1. Role of Factor Concentrates in Perioperative Coagulopathies Dr Neville Gibbs Department of Anaesthesia Sir Charles Gairdner Hospital

2. Conflicts of Interest None

3. Causes of Coagulopathy DiseasesDrugsDilutionDestructionDIC

4. DiseasesDrugsDilutionDestructionDIC Drop in temperature, pH, calcium

5. Treatment of Coagulopathy ProtaminePlasmaPlatelets Pharmacological agents

6. Treatment of Coagulopathy Protamine Plasma; fractions; Platelets Pharmacological agents

7. Treatment of Coagulopathy Protamine Plasma; fractions; factor concentrates Platelets Pharmacological agents

8. Treatment of Coagulopathy Protamine Plasma; fractions; factor concentrates Platelets Pharmacological agents DDAVP Tranexamic acid Recombinant factor VIIa

9. Treatment of Coagulopathy Protamine Plasma; fractions; factor concentrates Platelets Pharmacological agents DDAVP Tranexamic acid Recombinant factor VIIa Proline, Patience

10. Treatment of Coagulopathy Protamine Plasma; fractions; factor concentrates Platelets Pharmacological agents DDAVP Tranexamic acid Recombinant factor VIIa Proline, Patience

11. Haemostasis may be possible despite a severe coagulopathy Bleeding may occur despite normal coagulation Treatment required only for bleeding associated with coagulopathy Is Treatment Required?

12. Treatment of coagulopathy is ALWAYS associated with risk Treatment of coagulopathy is ALWAYS associated with cost Treatment of coagulopathy is NOT always associated with benefit! Benefits, Risks, and Costs

13. Consensus Guidelines

14. Consensus Summary Avoid hypothermia, acidosis, hypocalcemia and shock Plasma products to maintain INR 100mg/dL Platelets to maintain platelet count >50,000/mL Consider rFVIIa if conventional management has proved ineffective

15. Tranexamic Acid

16. Consensus Guidelines

19. Conventional Plasma Products Fresh Frozen Plasma 300mL factor levels >70% of normal Cryoprecipitate Cryoprecipitate20mL >70iu FVIII >140mg fibrinogen

20. Factor Concentrates Fibrinogen concentrate Prothombin complex concentrate Recombinant factor VIIa Factor XIII concentrate

21. Fibrinogen Concentrate Highly purified fibrinogen concentrate from pooled human plasma; pasteurized for viral inactivation Approved in some countries for the treatment of bleeding in patients with congenital and certain acquired fibrinogen deficiencies

22. Fibrinogen Concentrate 1 – 2g vials Stored at room T 5 year shelf-life

23. Fibrinogen Concentrate 1 – 2g vials Stored at room T 5 year shelf-life Possible to increase fibrinogen level >150mg/dL (unlike FFP):

24. Fibrinogen Concentrate 1 – 2g vials Stored at room T 5 year shelf-life Possible to increase fibrinogen level >150mg/dL (unlike FFP): improves clot firmness;

25. Fibrinogen Concentrate 1 – 2g vials Stored at room T 5 year shelf-life Possible to increase fibrinogen level >150mg/dL (unlike FFP): improves clot firmness; may reduce bleeding

26. Prothrombin Complex Concentrate Freeze-dried human factors II, IX, X ( ± small amounts of VII) Donor screening; viral inactivation

27. Prothrombin Complex Concentrate Freeze-dried human factors II, IX, X ( ± small amounts of VII) Donor screening; viral inactivation Indication: Warfarin reversal Dose 25-50iu/kg

28. Prothrombin Complex Concentrate Used for rapid reversal of warfarin effect Advantages vs FFP include low volume and faster action (<60min vs 2h); no thawing; long shelf-life Disadvantages include increased risk of thrombosis (? low protein C, S levels) Should be given with Vit K ( ± FFP!)

29. Prothrombin Complex Concentrate Need for 4 factor PCC or added FFP?

30. Prothrombin Complex Concentrate Need for 4 factor PCC or added FFP? Factor half-lives Factor II: 45-60h Factor VII: 4-6h Factor IX: 14-68h Factor X: 24-40h

31. Prothrombin Complex Concentrate Need for 4 factor PCC or added FFP? Factor half-lives Factor II: 45-60h Factor VII: 4-6h Factor IX: 14-68h Factor X: 24-40h

32. Prothrombin Complex Concentrate Need for 4 factor PCC or added FFP? Factor half-lives Factor II: 45-60h Factor VII: 4-6h Factor IX: 14-68h Factor X: 24-40h If warfarin stopped >6-12h, factor VII may not be necessary

33. Prothrombin Complex Concentrate Contraindications Allergy to PCC Active thrombosis DIC

34. Prothrombin Complex Concentrate Contraindications Allergy to PCC Active thrombosis DIC Patients at high risk of venous or arterial thrombosis (including MI)

35. Prothrombin Complex Concentrate Is there a role for prothombin complex concentrates in other perioperative coagulopathies?

36. Prothrombin Complex Concentrate Is there a role for prothombin complex concentrates in other perioperative coagulopathies? Only with ‘ethics approval’ and ‘informed consent’, or if there is no conventional alternative

37. Prothrombin Complex Concentrate Is there a role for conventional alternatives (ie. FFP) in the acute reversal of warfarin?

38. Prothrombin Complex Concentrate Is there a role for conventional alternatives (ie. FFP) in the acute reversal of warfarin? Only if there are contraindications to PCC

39. Recombinant FVIIa Approved Use –Patients with VIIIC deficiency with inhibitors; congenital VII deficiency Off Label Use –Extensive level IV evidence for use as ‘rescue therapy’ in trauma and surgery –Safety, cost, and consent issues –‘Justified’ only for life-threatening coagulopathic bleeding, unresponsive to maximal conventional therapy

41. Recombinant FVIIa Experience with RFVIIa Peak effect within minutes Requires adequate fibrinogen levels Less effective in hypothermic and acidotic patients Promotes haemostasis by correcting coagulopathy Ineffective if bleeding is not coagulopathic

42. Factor XIII Concentrate Approved for use for FXIII deficiency Has been shown to increase clot firmness in vitro and ex vivo ( Korte et al. Anesthesiology; 2009;110:239)

43. Summary 1. There is a definite role for prothrombin complex concentrate for acute reversal of warfarin effect; However, PCCs are relatively contraindicated for most other perioperative coagulopathies

44. Summary 2. There is a definite role for recombinant FVIIa as ‘rescue therapy’ in patients who have ongoing life-threatening bleeding and severe coagulopathy despite maximal conventional management

45. Summary 3. There is a potential role for fibrinogen concentrate to replace and increase fibrinogen levels in patients with dilutional coagulopathy; cryoprecipitate is the conventional alternative

46. Summary 4. There is a theoretical role for factor XIII concentrate in patients with a persistent perioperative coagulopathy

47. Summary 5. There is a theoretical potential for avoiding all conventional plasma products in the management of perioperative coagulopathy: This is the direction of current research into coagulation management