blood 1998; 91. 3. Gross PL, Aird WC. Semin thromb Hemost 2000;26.

30

Shock / Tissue hypoperfusion

A new paradigm: Acute coagulopathy of trauma-a primary phenomenon

Endothelium (genotype?)

Acidemia Dilution Hypotermia

TM ↑

TM / Thrombin complex

Thrombin ↓

Hypocoagulation

PC

aPC PAI-1-

V- VIII- PAI-1 ↓

tPA ↑

Hyperfibrinolysis

Subendothelial type III collagen

Von Willebrand Platelets

TF

Coagulation cascade

Consumption

31

LATE HYPERCOAGULABILITY AND THROMBOSIS RISK Hypercoagulable

state in severe trauma patients-in a few days

A possible explanation:protein C depletion

Risks of thrombosis

Schreiber MA, Differding J,Thorborg P,et al. J Trauma 2005; 58:475- 480.

32

Coagulation dysfunctions in severe trauma

Main topic: what is the acute coagulopathy of severe trauma:

1.A primary phenomenon or a secondary one (dilution, hypotermia, acidosis)?

2. A form of DIC(Disseminated

Intravascular Coagulation) or a totally different syndrome?

33

* Hess J R, Brohi K, Dutton RP, et al. The Coagulopathy of Trauma: A Review of Mechanisms. The Journal of Trauma: Injury, Infection, and Critical Care 2008; 65(4):748-754.

Coagulopathy in trauma: a form of DIC or not?

The Educational Initiative on Critical Bleeding in Trauma

(EICBT)

“… although there are similarities, the initiators, underlying mechanisms and management are different, and apling the generic “DIC” to trauma coagulopathy is unhelpful and potentially counterproductive.”

Terms proposed: “Acute Traumatic Coagulopathy”

“Early Coagulopathy of Trauma” “Trauma – Induced Coagulopathy” “Acute Coagulopathy of Trauma – Shock” *

34

Disseminated Intravascular Coagulation

35

Current Concepts: Disseminated Intravascular Coagulation. Levi, Marcel; ten Cate, Hugo New England Journal of Medicine. 341(8):586-592, August 19, 1999.

products.

Shock / Tissue hypoperfusion

A new paradigm: Acute coagulopathy of trauma-a primary phenomenon

Endothelium (genotype?)

Acidemia Dilution Hypotermia

TM ↑

TM / Thrombin complex

Thrombin ↓

Hypocoagulation

PC

aPC PAI-1-

V- VIII- PAI-1 ↓

tPA ↑

Hyperfibrinolysis

Subendothelial type III collagen

Von Willebrand Platelets

TF

Coagulation cascade

Consumption

36

Coagulopathy in trauma: a form of DIC or not?

Acute Coagulopathy of

Trauma Shock and Coagulopathy of Trauma: A Rebuttal. You Are Going Down the Wrong Path. Gardo S. The Journal of Trauma: Injury, Infection and Critical Care 2009; 67(2): 381-383

Aird: “I think it’s dangerous to start thinking up new terms . Call it what it is, call it DIC”. 37

Coagulation management in severe trauma: new evidences and challlenges

“Damage Control Hemostatic Resuscitation”:Massive

early transfusions protocols in a 1:1:1 ratio (red cells/ plasma/platelets)

Whole Warm Blood

Antifibrinolytics-Tranexamic acid

6

Massive early transfusions protocols in a 1:1:1 ratio(packed red blood cells/ fresh frozen plasma/platelets):

DAMAGE CONTROL HEMOSTATIC RESUSCITATION

Massive Transfusion: New Insights.Sihler, Kristen; MD, MS; Napolitano, Lena; MD, FCCP Chest. 136(6):1654-1667, December 2009.

. Coagulation management in massive bleeding.Griffee, Matthew; DeLoughery, Thomas; Thorborg, Per Current Opinion in Anaesthesiology. 23(2):263-268, April 2010

2

Massive early transfusions protocols in a 1:1:1 ratio (packed red blood cells/ fresh frozen plasma/platelets)

Warm Fresh Whole Blood

Spinella, PC, Perkins, JG, et al “Association of Warm Fresh Whole Blood with Survival” J Trauma. 2009; 66;S69-S76

Retrospective, 354 pts transfused ≥10 U of RBCs

Compared patients transfused

Fresh Whole Blood + (PRBC, FFP) Stored components (PRBC, FFP, aPLTs)

Groups compared equal in: Age, severity of injury Admission vital signs and labs, RBC amount Average patient was in hemorrhagic shock Base deficit of 6 and INR of 1.4

Days30.0025.0020.0015.0010.005.000.00

Surv

ival

1.0

0.9

0.8

0.7

0.6

0.5

Kaplan Meier Curve of 30 day survival

WFWB group CT group

Log rank test, p= 0.002

Warm Fresh Whole Blood

Blood Components Therapy

Variable WFWB (n=100) CT (n=254) p value

Pulmonary Embolism

7 (7%) 11 (4%) 0.3

Myocardial Infarction

1 (1%) 0 (0%) 0.28

Cerebral Stroke 0 (0%) 5 (2%) 0.33 ARDS 7 (7%) 7 (3%) 0.08 Deep Vein Thrombosis

15 (15%) 21 (8%) 0.06

Renal Failure 8 (8%) 7 (3%) 0.04

Comparison of adverse events between study groups

Potential mechanisms for WFWB association with improved survival Improved function of RBCs, plasma, platelets

in WFWB Thoroughly documented - Increased storage time for

all blood products leads to decreased function 1-4

WFWB use minimizes use of old RBCs Old RBCs: hyperinflammatory, immunomodulatory,

impair vasoregulation, poor O2 delivery

Increased anti-coagulants and preservatives in stored components

1 Spinella PC, Crit Care Med, 2007 2 Napolitano LM, Crit Care Clinics, 2004 3 Lavee J, J Thor Cardiov Surg, 1989 4 Mohr R, J Thor Cardiov Surg, 1988

Whole Fresh Warm Blood Studies-Limitations Retrospective Hypothesis generating not hypothesis testing

WFWB group had mix of WFWB, RBC, plasma Not available in database Crystalloid and colloid amounts AIS scores Cause of death

21

33

30

29

age Control Hemostatic Resuscitation

“Damage Control Resuscitation represents the most important advance in trauma care for hospitalized civilian and military casualties from this war.”

Cordts, Brosch and Holcomb, J Trauma, 2008

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

274 hospitals; 40 countries; 20 211 adult patients within 8 h of injury:-tranexamic acid (loading dose 1

g over 10 min then infusion of 1 g over 8 h) OR -placebo.

All-cause mortality significantly reduced with

tranexamic acid (p=0·0035).

The risk of death due to bleeding was significantly reduced (p=0·0077).

www.thelancet.com Published online June 15, 2010 DOI:10.1016/S0140-6736(10)60835-5

CRASH-2 TRIAL: Conclusions

“Tranexamic acid safely reduced the risk of death in bleeding trauma patients

…tranexamic acid should be considered for use in bleeding trauma patients.”

www.thelancet.com Published online June 15, 2010

DOI:10.1016/S0140-6736(10)60835-5

53

56

57

Thank you, bye !

58