Sepsis and coagulation

1
Sepsis and coagulation

• Christian Fenger-Eriksen
• Center for Haemophilia and Thrombosis,
• Department of Anaesthesiology,
• Aarhus University Hospital, Denmark
• chfen_at_dadlnet.dk

2
Outline of presentation

• Normal Haemostasis
• Coagulopathy of sepsis
• Disseminated Intravascular Coagulation
• Mechanism
• Diagnosis
• Treatment
• Dilutional coagulopathy
• Hyperfibrinolysis
• Anaemia
• Acidose/Hypotermi

3
The Haemostatic System anno 2009Primary
haemostasis
von Willebrand Factor
platelet
activated platelet
fibrinogen
4
The Haemostatic System anno 2009Secondary
haemostasis
Tissue factor-FVIIa
FVIIIa-FIXa Intrinsic tenase
FVa-FXa Prothrombinnase
FX
FXa
Thrombin
Fibrinogen
Fibrin
FXIII
5
HaemostasisBalance versus imbalance
Healthy
Bleeding tendency
Thrombophilia
6
HaemostasisThrombophilia versus bleeding

• Bleeding tendency
• DIC
• Consumption
• Hyperfibrinolyse
• Colloids
• Anaemia
• Hypotermia

• Thrombophilia
• DIC
• Tissue factor induced activation
• Bedrest
• Cancer
• Brain damage

7
Clinical picture Sepsis
8
Coagulopathy of sepsisInflammation and
coagulation

• Close relation between inflammtory response and
  coagulation activation
• Monocytes and microparticles express tissue
  factor
• LPS
• Activates FXII
• Interaction with endothelial cells Tissue
  factor
• Activates platelets
• Result Imbalance between intravascular fibrin
  formation and its removal

9
Coagulopathy of sepsisActivation
Tissue factor-FVIIa
Thrombin
Fibrinogen
Fibrin
Fibrinogen split products
10
Coagulopathy of sepsisRegulatory mechanism of
activation

• Antithrombin,
• The protein C system,
• Tissue factor pathway inhibitor

11
Coagulopathy of sepsisSystemic anticoagulation
Activated Protein C
Thrombomodulin

• TFPI
• Plasma/endothelial cells

Thrombin
Fibrin
Tissue factor-FVIIa

• Antithrombin TAT
• Rapid clearance of TAT
• Antithrombin negative acute phase protein

12
Dissemineret intravascular coagulationDefinition

• Intravascular activation and imbalance of
  inhibition and fibrinolysis
• Microthrombosis
• Brain (delirium/coma)
• Skin (necrosis)
• Kidney (oliguri/renal failure)
• Lungs (ARDS)
• Multi Organ Dysfunction Syndrome
• Bleeding

13
Dissemineret intravascular coagulationDiagnose

• Clinical diagnose
• Biochemistry
• Activation
• Platelets low/decreasing
• FII, VII and FX low
• Fibrinogen low/decreasing (acute phase)
• Fibrinolysis
• D-dimer high
• Consumption of inhibitors
• Antithrombin low
• Protein C normal
• TAT high

14
DIC score IOvert DIC

• Does the patient have an underlying disorder
  known to be associated with overt DIC, YES?
• Platelet count (109/l) (gt100 0 50-100
  1lt50 2)
• Fibrin-related marker
• (No increase 0 Moderate increase 2 Strong
  increase 3)
• Prolonged prothrombin time (lt3 s 0 3-6 s
  1 gt6 s 2)
• Fibrinogen (gt1.0 g/l 0 lt1.0 g/l 1)
• If the sum is 5, the patient status is
  compatible with overt DIC.

15
The coagulation cascadeSecondary haemostasis
Intrinsic pathway
Extrinsic pathway
APTT
PTrelativ
XII
XIIa
TF VII
TF VIIa
XI
XIa
IX
IXa
VIIIa

• DIC-screen
• Platelets
• APTT
• PT relativ
• Thrombintime
• Fibrin d-dimer
• Antithrombin
• Fibrinogen

X
Xa
Va
Prothrombin
Thrombin
Fibrinogen
Fibrin
16
Heparin induced thrombocytopenia

• Beware
• Isolated Thrombocytopenia without other affection
  
• Thrombosis during heparing treatment
• Incidens
• UFH 0.5-5
• LMH 0,05-0,5
• Patogenesis
• Antibody formation against platelets (activation)
  tissue factor release from monocytes
• 5-10 days after institution of treatment

17
Heparin induced thrombocytopenia

• Diagnose
• Isolated thrombocytopenia
• HIT antibody detection (2-5 days)
• HIT scoring system
• Treatmens
• Stop heparin treatment
• Thrombin inhibitor
• Argatroban (Novastan)

Christoffersen C., Ugeskr Læger 2009171(8)612
18
Coagulopathy of sepsisTreatment
Activated Protein C
Thrombomodulin

• TFPI
• Plasma/endothelial cells

Thrombin
Fibrin
Tissue factor-FVIIa

• Antithrombin TAT
• Rapid clearance of TAT
• Antithrombin negative acute phase protein

19
Antithrombin

• 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 Nov34(8)742-6. Review.
20
Tissue factor pathway inhibitor

• TFPI has been shown to attenuate IL-6 and IL-8
  release in an animal model
• A large RCT failed to show a reduced mortality in
  patients with severe sepsis

Levi M Crit Care. 20059(6)624-5.
21
Activated Protein CXigris

• Recombinant protein
• Indication
• Severe sepsis
• MODS
• Evidens
• 28 day mortality APC vs. Placebo
• Mortality 24,7 (APC) vs. 30,8 (Placebo)

E Tønnesen Ugeskr Læger 2004166(11)1002 Bernard
GR, Vincent JL, Laterre PF et al. N Engl J Med
2001344699-709.
22
Activated Protein CXigris

• Drug approval based on a single study
• Side effects
• Serious bleeding events APC (3.5) vs. placebo
  (2.0), p0.06
• First part of study
• 720 patients inrolled no effect of APC
  treatment
• Monitorering / duration of treatment
• Mode of action

Eichacker PQ. Crit Care Med. 2003 Jan31(1
Suppl)S94-6. Review. Costa V et al.BMC
Anesthesiol. 2007 Jun 2575.
23
Dissemineret intravascular coagulationTreatment

• Treat underlying disease
• Fresh frozen plasma
• Platelets pool only thrombocytopenia induced
  bleeding
• Fibrinogen concentrate only during massive
  bleeding and afibrinogenaemia
• Xigris
• Consult Local coagulation lab.

24
Hyperfibrinolysis

• Increased breakdown of the clot formed
• Induced by
• Release of fibrinolytic agents from damaged
  endothelial cells
• Hypoperfusion
• Massive bleeding
• Obstetric
• Urology
• Severe trauma (ISS lt25)

25
Hyperfibrinolysis

• Treatment tranexamic acid 15 mg/kg
• Remember to substitute consumptioned fibrinogen
• 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 May64(5)1211-7
WWW.CRASH2.LSHTM.AC.UK
26
Anaemia

• Changes flow conditions
• Haematocrit correlates inverse with bleeding time
  

Valeri R et al. Transfusion. 200141(8)977-983
27
Dilutional cogulopathyDefinition

• Ongoing Bleeding
• Intravenously fluid resuscitation
• Haemodilution

28
Dilutional coagulopathyCrystalloids 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

29
Dilutional coagulopathyCrystalloids 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

30
Colloid induced coagulopathyAquired 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
  Aug81(2)360-5

31
Coagulopathy of the bleeding patientDilution
Baseline 30 Haemodilution Relative decrease
Haematocrit 0.43 0.03 0.29 0.02 - 32 5
Platelet count (109L) 248 65 181 50 - 27 5
P-fibrinogen (µmol/L) 9.5 1.9 5.1 0.8 - 44 4.4
Trombin Generation (nMmin) 1471 309 1532 247 3.8 11
N20, significant different from baseline,
expected
Fenger-Eriksen C et al. J Thromb Haemost 2009
32
Postpartum hemorrhageFibrinogen and bleeding

• Fibrinogen level significantly associated with
  the worsening of bleeding
• Women requiring uterotonic prostaglandin-infusion
• Fibrinogen levels lt2 g/l
• Positive predictive value for PPH at 100
• Fibrinogen levels gt4 g/l
• Negative predictive value at 79

B Charbit et al. J Thromb Haemost 20075266-273
33
Fibrinogen substitution during massive bleeding

• 43 patients recieving fibrinogen concentrate
  (Haemocomplettan) at Skejby Hospital,
• Hypofibrinogenaemia and massive bleeding
• Increases fibrinogen
• Improves PT, APTT
• Reduces bleeding

Fenger-Eriksen C et al. Br J Anaesth 2008
Dec101(6)769-73
34
Dilutional coagulopathy

• Are crystalloids better?
• Probably yes regarding coagulation
• Large volumina are required
• Hyperchloremic acidosis
• Renal impairment
• Secondary impairment of coagulation

35
Thrombin generationAcidose and hypothermia
Martini el al J Trauma 2005(58-5) 1002-1010
36
Sepsis and coagulationConclusion

• Close relation between inflammtory response and
  coagulation activation
• Activation
• Imbalance of regulatory mechanism and
  fibrinlolysis
• Dysfunctional fibrinogen from colloids
• Acidosis
• Hypothermia
• Hyperfibrinolysis
• Anaemia
• Electrolyte disturbances

37
Blood transfusion

• Circulation 2007116254452

Murphy GJ et al. Circulation 2007116254452
38
Blood transfusion

• Am J Cardiol 2008102115119

Aronson D et al. Am J Cardiol 2008102115119
39

• N Engl J Med 2008358122939

Koch CG et al. N Engl J Med 2008358122939