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Hemostatic Strategies for

Minimizing Mortality in
Major Blood Loss

Dita Aditianingsih, MD
Department of Anaesthesia and Critical Care
University of Indonesia, Cipto Mangunkusumo Jakarta

Introduction

Over the last 10 years, the management of major


haemorrhage in trauma patients has changed radically,
due to the recognition that many bleeding patients have
an established coagulopathy before the dilutional effects
of fluid resuscitation

Acute Traumatic Coagulopathy (ATC) has been


demonstrated in patients who received little or no
intravenous fluid therapy, negating the long-held belief
that iatrogenic haemodilution is the main causative factor
in traumatic coagulopathy

The concept and clinical definition


of Acute Traumatic Coagulopathy

Prolonged prothrombin time (aPTT) and/or activated


partial thromboplastin time (PT)

Abnormal international normalised ratio (INR); platelet


count; fibrinogen level;

Disseminated intravascular coagulation (DIC) score of 14


(non-overt DIC) or 5 (overt DIC)

Abnormalities in clotting amplitude and clot lysis in whole


blood visco-elastic tests (initiation, formation and stability
of the blood clot )

Pathophysiology of
Acute Traumatic
Coagulopathy

Trias of death in trauma,


because that common practice is only the tip of the iceberg
Fluid resuscitation, Blood transfusion, bleeding control

ATC phase 2 :
resuscitation related
factors
Coagulopathy

Haemorrhagic
Shock

ATC phase 1 :
immediate activation of
multiple haemostatic
pathways
Hypoperfusions

Immediate effects of tissue injury:


Early Changes of ATC

aWeibelPalade bodies annea


endothelial wall releasing von Willebrand factor
and exposing P-selectin present on their inner wall,
onto the surface of the endothelial cell, enhancing
platelet recruitment

Simmons JW et al. Trauma-Induced CoagulopathyCurr Anesthesiol Rep (2014) 4:189199

Immediate effects of tissue injury:


Early Changes of ATC
Tissue
trauma
Endothelial
Glycocalyx
damage

Protein C
activation

FVa, FVIIIa inhibitor


Thrombin formation
block
PAI inhibition
Fibrinolysis

Haemorrhage
shock
Acidemia

Fibrinogen
depletion

FXa converts
Prothrombin to
Thrombin

Glycocalyx
disruption
Autoheparinisasi

Thrombin split
Fibrinogen into
Fibrin

WeibelPalade bodies
degranulation
TPA release fibrinolysis

Fibrin establish
with Platelet
Simmons JW et al. Trauma-Induced CoagulopathyCurr Anesthesiol Rep (2014) 4:189199

The main pathophysiological mechanisms involved in


3. Hormonal and cytokine.
Acute Traumatic Coagulopathy
Tissue plasminogen activator (t-PA)
and WeibelPalade body enhancing
platelet recruitment
TNF and IL-1 causing cleavage of and
sloughing of the glycocalyx increases
in platelet activating factor production
increase endothelial permeability

1. Consumption and loss.


Coagulation factors and
platelets are consumed during
the formation of extravascular
clots and thrombus
2.Dilution.
The reversal of Starling forces
and consequent shifts of
interstitial fluid into the vascular
compartment results in
autodilution of hemostasis

5.Immune activation
release of damage associated
molecular patterns (DAMPs),
aggravate tissue damage through
mechanisms including proteolytic
degradation and oxidative stress,

4. Hypoxia, acidosis and hypothermia. Impairing


the function of platelets and coagulation proteases and
increasing fibrinolysis are most pronounced once the pH is <
7.1 and core temperatureis < 33 C
Bougl et al. Annals of Intensive Care 2013, 3:1

Flowchart of initial management of traumatic hemorrhagic shock

Bougl et al. Annals of Intensive Care 2013, 3:1

Management of bleeding following major trauma:


an updated European guideline
Critical Care 2013

I. Initial resuscitation
and prevention of
further bleeding

II. Diagnosis and


monitoring of
bleeding

III. Rapid control of


bleeding

IV. Management of
bleeding and
coagulation

V. Tissue oxygenation,
fluid and hypothermia

Coagulation
management

Coagulation support
Calcium
Fresh frozen plasma
Platelets
Fibrinogen or cryoprecipitate
Antifibrinolytic agents
Recombinant activated coagulation factor VII
Protrombin complex concentrate
Desmopressin
Antithrombin III
Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Hemostatic Agents

Antifibrinolytic
agents

Tranexamic acid should be administered as early as


possible to the trauma patient who is bleeding or at risk
of significant haemorrhage at a loading dose of 1 g
infused over 10 min, followed by an intravenous infusion
of 1 g over 8 h.

Tranexamic acid should be administered to the bleeding


trauma patient within 3 h after injury.

Protocols for the management of bleeding patients may


consider administration of the first dose of tranexamic
acid en route to the hospital
Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

TRANEXAMIC TIMING

Early Rx <1hr from injury: Mortality due to bleeding 5.3% vs


7.7% placebo

Rx 1-3hrs from injury: Mortality due to bleeding 4.8% vs 6.1%


placebo)

Rx > 3hrs from injury: Mortality due to bleeding 4.4% vs 3.1%


placebo

Calcium

Ionised calcium levels should be monitored and


maintained within the normal range during
massive transfusion

Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Fresh Frozen Plasma

Plasma or fibrinogen should be administered


initially in patients with massive bleeding.

If further plasma is administered, an optimal


plasma:red blood cell ratio may be at least 1:2.

Plasma transfusion should be avoided in


patients without any substantial bleeding
Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Indication of FFP

Normalized ratio (INR) at or greater than 1.5

Coagulation factor replacement in patients with


congenital factor deficiencies (such as factors II, V, VII,
X and XI

Rapid reversal of warfarin in an actively bleeding patient

A1020 ml/kg dose of plasma typically increases


circulating coagulation factor levels by 2030%37

Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

fresh frozen plasma (FFP)

Frozen at or below 18C within 24 hours after collection

Plasma contains ABO isoagglutinins, the naturally


occurring antibodies directed against ABO antigens, and
therefore must be ABO-compatible with the recipients red
cells

RhD compatibility between donor and recipient is not


required for plasma transfusion

Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Fibrinogen & cryoprecipitate

Fibrinogen concentrate or cryoprecipitate should be


administered if significant bleeding is accompanied by
thromboelastometric signs of a functional fibrinogen
deficit or a plasma fibrinogen level of less than 1.5-2.0 g/l

An initial fibrinogen dose of 3-4 g or 50 mg/kg of


cryoprecipitate Each unit of cryoprecipitate is expected
(according to FDA requirement) to contain at least more
than 80 IU FVIII and more than 150 mg fibrinogen, with
typical adult doses ranging from 6 to 10 pooled units

Repeat doses may be guided by viscoelastic monitoring


and laboratory assessment of fibrinogen levels.
Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Fibrinogen & cryoprecipitate

Contains enriched amounts of factor VIII, von


Willebrand factor (vWF), fibrinogen, fibronectin and
factor XIII .
13

Does not need to be ABO compatible

Pregnant women (35 and 42 weeks gestation) show a


marked elevation in fibrinogen levels, 350 to 650 mg/dl
as compared to 197401 mg/dl in non-pregnant
individuals .
80

the fibrinogen level decreases more rapidly in the


obstetric patient undergoing massive hemorrhage
Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Platelets

Therapeutic platelet transfusion in the context of massive


transfusions or DIC should be administered with the aim of
keeping the recipients platelet count above 50x109/l.
9

A platelet count above 100x10 /l in patients with ongoing


bleeding and/or traumatic brain injury may be maintained.
Platelets may be administered in patients with substantial
bleeding or intracranial haemorrhage who have anti platelet
therapy

An initial dose of 4-8 platelet concentrates or 1 aphaeresis


pack may be used

Should be ABO compatible with the recipient


Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Desmopressin

Desmopressin may not be administered routinely in the


bleeding trauma patient

Desmopressin (0.3 g/kg) may be administered if the patient


has been treated with acetylsalicylic acid alone or or von
Willebrand disease.

Platelet function may be measured in patients treated or


suspected of being treated with antiplatelet agents

Platelet concentrates may be used if platelet dysfunction is


documented in a patient such as von Willebrand disease
with continued microvascular bleeding
Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Prothrombin
complex concentrate

Prothrombin complex concentrate (PCC) should be


used early for the emergency reversal of vitamin K
Dependent oral anticoagulants or deficiency
prothrombin, targeting normalisation INR

Contain factor II, VII, IX, X, protein C, S, AT III

Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Prothrombin
complex concentrate

PCC may be administered in the bleeding patient with


thromboelastometric evidence of delayed coagulation
initiation if a concentrate-based goal-directed strategy is
applied

Substrate-specific anti-factor Xa activity may be measured in


patients treated or suspected of being treated with oral antifactor Xa agents such as rivaroxaban, apixaban or
endoxaban. Reversal may be achieved with high-dose (25-50
U/kg) PCC if bleeding is life threatening.

PCC may not be administered in patients treated or suspected


of being treated with oral direct thrombin inhibitors such as
dabigatran
Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Recombinant activated
coagulation factor VII

Recombinant factor VIIa (rVIIa) has also been demonstrated to be


useful in cases of severe bleeding, as is seen in DIC,

Treatment with recombinant activated coagulation factor VIIa


(rFVIIa) may be considered if major bleeding and traumatic
coagulopathy persist despite standard attempts to control
bleeding and use of conventional haemostasis measures.

rFVIIa may not be used in patients with intracranial haemorrhage


caused by isolated head trauma, the risks and benefits of its use
in patients with DIC should be carefully considered before
administration due tothe procoagulant effect of rVIIa
Spahn et al. Management of bleeding following major trauma: an updated European guidelineCritical Care 2013, 17:R76

Summary

ATC have become clearer to the trauma patients, is


required to increase our understanding of the
pathophysiology of traumatic coagulopathy and
improve haemostatic management and outcomes

Coagulation monitoring and measures to support


coagulation should be implemented as early as
possible following traumatic injury and used to
guide haemostats therapy

Thank you