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Inflammation & Coagulation

This seminar discusses the relationship between inflammation and coagulation, including the activation of the natural anti-coagulation system, the effects of inflammation on coagulation, and the effects of coagulation on inflammation. The potential therapeutic use of anti-coagulants in sepsis is also examined.

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Inflammation & Coagulation

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  1. Inflammation & Coagulation Dr Rex Lam ICU Friday Seminar PYNEH 21st July, 2006

  2. Clot formation

  3. Natural anti-coagulation system X X Protein S Tissue Factor Pathway-Inhibitor Xa Activated Protein C X Thrombomodulin Thrombin Anti-thrombin Heparin Protein C EPCR Plasminogen Plasmin

  4. The Physiological Cascade TNF-, IL-1, IL-6 Extrinsic Pathway

  5. Effects of inflammation on coagulation Endotoxin Inflammatory mediators Factor VII Tissue factor Factor VIIa APC Thrombin Anti-thrombin Fibrinogen Fibrin Platelets VWF Plasminogen activator inhibitor-1 Fibrinolysis Procoagulant state

  6. Effects of inflammation on coagulation Inflammation initiates coagulation Fibrin immobilizes pathogens • Prevents bacteria accessing systemic circulation • Facilitates engulfment & disposal of bacteria

  7. TF-VIIa Activates protease activated receptors expression of leucocyte adhesion molecules. Expression of MHC II molecules and reactive oxygen species from macrophages/monocytes. Platelets Release pro-inflammatory mediator & induces TF synthesis. Anti-thrombin Leucocyte adhesion Prostacyclin NF- κformation Thrombomodulin Leucocyte adhesion molecules Dampens mitogen activated kinase & NF- κresponses in endothelium. Activated protein C Chemotaxis & cytokines. Effects of coagulation on inflammation Anti-coagulation = Anti-inflammatory Coagulation = Proinflammatory

  8. Inflammation & Coagulation Inflammation Anti-coagulation = Anti-inflammatory Coagulation = Pro-inflammatory + - Anti-coagulation Coagulation Diffuse endovascular injury, thrombosis of microvasculature, MOF & Death

  9. Sepsis • Despite improvements in standards of care & antibiotic therapy, sepsis still remains the commonest cause of death among hospitalized patients in non-cardiac ICUs. • Mortality of severe sepsis 30-50%.

  10. Therapeutic potential of anti-coagulants? Factor VII Tissue factor Tissue Factor Pathway-I Factor VIIa APC Thrombin Anti-thrombin PC T Thrombo-modulin EPCR Fibrinogen Fibrin Platelets Clot

  11. 1. Activated Protein C NEJM 2001;344:699 1 2 4 3 APC during sepsis & associated with death. rAPC   plasma D-dimer & IL-6 levels

  12. PROWESS • A randomized, double-blind, placebo-controlled, multicenter, phase 3 trial. • Recombinant human activated protein C (detrocogin alfa activated) vs placebo. • July 1998 → June 2000. • Included if: • Known / suspected infection; & • ≥3 signs of SIRS; & • Sepsis-induced dysfunction of ≥1 organ / system that lasted <24hrs. NEJM 2001;344:699

  13. PROWESS Drotrecogin -a 24g/kg/hr infusion x 96hrs Patients meeting inclusion criteria 28days or till death 850 NS infusion x 96hrs 1690 840 • D-dimer level • IL-6 level • Neutralizing Ab vs APC Mortality from any cause NEJM 2001;344:699

  14. PROWESS • 28days mortality: • 30.8% placebo • 24.7% APC • NNT = 16 NEJM 2001;344:699

  15. PROWESS In November 2001, FDA approved DrotAA for adults with severe sepsis & a high risk of death i.e. APACHE ≥25 or MOF Neutralizing Ab vs APC was not detected in any patient. NEJM 2001;344:699

  16. ADDRESS • To evaluate the efficacy of DrotAA in adults with severe sepsis & a low risk of death. • No difference in 28-day mortality. • Mortality in patients with recent OT + 1 organ dysfunction given DrotAA. NEJM 2005;353:1332

  17. 2. Anti-thrombin III

  18. KyberSept • Double-blind, placebo-controlled, multicenter phase 3 trial. • 3/1997 → 1/2000. • Placebo 1% albumin vs antithrombin III 6000IU loading + 6,000IU/day x 4/7. • 1o outcome = all-cause mortality at D28. JAMA 2001;286:1869

  19. KyberSept • Inclusion criteria: • ≥18 years; • A suspected source of infection, core To >38.5oC or <35.5oC, WCC >10x103/μL or <3.5x103/μL; • ≥3 of the following 6: • AR >100/min; • RR >24/min or on mechanical ventilation; • SBP <90mmHg despite fluid or need of vasoactive agents; • Plt <100x10/L; • Lactate or metabolic acidosis; • UO <20ml/hr despite fluid JAMA 2001;286:1869

  20. KyberSept No significant differences in mortality JAMA 2001;286:1869

  21. KyberSept • Bleeding in antithrombin group: (22% vs 12.8% placebo; p<.001) Difference most marked in patients given antithrombin III + heparin. • Bleeding incidents → mortality: 50.7% & 51.4% vs 36.9% & 35.4% • Significantly patients given antithrombin III developed new CVS dysfx <7days of study entry. ? Associated with bleeding events. JAMA 2001;286:1869

  22. KyberSept Placebo 52.5% 15% Absolute improvement in 90-day mortality. Antithrombin 44.9% JAMA 2001;286:1869

  23. 3. Tissue factor pathway inhibitor Heparin TF-VIIa Xa X X Xa

  24. OPTIMIST • A randomized, double-blind, placebo-controlled, phase 3 trial. • 3/2000 → 9/2001. • Inclusion criteria: • ≥2 SIRS; & • ≥2 organ dysfunction or hypoperfusion; • INR ≥1.2. • Placebo vs Tifacogin 0.025mg/kg/hr x 96hrs. • 1o endpoint = Death from any cause ≤28/7. JAMA 2003;290:238

  25. OPTIMIST 34.2% 33.9% 29.1% vs 38.9% p=.006 Tifacogin: No effect on all-cause mortality in patients with severe sepsis & high INR. JAMA 2003;290:238

  26. OPTIMIST Cumulative mortality 22.9% placebo (P=.51) 12% Tifacogin JAMA 2003;290:238

  27. OPTIMIST • Bleeding in tifacogin group: • INR ≥1.2 ~ 6.5% vs 4.8% placebo; • INR <1.2 ~ 6.0% vs 3.3% placebo. • Commonest = GIB & hemoptysis. No survival benefit provided by tifacogin in patients with severe sepsis + high INR. Associated with risk of bleeding. JAMA 2003;290:238

  28. Why did Antithrombin & TFPI fail? • Anti-inflammatory effects more important than anticoagulant effects in the treatment of sepsis? • Inadequate dosage of antithrombin III and TFPI? • Problems with study design? • Confounding effects of heparin?

  29. 4. Heparin • Studies on the effect of heparin on sepsis have not been done. • In both KyberSept & OPTIMIST, mortality was lowest in placebo + heparin group. However, • Those who received low-dose prophylactic heparin were less severely ill; • Not randomized to receiving heparin • The true effect of heparin is difficult to assess. • Should be used as DVT prophylaxis in patients with severe sepsis unless contraindicated.

  30. Early goal-directed tx Culture before A/B Antibiotic iv <1hr Source control Fluid resuscitation Vasopressors Dobutamine in C.O. Steroids rhAPC Transfuse if Hb<7.0g/dL TV & Pplat<30cmH2O in ALI/ARDS Sedation protocol, avoid NMB Glucose <8.3mmol/L CVVH = intermittent HD HCO3 use not supported DVT prophylaxis Stress ulcer prophylaxis Consider limitation of support Surviving sepsis campaign Crit Care Med 2004;32:858

  31. Prevention of nosocomial infections • Head tilt in ventilated patients; • Appropriate stress ulcer prophylaxis; • Sterile precautions during CVC insertion; • Hand washing.

  32. Take home messages • Coagulation & inflammatory cascades are closely intertwined to facilitates removal of pathogens. • Microvascular thrombosis, MOF & death if processes run out-of-control. • APC is beneficial in severe sepsis + risk of death. • No role x antithrombin III or TFPI supplementation in sepsis at present. • Anticoagulant is only part of the surviving sepsis campaign. • Prevention of nosocomial sepsis is equally, if not more important.

  33. References • Br J Haematol 2005; 131: 417-430. • Blood 2003; 101(10): 3765-3777. • NEJM 2001; 344(10): 699-709. • NEJM 2005; 353(13): 1332-1341. • JAMA 2003; 290(2): 238-247. • JAMA 2003; 290(2): 256-258. • JAMA 2001;286(15):1869-1878. • JAMA 2001; 286(15): 1894-1896. • Crit Care Med 2004; 32(3): 858-873.

  34. The end Thank you

  35. PROWESS

  36. PROWESS

  37. 2. Anti-thrombin III

  38. OPTIMIST

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