1. Coagulation ICU – RLH Mike Cunningham 11 th December 2008

2. Bleeding ● Clotting cascade ● Investigations Sepsis ● Coagulopathy ● APC ● TFPI

3. Classical coagulation cascade

4. Current coagulation cascade Riewald M, Ruf W. Science Review: Role of coagulation protease cascades in sepsis. Critical Care 2003,7:123-129

5. Current coagulation cascade Prothrombinase complex

6. Current coagulation cascade

8. Feedback

9. Investigations ● PT / INR [12-16s / 1-1.3] ● APTT ● Fibrinogen ● FDP's ● TEG Abnormalities indicated ● Extrinsic and common pathways ● Deficiency / inhibition of VII, X, V, II and fibrinogen Most common causes ● Liver disease ● Warfarin ● DIC

10. Investigations ● PT / INR ● APTT [23-31s] ● Fibrinogen ● FDP's ● TEG Abnormalities indicated ● Intrinsic and common pathways ● Deficiency / inhibition of X11, IX, VIII, X, V, II and fibrinogen Most common causes ● Liver disease ● Heparin ● DIC ● Haemophilia A & B

11. Investigations ● PT / INR ● APTT ● Fibrinogen [1.5-4 g/l] ● FDP's ● TEG Abnormalities indicated ● Reduced production ● Increased consumption Most common causes ● Liver disease ● DIC ● Primary fibrinolysis

12. Investigations ● PT / INR ● APTT ● Fibrinogen ● FDP's [<10mg/ml] ● TEG Abnormalities indicated ● Fibrinolysis Most common causes ● DIC ● Primary fibronolysis

13. TEG

15. Coagulation and sepsis ● Excessive stimulation of immune system ● Coagulation cascade triggered ● Bidirectional [1] ● Coagulopathy ●... 1. Levi M, van der Poll T, Buller HR. Biderectional relation between inflammation and coagulation. Circulation. 2004, 109:2698

16. Anticoagulant actions

17. Protease-activated receptors Riewald M, Ruf W. Science Review: Role of coagulation protease cascades in sepsis. Critical Care 2003,7:123-129

18. APC – What does it do ? ● Protein C deficiency ● Thrombomodulin & EPCR downregulation ● Reduction in free protein-S Recombinant human activated protein C: current insights into its mechanism of action. Marcel Levi1 and Tom van der Poll. Critical Care 2007, 11(Suppl 5):S3 Inflammation Coagulation PAR-1

19. What next ? ● OPTIMIST ● Phase 3 trial of TFPI (Tifacogin). ● NO SD ● Severe CAP without heparin ? ● CAPTIVATE ● Results due Tissue Factor as an initiator of coagulation and inflammation in the lung. Van der Poll T. Critical Care 2008, 12(Supp 6):S3

20. TF pathway in lung injury ● Sepsis results in increased TF expression. ● Little change in TFPI ● Animal models show reduced lung injury with rTFPI. Tissue Factor as an initiator of coagulation and inflammation in the lung. Van der Poll T. Critical Care 2008, 12(Supp 6):S3

21. Conclusion ● Traditional model of coagulation cascade is limited ● Current tests are flags ● Early changes in clotting may be important indicators of sepsis ● Tight correlation between inflammation and coagulation ● TF pathway key in thrombin production ● PAR signaling likely to be key to link with inflammation. ● Activation of protein C pathway in clinical use ● Blockade of TF shows some benefit in pre-clinical studies. ● Invest now !!!!!!!

22. Questions ?

25. Drug actions ● Heparins ● Warfarin ● Danaparoid ● Aspirin ● Vitamin K ● Activated Protein C ● Bind to anti-thrombin ● Increase activity 2300 fold ● AT cleaves several of the serine proteases ● Affinity of AT (decreasing): ● Thrombin, Xa, XIIa, Xia and IXa

26. Drug actions ● Heparins ● Warfarin ● Danaparoid ● Aspirin ● Vitamin K ● Activated Protein C ● Inhibits reduction of Vit K 2,3- epoxide ● Vit K oxidised to epoxide during carboxylation of clotting factors II, V, IX and X ● 99% protein bound

27. Von Willebrand Factor ● Large, multimeric glycoprotein ● Present in plasma – binds VIII ● Attaches to platelet GP1b receptor, collagen and platelet integrin ● Releases VIII promoted by thrombin ● Platelet binding promoted by shear forces