Aprotinin: The 58-Amino-Acid Protease Inhibitor Withdrawn and Reinstated
Protease inhibitor polypeptides
Aprotinin is a 58-amino-acid polypeptide from bovine lung that inhibits several serine proteases, and its history is one of the most debated safety stories in cardiac surgery. It is also better known to biochemists as BPTI, a small, tightly folded protein that became a model system for studying how proteins fold.
What is aprotinin?
Aprotinin, also called bovine pancreatic trypsin inhibitor (BPTI), is a natural proteinase inhibitor. The FDA label for the former brand Trasylol describes it as obtained from bovine lung, with 58 amino acid residues, a molecular weight of about 6,512 daltons and one chain held by three disulfide bridges. In UniProt entry P00974 the precursor is 100 residues long, and the mature chain spans positions 36 to 93. Counting from the first residue of the mature protein, the disulfides join Cys5 to Cys55, Cys14 to Cys38 and Cys30 to Cys51.
Those three cross-links are what lock this small chain into a rigid shape, the same structural principle described in disulfide bonds in peptides. Sources describe it as strongly basic, with many lysine and arginine residues relative to acidic ones.
How aprotinin is studied to work
UniProt records that aprotinin inhibits trypsin, kallikrein, chymotrypsin and plasmin. The label explains that inhibiting kallikrein and plasmin dampens fibrinolysis (the breakdown of clots), inflammation and thrombin generation during cardiopulmonary bypass. Reviews note that blocking kallikrein limits formation of factor XIIa, and that direct inhibition of plasmin slows clot breakdown. In other words, the drug works by physically occupying the active sites of these enzymes, a lock-and-key behaviour typical of Kunitz-type inhibitors.
A short history
Kunitz and Northrop reported a crystalline trypsin inhibitor from beef pancreas in 1936, and Kraut and Bhargava described purification from bovine lung in 1964. Because BPTI is small, stable and well characterised, it became a staple of protein-folding research. A 1990 Nature study by Staley and Kim showed that native-like subdomains in partially folded intermediates explain much of how its disulfide bonds form. Its use as a surgical drug came later, as an antifibrinolytic given to reduce bleeding in cardiac surgery.
What the human evidence shows
In 2006 Mangano and colleagues published an observational study in the New England Journal of Medicine of 4,374 patients having heart revascularisation at 69 centres. It reported higher odds of dialysis-requiring kidney failure with aprotinin (odds ratios of about 2.59 in complex and 2.34 in primary surgery) and signals of cardiovascular and cerebrovascular harm, which were not seen with tranexamic acid or aminocaproic acid. Observational studies cannot prove cause, and the findings were contested.
The randomised BART trial (Fergusson and colleagues, NEJM 2008) enrolled 2,331 high-risk cardiac surgery patients to aprotinin (781), tranexamic acid (770) or aminocaproic acid (780). Massive bleeding occurred in 9.5 percent versus 12.1 percent in each comparison group, a difference that was not conclusive (risk ratio 0.79, 95 percent confidence interval 0.59 to 1.05). Thirty-day mortality was 6.0 percent with aprotinin versus 3.9 and 4.0 percent, and the trial was stopped early because of the mortality difference.
Regulatory history
On 12 September 2007 two FDA advisory committees recommended continued US marketing with label changes and further randomised trials. In early November 2007, after BART was halted, the FDA suspended marketing and the manufacturer suspended it worldwide. In February 2012 the EMA committee recommended lifting the European suspension, saying the BART results were unreliable because of imbalances in heparin use and monitoring, problems excluding some patients, and a lack of replication. It restricted use to isolated coronary bypass surgery at high risk of major blood loss, after considering alternatives, with a heparin warning and an EU registry. Current marketing status in individual countries after 2012 is not covered here and varies.
Safety information on the label
The label carries a boxed warning for fatal anaphylactic or anaphylactoid reactions, including at the test dose, with greater risk on re-exposure within 12 months. It also warns of kidney dysfunction and dialysis, especially with existing kidney impairment or concurrent aminoglycoside antibiotics. As an animal-derived polypeptide, it is a reminder that protein and peptide products can provoke immune responses, a theme discussed in peptide secondary structure and oral peptide delivery.
Frequently asked questions
Is aprotinin a peptide or a protein?
At 58 residues it sits at the boundary and is commonly called a polypeptide or a small protein. Its three disulfide bonds give it a stable folded structure.
Why is it called BPTI?
BPTI stands for bovine pancreatic trypsin inhibitor, the name biochemists use for the same molecule in folding and structure research.
What does it inhibit?
UniProt lists trypsin, kallikrein, chymotrypsin and plasmin, all serine proteases.
Does this article give dosing or handling instructions?
No. It summarises published facts. For general laboratory concentration arithmetic, see the reconstitution calculator, which is lab math and not medical guidance.
References
- UniProt P00974 — Pancreatic trypsin inhibitor (BPTI), Bos taurus
- FDA Trasylol (aprotinin) prescribing information, 2006
- Mangano DT et al. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006 (PMID 16436767)
- Fergusson DA et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery (BART). N Engl J Med 2008 (PMID 18480196)
- EMA: European Medicines Agency recommends lifting suspension of aprotinin (2012)
- Kunitz M, Northrop JH. Isolation of a trypsin inhibitor from beef pancreas, 1936 (PMID 19872978)
- Kraut H, Bhargava AS. Inhibitor purified from bovine lung, 1964 (PMID 14330402)
- Staley JP, Kim PS. BPTI disulfide folding intermediates. Nature 1990;344:685-688
Informational only — not medical advice. This article is for educational purposes. It does not recommend, sell or instruct personal human use of any compound. Consult a qualified healthcare professional for any health decision. Content is intended for adults 21+. Verify scientific details against the primary sources cited.