1 / 39

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

tevy
Télécharger la présentation

Sepsis and coagulation

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related