Transcript Dilutional coagulopathy induced by plasma expanders

Sepsis and coagulation
Christian Fenger-Eriksen
Center for Haemophilia and Thrombosis,
Department of Anaesthesiology,
Aarhus University Hospital, Denmark
[email protected]
Outline of presentation
Normal Haemostasis
o Coagulopathy of sepsis

o Disseminated Intravascular Coagulation
o Mechanism
o Diagnosis
o Treatment
o Dilutional coagulopathy
o Hyperfibrinolysis
o Anaemia
o Acidose/Hypotermi
The Haemostatic System anno 2009
Primary haemostasis
= platelet
= fibrinogen
= activated platelet
= von Willebrand
Factor
The Haemostatic System anno 2009
Secondary haemostasis
Tissue factor-FVIIa
FVa-FXa
Prothrombinnase
FVIIIa-FIXa
Intrinsic tenase
FX
FXa
Thrombin
Fibrinogen
Fibrin
FXIII
Haemostasis
Balance versus imbalance
Thrombophilia
Healthy
Bleeding tendency
Haemostasis
Thrombophilia versus bleeding
Thrombophilia
Bleeding tendency
•
DIC
•
DIC
•
Tissue factor induced
activation
•
Consumption
•
Hyperfibrinolyse
•
Bedrest
•
Colloids
•
Cancer
•
Anaemia
•
Brain damage
•
Hypotermia
Clinical picture
Sepsis
Coagulopathy of sepsis
Inflammation and coagulation
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Close relation between inflammtory response and
coagulation activation
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Monocytes and microparticles express tissue factor
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LPS
 Activates FXII
 Interaction with endothelial cells – Tissue factor
 Activates platelets
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Result: Imbalance between intravascular fibrin
formation and its removal
Coagulopathy of sepsis
Activation
Tissue factor-FVIIa
Thrombin
Fibrinogen
Fibrin
Fibrinogen split products
Coagulopathy of sepsis
Regulatory mechanism of activation
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Antithrombin,
The protein C system,
Tissue factor pathway inhibitor
Coagulopathy of sepsis
Systemic anticoagulation
Activated Protein C
TFPI
•Plasma/endothelial cells
Tissue factor-FVIIa
Thrombomodulin
Thrombin
Fibrin
Antithrombin – TAT
•Rapid clearance of TAT
•Antithrombin negative acute phase protein
Dissemineret intravascular coagulation
Definition

Intravascular activation and imbalance of inhibition
and fibrinolysis
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Microthrombosis
 Brain (delirium/coma)
 Skin (necrosis)
 Kidney (oliguri/renal failure)
 Lungs (ARDS)
 Multi Organ Dysfunction Syndrome
 Bleeding
Dissemineret intravascular coagulation
Diagnose
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Clinical diagnose
Biochemistry:
 Activation:
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Fibrinolysis:
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Platelets low/decreasing
FII, VII and FX low
Fibrinogen low/decreasing (acute phase)
D-dimer high
Consumption of inhibitors:
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Antithrombin low
Protein C normal
TAT high
DIC score I
Overt DIC
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Does the patient have an underlying disorder known to be
associated with overt DIC, YES?
Platelet count (10*9/l): (>100 = 0; 50-100 = 1;<50 = 2)
Fibrin-related marker:
(No increase = 0; Moderate increase = 2; Strong increase = 3)
Prolonged prothrombin time: (<3 s = 0; 3-6 s = 1; >6 s = 2)
Fibrinogen: (>1.0 g/l = 0; <1.0 g/l: 1)

If the sum is ≥5, the patient status is compatible with overt
DIC.
The coagulation cascade
Secondary haemostasis
APTT
Intrinsic pathway
Extrinsic pathway
XII XIIa
TF
VIIa
XI XIa
IX
DIC-screen
•Platelets
•APTT
•PT relativ
•Thrombintime
•Fibrin d-dimer
•Antithrombin
•Fibrinogen
TF
VII
PTrelativ
IXa
VIIIa
X
Xa
Va
Prothrombin Thrombin
Fibrinogen Fibrin
Heparin induced thrombocytopenia
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Beware:
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Incidens:
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Isolated Thrombocytopenia without other
affection
Thrombosis during heparing treatment
UFH; 0.5-5%
LMH; 0,05-0,5%
Patogenesis:
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Antibody formation against platelets
(activation) + tissue factor release from
monocytes
5-10 days after institution of treatment
Heparin induced thrombocytopenia
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Diagnose:
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Isolated thrombocytopenia
HIT antibody detection (2-5 days)
HIT scoring system
Treatmens:
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Stop heparin treatment
Thrombin inhibitor
 Argatroban (Novastan)
Christoffersen C., Ugeskr Læger 2009;171(8):612
Coagulopathy of sepsis
Treatment
Activated Protein C
TFPI
•Plasma/endothelial cells
Tissue factor-FVIIa
Thrombomodulin
Thrombin
Fibrin
Antithrombin – TAT
•Rapid clearance of TAT
•Antithrombin negative acute phase protein
Antithrombin
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Small clinical trials:
 improvement of a DIC score
 shortening of the duration of DIC
 improvement in organ function
Randomized, controlled clinical trial, 2314 patients
with severe sepsis (Kybersept trial9
 Identical mortality between treatment with
antithrombin for 4 days versus placebo

Trend; Decreased mortality in subgroup of
patients who did not receive heparin
M Levi M, Schouten M, van der Poll T. Semin Thromb Hemost. 2008 Nov;34(8):742-6. Review.
Tissue factor pathway inhibitor
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TFPI has been shown to attenuate IL-6 and IL-8
release in an animal model
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A large RCT failed to show a reduced mortality in
patients with severe sepsis
Levi M Crit Care. 2005;9(6):624-5.
Activated Protein C
Xigris
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Recombinant protein
Indication:
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Severe sepsis
MODS
Evidens:
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28 day mortality APC vs. Placebo
Mortality 24,7% (APC) vs. 30,8% (Placebo)
E Tønnesen Ugeskr Læger 2004;166(11):1002
Bernard GR, Vincent JL, Laterre PF et al. N Engl J Med 2001;344:699-709.
Activated Protein C
Xigris
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Drug approval based on a single study
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Side effects:
 Serious bleeding events APC (3.5%) vs.
placebo (2.0%), p=0.06
First part of study
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720 patients inrolled – no effect of APC
treatment
Monitorering / duration of treatment
Mode of action
Eichacker PQ. Crit Care Med. 2003 Jan;31(1 Suppl):S94-6. Review.
Costa V et al.BMC Anesthesiol. 2007 Jun 25;7:5.
Dissemineret intravascular coagulation
Treatment
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Treat underlying disease
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Fresh frozen plasma
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Platelets pool – only thrombocytopenia induced
bleeding
Fibrinogen concentrate – only during massive bleeding
and afibrinogenaemia
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Xigris
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Consult: Local coagulation lab.
Hyperfibrinolysis
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Increased breakdown of the clot formed
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Induced by
 Release of fibrinolytic agents from damaged
endothelial cells
 Hypoperfusion
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Massive bleeding
Obstetric
Urology
Severe trauma (ISS <25)
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Hyperfibrinolysis
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Treatment; tranexamic acid 15 mg/kg
 Remember to substitute consumptioned fibrinogen
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CRASH II study
 20,000 trauma patients
 Ongoeing bleeding or significant risk for bleeding
 RCT; tranexamic acid or placebo
 End-points; Death and transfusion requirements
Brohi K et al J Trauma. 2008 May;64(5):1211-7;
WWW.CRASH2.LSHTM.AC.UK
Anaemia
• Changes flow conditions
• Haematocrit correlates inverse with bleeding time
Valeri R et al. Transfusion. 2001;41:(8):977-983
Dilutional cogulopathy
Definition
Ongoing Bleeding
+
Intravenously fluid resuscitation
= Haemodilution
Dilutional coagulopathy
Crystalloids vs colloids
• Porcine model of bleeding
– 30 pigs, removal of 60% of blood volume
– Substitution with:
• Hypertonic saline + HES 200/0.65 (HyperHaes)
• HES 130/0.4 (Voluven)
• Gelatine (Gelofusin)
– Hepatic incision
Dilutional coagulopathy
Crystalloids vs colloids, Blood loss
• Hypertonic saline + HES 200/0.65 (HyperHaes)
– 725 (375 - 900) ml
• HES 130/0.4 (Voluven)
– 1600 (1500 - 1800) ml
• Gelatine (Gelofusin)
– 1625 (1275 -1950) ml
Colloid induced coagulopathy
Aquired fibrinogen deficiency
– Dys-functional fibrinogen with compromised polymerization induced
by hydroxyethyl starch plasma expanders
– Reduces clot strength
– Increases bleeding
Fries et al. Br J Anaest 95(2):172-7 (2005)
Fenger-Eriksen et al. Br J Anaest 94(3)324-29 (2005)
E de Jonge et al. Crit Care Med 2001 Vol 29 1261-67
Haas T et al Anesth Analg 2008 Apr; 106(4):1078-86
Hiippala ST et al., Anesth Analg. 1995 Aug;81(2):360-5
Coagulopathy of the bleeding patient
Dilution
Baseline
30% Haemodilution Relative decrease %
0.43 ± 0.03
0.29 ± 0.02
- 32 ± 5
Platelet count (10*9L)
248 ± 65
181 ± 50*
- 27± 5
P-fibrinogen (µmol/L)
9.5 ± 1.9
5.1 ± 0.8*
- 44 ± 4.4**
1471 ± 309
1532 ± 247
+ 3.8 ± 11
Haematocrit
Trombin Generation (nM*min)
N=20, *significant different from baseline, ** expected
Fenger-Eriksen C et al. J Thromb Haemost 2009
Postpartum hemorrhage
Fibrinogen and bleeding
•
Fibrinogen level significantly associated with the worsening
of bleeding
•
Women requiring uterotonic prostaglandin-infusion
–
–
–
–
Fibrinogen levels <2 g/l
Positive predictive value for PPH at 100%
Fibrinogen levels >4 g/l
Negative predictive value at 79%
B Charbit et al. J Thromb Haemost 2007;5:266-273
Fibrinogen substitution during massive
bleeding
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43 patients recieving fibrinogen concentrate
(Haemocomplettan) at Skejby Hospital,
Hypofibrinogenaemia and massive bleeding
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Increases fibrinogen
Improves PT, APTT
Reduces bleeding
16
p<0,0001
14
12
p<0,0001
10
Units

8
6
p<0,001
4
2
0
PRBC
FFP
Pooled platelets
Fenger-Eriksen C et al. Br J Anaesth 2008 Dec;101(6):769-73
Dilutional coagulopathy
• Are crystalloids better?
• Probably yes regarding coagulation
• Large volumina are required
– Hyperchloremic acidosis
• Renal impairment
• Secondary impairment of coagulation
Thrombin generation
Acidose and hypothermia
Martini el al J Trauma 2005(58-5) 1002-1010
Sepsis and coagulation
Conclusion
• Close relation between inflammtory response and
coagulation activation
o Activation
o Imbalance of regulatory mechanism and fibrinlolysis
o Dysfunctional fibrinogen from colloids
o Acidosis
o Hypothermia
o Hyperfibrinolysis
o Anaemia
o Electrolyte disturbances
Blood transfusion
Circulation 2007;116:2544–52
Murphy GJ et al. Circulation 2007;116:2544–52
Blood transfusion
Am J Cardiol 2008;102:115–119
Aronson D et al. Am J Cardiol 2008;102:115–119
N Engl J Med 2008;358:1229–39
Koch CG et al. N Engl J Med 2008;358:1229–39