Aprotinin

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Aprotinin

Aprotinin (Trasylol®, Bayer) is medication administered by injection used to reduce bleeding during complex surgery, such as heart and liver surgery. Its main effect is the slowing down fibrinolysis, the process that leads to the breakdown of blood clots. The aim in its use is to decrease need for blood transfusions during surgery, as well as end-organ damage due to hypotension (low blood pressure) as a result of marked blood loss.

Chemistry

Aprotinin is a 58 amino acid polypeptide extracted from cow lung. It has a molecular weight of 6512Mannucci PM. Hemostatic drugs. N Engl J Med 1998;339:245-53. PMID 9673304.Mahdy AM, Webster NR. Perioperative systemic haemostatic agents. Br J Anaesth 2004;93:842-58. PMID 15277296.. It has disulfide bonds in three places: between residues 5 and 55, 14 and 38 as well as 30 and 51.Kassell B, Laskowski M Sr. The basic trypsin inhibitor of bovine pancreas. V. The disulfide linkages. Biochem Biophys Res Commun 1965;20:463-8. PMID 5860161. Its amino acid sequence is RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA KRNNF KSAED CMRTC GGA.Kassell B, Radicevic M, Ansfield MJ, Laskowski Sr M. The basic trypsin inhibitor of bovine pancreas IV. The linear sequence of the 58 amino acids. Biochem Biophys Res Commun 1965;18:255-8. PMID 14282026.

Mode of action

Aprotinin inhibits several serine proteases, specifically trypsin, chymotrypsin and plasmin at a concentration of about 125,000 IU/ml, and kallikrein at 300,000 IU/ml. Its action on kallikrein leads to the inhibition of the formation of factor XIIa. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis.

Efficacy

In cardiac surgery with a high risk of significant blood loss, aprotinin signficantly reduced bleeding, mortality and hospital stay. Beneficial effects were also reported in high-risk orthopedic surgery. In liver transplantation, initial reports of benefit were overshadowed by concerns about toxicityXia VW, Steadman RH. Antifibrinolytics in orthotopic liver transplantation: current status and controversies. Liver Transpl 2005;11:10-8. PMID 15690531.

In a meta-analysis performed in 2004, transfusion requirements decreased by 39% in coronary artery bypass graft (CABG) surgerySedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004;128:442-8. PMID 15354106.. In orthopedic surgery, a decrease of blood transfusions was likewise confirmedShiga T, Wajima Z, Inoue T, Sakamoto A. Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials. Anesth Analg 2005;101:1602-7. PMID 16301226..

Safety

There have been concerns about the safety of aprotinin. Anaphylaxis (a severe allergic reaction) occurs at a rate of 1:200 in first-time use, but serology (measuring antibodies against aprotinin in the blood) is not carried out in practice to predict anaphylaxis risk because the correct interpretation of these tests is difficult.

Thrombosis, presumably from overactive inhibition of the fibrinolytic system, may occur at a higher rate, but until 2006 there was limited evidence for this association. Similarly, while biochemical measures of renal function were known to occasionally deteriorate, there was no evidence that this greatly influenced outcomes. A study performed in cardiac surgery patients reported in 2006 showed that there was indeed a risk of acute renal failure, myocardial infarction and heart failure, as well as stroke and encephalopathyMangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-65. PMID 16436767. The study authors recommend older antifibrinolytics (such as tranexamic acid) in which these risks were not documented.

No cases of bovine spongiform encephalopathy transmission by aprotinin have been reported, although the drug was withdrawn in Italy due to fears of this .

In vitro use

Small amounts of aprotinin can be added to tubes of drawn blood to enable laboratory measurement of certain rapidly degraded proteins such as glucagon.

History

Initially named "kallikrein inactivator", aprotinin was first isolated from cow parotid glands in 1928Kraut H, Frey EK, Bauer E. Z Physiol Chem 1928;175:97-114. and independently as "bovine pancreatic trypsin inhibitor" from cow pancreas in 1936.Kunitz M, Northrup J. Isolation from beef pancreas of crystalline trypsinogen, trypsin, trypsin inhibitor, and an inhibitor trypsin compound. J Gen Physiol 1936;19:991-1007. PDF. It was purified from bovine lung in 1964.Kraut H, Bhargava N. Versuche zur Isolierung des Kallikrein-Inaktivators aus Rinderlunge and seine Identifizierung mit dem Inaktivator aus Rinderparotis. Z Physiol Chem 1964;328:231-7. PMID 14330402. As it inhibits pancreatic enzymes, it was initially used in the treatment for acute pancreatitis, in which destruction of the gland by its own enzymes is thought to be part of the pathogenesis.Nugent FW, Warren KW, Jonasson H, Garciadeparedes G. Early experience with trasylol in the treatment of acute pancreatitis. South Med J 1964;57:1317-21. PMID 14195953. Its use in major surgery commenced in the 1960s.Tice DA, Worth Jr MH, Clauss RH, Reed GH. The inhibition of trasylol of fibrinolytic activity associated with cardiovascular operations. Surg Gynecol Obstet 1964;119:71-4. PMID 14179354.

References

External links

Trasylol.com (official Bayer website)

Antifibrinolytics