The Role of Aprotinin in Cardiac Surgery

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The Role of Aprotinin in Cardiac Surgery

• Mike Poullis

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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

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Overview

• 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

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Basic Science
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Heparin and Aprotinin

• Usually monitor ACT
• Need to monitor KCT
• More heparin needed

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Heparin and Aprotinin II
CLOT
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Thrombin
Intrinsic
Extrinsic VII
Endothelium
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Thrombin and Aprotinin

• Aprotinin inhibits the effects of thrombin

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Platelets
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Platelets

• Cellular constituent of coagulation system
• Number can be normal but dont work
• Platelet Agonists (Afferent)
• Agonist Receptor
• Adrenaline alpha
• Collagen VLA
• ADP ADP
• Thrombin PAR I and IV

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Platelet
PAR-1 (Thrombin receptor)
PAR-4
Platelet
ADP
Microaggregation and Macroaggregation
Collagen
Adrenaline
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Mechanism of G protein receptor activation by
soluble ligand eg ADP
Soluble ligand
(Reversible)
Cell Membrane
G protein
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Protease Activated Receptors (PAR)

• Thrombin is the classic

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Mechanism of G protein receptor activation by
protease eg Thrombin
Protease eg thrombin
(Irreversible)
Cell Membrane
G protein
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(cont)
Tethered ligand
(Irreversible)
Peptide
Cell Membrane
G protein
Activation
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PAR activating peptides
PAR activating peptide
(reversible)
Cell Membrane
G protein
Activation
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Actions proteolytic inhibitors eg Aprotinin
Protease eg thrombin
Aprotinin
Cell Membrane
G protein
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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

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

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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.

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Neutrophils

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

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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.

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Fibrinolysis

• Natural mechanism to prevent uncontrolled
  coagulation

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Fibrinolysis and Aprotinin

• D-dimer levels reduced by aprotinin
• Direct effect on plasmin

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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

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Dosages of Aprotinin

• High dose
• Initial bolus of 2106 KIU (280 mg)
• Infusion of 70 mg/h (5105 KIU),
• addition of 280 mg to the pump prime fluid.
• Low dose
• Initial bolus of 1106 KIU (140 mg)
• Infusion of 35 mg/h (2.5105 KIU)
• 50 ml/hr
• Remember high ACTs or use KCT

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Adverse effects

• Anaphylactic reaction
• Graft occlusion
• Renal impairment
• Microvascular occlusion

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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

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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 Nov116(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.

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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 52(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

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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 131(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-Feb12(1 Pt
  1)S14-8

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Hypothermic circulatory arrest

• Stasis
• Renal Failure
• Bleeding
• ???Inflammation

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Hypothermic circulatory arrest

• Pro aprotinin should be used in patients
  undergoing hypothermic circulatory
  arrest.Royston D.
• J Cardiothorac Vasc Anesth 2001 Feb15(1)121-5
• Con aprotinin should not be used in patients
  undergoing hypothermic circulatory
  arrest.Gravlee GP.
• J Cardiothorac Vasc Anesth 2001 Feb15(1)126-8

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Cardiac Transplantation

• Defining the role of aprotinin in heart
  transplantation.Prendergast TW, et al.
• Ann Thorac Surg 1996 Sep62(3)670-4
• Risk of anaphylaxis from aprotinin re-exposure
  during LVAD removal and heart transplantation.Mi
  lano CA, Patel VS, Smith PK, Smith MS.
• J Heart Lung Transplant 2002 Oct21(10)1127-30

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Factor V Leiden

• Aprotinin, cardiac surgery, and factor V
  Leiden.Sweeney JD, et al.
• Transfusion 1997 Nov-Dec37(11-12)1173-8
• Protein C inhibition by aprotinin
• 10 of cardiac surgery population are Factor V
  Leiden Ve

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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

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PAF
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Drugs to treat HIT

• LMW
• Ancrod
• Aprotinin
• Thrombin antagonists Hirudin
• Ancrod - aprotinin interaction is important

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Bleeding Post CPB in ITU

• No real evidence, all anecdotal

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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 Jan23(1)60-5

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Cerebral dysfunction

• Etiology and incidence of brain dysfunction
  after cardiac surgery.Murkin JM.
• J Cardiothorac Vasc Anesth 1999 Aug13(4 Suppl
  1)12-7

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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 Oct24(10)1677-89

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Personal Arrogant Opinion

• Acute endocarditis
• Hypothermic circulatory arrest
• Neither of the above for bleeding
• Excessive fibrinolysis ? As dictated by TEG

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Remember

• If intravenous aprotinin does not stop the
  bleeding, try putting the bottles in the holes
• Mike Desmond, CTC

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Hot dates

• Monday Teaching 7.30am start
• Friday 13th Audit