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Sepsis and coagulation

Sepsis and coagulation. Christian Fenger-Eriksen Center for Haemophilia and Thrombosis, Department of Anaesthesiology, Aarhus University Hospital, Denmark chfen@dadlnet.dk. Outline of presentation. Normal Haemostasis Coagulopathy of sepsis Disseminated Intravascular Coagulation

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Sepsis and coagulation

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  1. Sepsis and coagulation Christian Fenger-Eriksen Center for Haemophilia and Thrombosis, Department of Anaesthesiology, Aarhus University Hospital, Denmark chfen@dadlnet.dk

  2. Outline of presentation • Normal Haemostasis • Coagulopathy of sepsis • DisseminatedIntravascularCoagulation • 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 FVa-FXa Prothrombinnase FVIIIa-FIXa Intrinsic tenase FX FXa Thrombin Fibrin Fibrinogen 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 Fibrin Fibrinogen 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 Tissue factor-FVIIa Thrombin Fibrin • 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 (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.

  15. The coagulation cascadeSecondary haemostasis Intrinsicpathway Extrinsicpathway APTT PTrelativ XII XIIa TF VII TF VIIa XI XIa IX IXa VIIIa • DIC-screen • Platelets • APTT • PT relativ • Thrombintime • Fibrind-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: • Isolatedthrombocytopenia • HIT antibodydetection (2-5 days) • HIT scoring system • Treatmens: • Stop heparintreatment • Thrombin inhibitor • Argatroban (Novastan) Christoffersen C., Ugeskr Læger 2009;171(8):612

  18. Coagulopathy of sepsisTreatment Activated Protein C Thrombomodulin • TFPI • Plasma/endothelial cells Tissue factor-FVIIa Thrombin Fibrin • 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 Nov;34(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. 2005;9(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 2004;166(11):1002 Bernard GR, Vincent JL, Laterre PF et al. N Engl J Med 2001;344:699-709.

  22. Activated Protein CXigris • Drug approval based on a single study • Side effects: • Serious bleeding events APC (3.5%) vs. placebo (2.0%), p=0.06 • 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 Jan;31(1 Suppl):S94-6. Review. Costa V et al.BMC Anesthesiol. 2007 Jun 25;7:5.

  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 <25)

  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 May;64(5):1211-7; WWW.CRASH2.LSHTM.AC.UK

  26. Anaemia • Changes flow conditions • Haematocrit correlates inverse with bleeding time Valeri R et al. Transfusion. 2001;41:(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 Aug;81(2):360-5

  31. Coagulopathy of the bleeding patientDilution N=20, *significant different from baseline, ** expected Fenger-Eriksen C et al. J Thromb Haemost 2009

  32. Postpartum hemorrhageFibrinogen and bleeding • Fibrinogenlevelsignificantlyassociatedwith the worsening of bleeding • Womenrequiringuterotonicprostaglandin-infusion • Fibrinogenlevels <2 g/l • Positive predictivevalue for PPH at 100% • Fibrinogenlevels >4 g/l • Negative predictivevalue at 79% B Charbit et al. J Thromb Haemost 2007;5:266-273

  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 Dec;101(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 2007;116:2544–52 Murphy GJ et al. Circulation 2007;116:2544–52

  38. Blood transfusion Am J Cardiol 2008;102:115–119 Aronson D et al. Am J Cardiol 2008;102:115–119

  39. N Engl J Med 2008;358:1229–39 Koch CG et al. N Engl J Med 2008;358:1229–39

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