The Role of Aprotinin in Cardiac Surgery

1. The Role of Aprotinin in Cardiac Surgery Mike Poullis

2. What is it? • A Kunitz non specific serine protease inhibitor • 6,500 Da cationic protein • Inhibits trypsin, plasmin, kallikrein, and elastase in a dose-dependent manner • Originally isolated from Bovine lung tissue • The role of aprotinin in the lung, which is present in a number of species, remains unexplained. • Found in Mast cells

3. Basic Science Heparin Thrombin Platelets Kallikrein-Kinnin system Neutrophils Fibrinolysis Clinical Dosage Adverse affects Routine CABG Redo CABG Endocarditis Hypothermic circulatory arrest Cardiac Transplantation Factor V Leiden HIT, HITT Bleeding post CPB in ITU Pulmonary dysfunction Cerebral dysfunction Cost Overview

4. Basic Science

5. Heparin and Aprotinin • Usually monitor ACT • Need to monitor KCT • More heparin needed

6. Heparin and Aprotinin II CLOT

7. Thrombin Intrinsic Extrinsic VII Endothelium

8. Thrombin and Aprotinin • Aprotinin inhibits the effects of thrombin

9. Platelets

10. Platelets • Cellular constituent of coagulation system • Number can be normal but don’t work • Platelet Agonists (Afferent) • Agonist Receptor • Adrenaline alpha • Collagen VLA • ADP ADP • Thrombin PAR I and IV

11. Platelet PAR-1 (Thrombin receptor) PAR-4 Platelet ADP Microaggregation and Macroaggregation Collagen Adrenaline

12. Mechanism of G protein receptor activation by soluble ligand eg ADP Soluble ligand (Reversible) Cell Membrane G protein

13. Protease Activated Receptors (PAR) • Thrombin is the classic

14. Mechanism of G protein receptor activation by protease eg Thrombin Protease eg thrombin (Irreversible) Cell Membrane G protein

15. (cont) Tethered ligand (Irreversible) Peptide Cell Membrane G protein Activation

16. PAR activating peptides PAR activating peptide (reversible) Cell Membrane G protein Activation

17. Actions proteolytic inhibitors eg Aprotinin Protease eg thrombin Aprotinin Cell Membrane G protein

18. Platelets and Aprotinin • Aprotinin inhibits thrombin induced platelet aggregation but not adrenaline, collagen, and ADP induced aggregation • Neutrophil enzymes can cleave PAR receptor and make it functionless

19. PAR deactivation Protease eg thrombin Deactivator eg elastase aa 43/44 & 55/56 aa 41/42 (Irreversible) NH2 Cell Membrane G protein

20. Kallikrein-Kinnin system • Activated by contact with foreign surfaces liberates factor XII • Factor XII and prekallikrein drive the process • Kallikrein directly activates neutrophils • Kallikrein activates complement • Kallikrein helps form bradykinin • Kallikrein activates factor XII

22. Kallikrein-Kinnin system and Aprotinin • High-dose aprotinin inhibits the kallikrein-C1-INH complex formation. • Low dose aprotinin significantly, but incompletely inhibits the increase in kallikrein-C1-INH complex levels.

23. Neutrophils • Activated during CPB directly and indirectly • Release neutrophil elastase, cathepsin G, lysozymes, and myeloperoxidase • Main target of anti inflammatory treatment

24. Neutrophils and Aprotinin • Low-dose and pump prime only aprotinin treatments blunt CPB-induced CD11b upregulation. • High-dose aprotinin significantly decreases CD11b/CD18 up regulation following CPB onset.

25. Fibrinolysis • Natural mechanism to prevent uncontrolled coagulation

26. Fibrinolysis and Aprotinin • D-dimer levels reduced by aprotinin • Direct effect on plasmin

28. Clinical • Dosage • Adverse affects • Routine CABG • Redo CABG • Endocarditis • Hypothermic circulatory arrest • Cardiac Transplantation • Factor V Leiden • HIT, HITT • Bleeding post CPB in ITU • Pulmonary dysfunction • Cerebral dysfunction • Cost

29. Dosages of Aprotinin • High dose • Initial bolus of 2*106 KIU (280 mg) • Infusion of 70 mg/h (5*105 KIU), • addition of 280 mg to the pump prime fluid. • Low dose • Initial bolus of 1*106 KIU (140 mg) • Infusion of 35 mg/h (2.5*105 KIU) • 50 ml/hr • Remember high ACTs or use KCT

30. Adverse effects • Anaphylactic reaction • Graft occlusion • Renal impairment • Microvascular occlusion

31. Uses for aprotinin • Routine CABG • Redo CABG • Endocarditis • Hypothermic circulatory arrest • Cardiac Transplantation • Factor V Leiden • HIT, HITT • Bleeding post CPB in ITU • Pulmonary dysfunction • Cerebral dysfunction • Cost

32. Routine CABG Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial.Alderman EL, et al. J Thorac Cardiovasc Surg 1998 Nov;116(5):716-30 13 international sites were randomized to receive intraoperative aprotinin (n = 436) or placebo (n = 434). Probability of early vein graft occlusion was increased by aprotinin, but this outcome was promoted by multiple risk factors for graft occlusion.

33. Redo CABG Effect of aprotinin on need for blood transfusion after repeat open-heart surgery.Royston D, Bidstrup BP, Taylor KM, Sapsford RN.Lancet 1987 Dec 5;2(8571):1289-91 22 patients undergoing repeat open-heart surgery through a previous median sternotomy wound 11 received high dose aprotinin Their mean blood loss was 286 ml compared with 1509 ml in the 11 control patients

34. Endocarditis Effect of aprotinin on need for blood transfusion in patients with septic endocarditis having open-heart surgery.Bidstrup BP, Royston D, Taylor KM, Sapsford RN. Lancet 1988 Feb 13;1(8581):366-7 Improved outcome for seriously ill open heart surgery patients: focus on reoperation and endocarditis.Taylor KM. J Heart Lung Transplant 1993 Jan-Feb;12(1 Pt 1):S14-8

35. Hypothermic circulatory arrest • Stasis • Renal Failure • Bleeding • ???Inflammation

36. Hypothermic circulatory arrest Pro: aprotinin should be used in patients undergoing hypothermic circulatory arrest.Royston D. J Cardiothorac Vasc Anesth 2001 Feb;15(1):121-5 Con: aprotinin should not be used in patients undergoing hypothermic circulatory arrest.Gravlee GP. J Cardiothorac Vasc Anesth 2001 Feb;15(1):126-8

37. Cardiac Transplantation Defining the role of aprotinin in heart transplantation.Prendergast TW, et al. Ann Thorac Surg 1996 Sep;62(3):670-4 Risk of anaphylaxis from aprotinin re-exposure during LVAD removal and heart transplantation.Milano CA, Patel VS, Smith PK, Smith MS. J Heart Lung Transplant 2002 Oct;21(10):1127-30

38. Factor V Leiden Aprotinin, cardiac surgery, and factor V Leiden.Sweeney JD, et al. Transfusion 1997 Nov-Dec;37(11-12):1173-8 Protein C inhibition by aprotinin 10 % of cardiac surgery population are Factor V Leiden +Ve

39. HIT, HITT, CPB and Aprotinin • PF-4 and heparin antibody • Clinical suspicion • Immunoassay • Bioassay • How do you develop HIT? • Tissues and blood cell activation • Heparin exposure • Antibody formation • Antibody has to have a functional Fc

40. PAF

41. Drugs to treat HIT • LMW • Ancrod • Aprotinin • Thrombin antagonists Hirudin • Ancrod - aprotinin interaction is important

43. Bleeding Post CPB in ITU • No real evidence, all anecdotal

44. Pulmonary Dysfunction The effect of aprotinin on ischemia-reperfusion injury in an in situ normothermic ischemic lung model.Eren S, et al. Eur J Cardiothorac Surg 2003 Jan;23(1):60-5

45. Cerebral dysfunction Etiology and incidence of brain dysfunction after cardiac surgery.Murkin JM. J Cardiothorac Vasc Anesth 1999 Aug;13(4 Suppl 1):12-7;

46. Cost A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit.Robinson D, Bliss E. Clin Ther 2002 Oct;24(10):1677-89

47. Personal Arrogant Opinion • Acute endocarditis • Hypothermic circulatory arrest • Neither of the above for bleeding • Excessive fibrinolysis ? As dictated by TEG

48. Remember “If intravenous aprotinin does not stop the bleeding, try putting the bottles in the holes” Mike Desmond, CTC

49. Hot dates • Monday Teaching 7.30am start • Friday 13th Audit