The Role of Aprotinin in Cardiac Surgery

Mike Poullis

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

OverviewBasic 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

Basic Science

Heparin and Aprotinin

• Usually monitor ACT

• Need to monitor KCT

• More heparin needed

Heparin and Aprotinin II

CLOT

Thrombin

Extrinsic VIIIntrinsic

Endothelium

Thrombin and Aprotinin

• Aprotinin inhibits the effects of thrombin

Platelets

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

Platelet

Platelet

Microaggregationand Macroaggregation

PAR-1 (Thrombin receptor)

PAR-4

ADP

Adrenaline Collagen

Mechanism of G protein receptor activation by soluble ligand eg ADP

Cell Membrane

G protein

Soluble ligand(Reversible)

Protease Activated Receptors (PAR)

• Thrombin is the classic

Mechanism of G protein receptor activation by protease eg Thrombin

Cell Membrane

G protein

Protease eg thrombin(Irreversible)

(cont)

Cell Membrane

G protein

(Irreversible)Tethered ligand

Activation

Peptide

PAR activating peptides

Cell Membrane

G protein

(reversible)PAR activating peptide

Activation

Actions proteolytic inhibitors eg Aprotinin

Cell Membrane

G protein

Protease eg thrombinAprotinin

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

PAR deactivation

Cell Membrane

G protein

Protease eg thrombin

(Irreversible)

Deactivator eg elastase

aa 41/42

NH2

aa 43/44 & 55/56

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

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.

Neutrophils

• Activated during CPB directly and indirectly

• Release neutrophil elastase, cathepsin G, lysozymes, and myeloperoxidase

• Main target of anti inflammatory treatment

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.

Fibrinolysis

• Natural mechanism to prevent uncontrolled coagulation

Fibrinolysis and Aprotinin

• D-dimer levels reduced by aprotinin

• Direct effect on plasmin

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

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

Adverse effects

• Anaphylactic reaction

• Graft occlusion

• Renal impairment

• Microvascular occlusion

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

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.

Redo CABGEffect 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

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

Hypothermic circulatory arrest

• Stasis

• Renal Failure

• Bleeding

• ???Inflammation

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

Cardiac TransplantationDefining 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

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

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

PAF

Drugs to treat HIT

• LMW

• Ancrod

• Aprotinin

• Thrombin antagonists Hirudin

• Ancrod - aprotinin interaction is important

Bleeding Post CPB in ITU

• No real evidence, all anecdotal

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

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;

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

Personal Arrogant Opinion

• Acute endocarditis

• Hypothermic circulatory arrest

– Neither of the above for bleeding

• Excessive fibrinolysis ? As dictated by TEG

Remember

“If intravenous aprotinin does not stop the bleeding, try putting the bottles in the holes”

Mike Desmond, CTC

Hot dates

• Monday Teaching 7.30am start

• Friday 13th Audit