Aprotinin
A bovine trypsin inhibitor that cut bleeding in bypass surgery, then left the US market over a mortality signal
Aprotinin is a small protein extracted from cattle lung that blocks several serine proteases, among them plasmin and kallikrein. Sold as Trasylol, it was given during heart surgery to reduce blood loss and transfusions. After a randomised trial found more deaths than with cheaper alternatives, it was withdrawn from the US market in 2008; Europe later allowed it back for a narrow group of high-risk patients.
Last FDA label of a product discontinued in the US (not a current US recommendation): 1 mL test dose, 2 million KIU (280 mg) loading, 2 million KIU in the pump prime, then 500,000 KIU (70 mg) per hour, Continuous during surgery, Intravenous, central line Details ↓
Recommended Dosing
Last FDA label of a product discontinued in the US (not a current US recommendation)
From the last US prescribing information of a product discontinued in the US (see the regulatory status on this page). It records what that label said while the product was sold there; it is not a current US recommendation. Other doses studied, if any, are in the full dosing data below.
What is it?
Aprotinin is a natural protease inhibitor taken from cattle. It is a 58-amino-acid chain, folded tight by three disulfide bonds, that blocks several enzymes involved in clotting and inflammation. Chemists call it bovine pancreatic trypsin inhibitor. As a medicine it was purified from cattle lung and sold by Bayer as Trasylol. Its job in the operating room was to stop the heart-lung machine from dissolving clots too fast, so that patients bled less after cardiac surgery and needed fewer transfusions.
The early results were striking. In a small 1987 London trial of repeat heart operations, patients given high-dose aprotinin lost about a fifth as much blood as untreated patients and needed far fewer units of blood. A 1996 US trial of 704 first-time bypass patients found that high, low and pump-prime-only doses all cut bleeding, though the benefit was hard to show in people at low risk of bleeding to begin with. FDA approved Trasylol in December 1993.
Doubts arrived in 2006. A large observational study linked aprotinin to kidney failure needing dialysis, heart attack and stroke, and a follow-up of the same patients found higher five-year mortality. Hospital billing records from more than 78,000 US bypass patients, and ten years of Duke University data, pointed the same way. Observational studies can mislead, because surgeons tend to give a bleeding-prevention drug to sicker patients, so the question went to a randomised trial.
That trial, BART, randomised 2,331 high-risk cardiac surgery patients to aprotinin, tranexamic acid or aminocaproic acid and was stopped early. Aprotinin reduced massive bleeding only slightly, but 6.0% of its patients died within 30 days against about 4% on either lysine analogue. Bayer suspended marketing worldwide in November 2007. In May 2008, after BART was published, it told FDA it would remove the remaining supplies from US hospital pharmacies, and the drug was offered afterwards only as an investigational product under a special protocol.
Aprotinin did not disappear everywhere. European regulators allowed it back for adults at high risk of major blood loss during isolated coronary bypass surgery, and required a registry. That registry has followed more than 5,000 patients across 83 European centres, mostly in operations sicker than the approved indication, and has not found event rates beyond those expected for such surgery. Meta-analyses still disagree about who, if anyone, gains enough to justify the risk.
Two safety problems are specific to this molecule. Because it is a foreign protein, the immune system can learn to recognise it, and a second exposure within months carries a real risk of anaphylaxis, sometimes fatal. It also prolongs the activated clotting time used to monitor heparin during bypass, which can make anticoagulation look stronger than it is. Neither problem has anything to do with peptides sold for self-use: aprotinin is a hospital drug given by an anaesthetist with bypass equipment ready.
Mechanism of Action
Aprotinin is a broad serine protease inhibitor. Its main surgical effect is to slow clot breakdown and blunt the inflammatory response that the heart-lung machine sets off.
Plasmin and kallikrein
Lower blood levels block plasmin, which dissolves clots; higher levels also block kallikrein, which starts the contact pathway of clotting and inflammation (PMID 7517106).
Platelet sparing
Studies suggest it protects platelet adhesion and aggregation receptors from damage during bypass, though how much this adds to the effect is unmeasured (PMID 39628415).
Kidney handling
The 2006 US label notes a risk of kidney dysfunction; observational data and a meta-analysis link it to creatinine rises (PMIDs 19185048, 16533273).
Published Research
The studies behind aprotinin, read from their PubMed abstracts. Almost all are in heart surgery; the key safety evidence comes from observational studies, one stopped randomised trial and later European registry data.
The 1987 trial that started it
In 22 patients having repeat open-heart surgery, the 11 given about 700 mg of aprotinin through the operation lost a mean 286 mL of blood against 1,509 mL without it, and needed about one-eighth as much transfused blood.
Three dose regimens in first-time bypass
Among 704 first-time bypass patients, high-dose, low-dose and pump-prime-only aprotinin all reduced bleeding and transfusion against placebo, with no difference in deaths, kidney failure or stroke; benefit was not consistent in low-risk patients, and the pump-prime-only dose had slightly more possible heart attacks.
How long it stays in the blood
Infusions of 500,000 and 1,000,000 KIU in 28 cardiac surgery patients gave clearance of about 35 mL/min and a steady-state volume of 26.5 L; the authors calculated that about 2,000,000 KIU is needed to reach the level that blocks kallikrein, while a smaller dose suffices to block plasmin.
Liver resection, outside heart surgery
In 97 patients having planned liver resection, large-dose aprotinin lowered blood loss (about 1.2 L against 1.65 L) and the share of patients transfused (17% against 39%) compared with placebo, with no thrombosis or kidney problems recorded.
It confuses the heparin test
During bypass with standard heparin, the activated clotting time ran about twice as long in aprotinin patients, while clotting tests triggered with high-dose thromboplastin or thrombin were unaffected; the authors proposed those tests for monitoring heparin when aprotinin is used.
The 2006 observational alarm
In an observational study of 4,374 revascularisation patients, aprotinin was linked, after propensity adjustment, to about twice the risk of kidney failure needing dialysis, and in primary surgery to more heart attacks, heart failure and stroke; tranexamic and aminocaproic acid showed no such links.
Five-year deaths in the same cohort
Following 3,876 bypass patients for five years, 20.8% of those given aprotinin had died against 12.7% of those given no bleeding drug (adjusted hazard ratio 1.48); neither lysine analogue was associated with more deaths.
Matched against tranexamic acid
Matching 449 high-transfusion-risk patients given aprotinin with 449 given tranexamic acid, transfusion rates were similar, but kidney dysfunction occurred in 24% on aprotinin against 17% on tranexamic acid.
US hospital records: 78,000 bypass patients
In administrative data on 33,517 bypass patients given aprotinin and 44,682 given aminocaproic acid, in-hospital death was 4.5% against 2.5%; after adjusting for 41 characteristics the risk was 64% higher, and other analyses designed to limit confounding still found an excess.
Ten years of Duke University data
Among 10,275 coronary surgery patients, those given aprotinin had worse long-term survival than those given aminocaproic acid (hazard ratio 1.27) or no bleeding drug, and larger rises in creatinine, though dialysis was not more common.
BART: the randomised trial that ended its US use
In 2,331 high-risk cardiac surgery patients, the trial stopped early: massive bleeding was 9.5% with aprotinin against about 12% with either lysine analogue, but 30-day death was 6.0% against 3.9% and 4.0% (relative risk 1.53 against both combined); the authors said this ruled out its use in high-risk surgery.
Pooling the observational studies
A meta-analysis of 11 observational studies found aprotinin associated with kidney dysfunction (risk ratio 1.42) and with long-term death (hazard ratio 1.22); longer bypass time explained part of the kidney signal, and the authors could not rule out leftover confounding.
Does risk level change the answer?
Pooling 31 randomised and observational studies with 33,501 patients, early death was higher with aprotinin than lysine analogues in low-risk (risk ratio 1.58) and intermediate-risk patients, but not in high-risk patients (1.03), where the authors thought it might still help.
Anaphylaxis after 12,403 exposures
In one centre's records, reactions to aprotinin occurred in 0.09% of first exposures, none severe, and in 1.5% of re-exposures; all five severe reactions came within six months of a previous dose, and the reaction rate fell from 4.1% under six months to 0.4% after a year.
Re-exposure in children
Among 509 re-exposures in children having heart surgery, 2.6% caused a systemic allergic reaction; in this cohort the systemic rate was no higher when the previous dose had been within a year.
Children's heart surgery: pooled data
Across 32 studies of about 64,000 paediatric cardiac operations, aprotinin reduced blood loss, transfusion and re-operation for bleeding without changing 30-day mortality, but raised the odds of needing kidney replacement therapy (odds ratio 1.29).
The European registry after relicensing
From 2016 to 2020, 5,309 patients in 83 European centres received aprotinin, three-quarters outside the approved isolated bypass indication; in-hospital death was 1.3% in isolated bypass and 8.3% in the more complex operations, and 0.2% had allergic reactions, which the authors judged in line with the literature.
Half dose or full dose?
In 6,664 registry patients, the full-dose regimen led to less re-operation for bleeding within two days (3.2% against 4.4%) with no difference in 7-day death or major cardiac events, but more early kidney injury in people with chronic kidney disease.
Skull surgery in children
In a randomised trial of 90 children having craniosynostosis surgery, aprotinin and tranexamic acid both reduced blood loss relative to body size and the need for transfusion compared with no drug, with no serious adverse events.
The case as it stood in 2008
This review describes aprotinin as an antifibrinolytic and anti-inflammatory serine protease inhibitor that reduces transfusion, records that the maker halted shipments worldwide after BART was stopped in 2007, and advised reserving it for patients at high risk of blood loss.
Does it protect platelets?
A scoping review of 64 studies found that most reported a platelet-sparing effect of aprotinin, through several proposed receptor and enzyme pathways, but none measured how much of its blood-saving effect this explains.
Dosing Data
These are the last US label's two regimens for coronary bypass surgery with cardiopulmonary bypass. Trasylol has not been marketed in the US since 2008, so no current US label exists; the figures are printed so the trials make sense, not as a dose anyone can obtain.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no regulator's label that says in what form Aprotinin is supplied. It is prepared and given by clinical staff, not bought and mixed at home: the next part says where.
Mixing a vial: a worked example
Nothing to mix at home, and no syringe units to work out: Aprotinin is prepared and given by clinical staff, in the operating room, during heart surgery.
In the carded trials it was infused through open-heart operations to reduce bleeding; its last US label was for bypass surgery.
Source: PMID 2446091 and PMID 8957369 (studies carded under Research below).
Storage before and after mixing
Unknown: no label on file says how Aprotinin is stored. It is kept and prepared by the hospital or clinic that gives it (see the part above); the home rules for a mixed vial in the mixing guide do not apply to it.
How it is taken
As the approved label gives it: Intravenous, central line (Continuous during surgery; Label regimen A (full dose)).
Source: Last FDA label of a product discontinued in the US (not a current US recommendation): the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: a half-life of about 150 minutes after distribution; terminal phase about 10 hours. After about five half-lives almost none is left.
How long the doses were given: Label regimen A (full dose): Until the patient leaves the operating room; Label regimen B (half dose): Until the patient leaves the operating room.
When effects appear: unknown; no source on this page gives a time to effect for Aprotinin. Results reported in the studies are under Published Research.
Source: half-life: Trasylol (aprotinin injection) US prescribing information, revised November 2006, the last version on Drugs@FDA (application 020304, supplement 22); not on DailyMed: Bayer suspended US marketing in November 2007 and removed remaining stock in May 2008, Clinical Pharmacology; Last FDA label of a product discontinued in the US (not a current US recommendation), the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: Higher death rates than lysine analogues in BART and several observational studies; Kidney dysfunction and, in some studies, kidney failure needing dialysis; Allergic and anaphylactic reactions, most often on re-exposure within months; Heart attack, heart failure and stroke signals in observational data; Falsely long activated clotting times during heparin monitoring. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Aprotinin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“From the studies above”).
Interactions
- heparin: under standard heparinisation during bypass, the celite activated clotting time ran about twice as long with aprotinin, so that test overstates heparin's effect; high-dose thromboplastin and thrombin times were not affected
Every peptide's record, with its source: the interaction matrix.
Source: human study, PMID 7524456.
Checking what you bought
Unknown: no published independent test of Aprotinin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Aprotinin's expected mass, 6,511.5 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Discontinued (FDA-approved December 29, 1993 as Trasylol (application 020304, Bayer)). Elsewhere: approved in EU (restricted to adults at high risk of major blood loss in isolated coronary bypass surgery, with a registry). Sport: Unsettled (S0 may apply).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
From the studies above.
Contraindications & Cautions
From the boxed warning and warnings of the last US Trasylol label (revised November 2006, Drugs@FDA).
Legal Status
Aprotinin was an FDA-approved surgical drug; it has not been marketed in the US since 2008.
Frequently Asked Questions
?Is aprotinin still used?
Not in the US, where it has not been sold since 2008. Some European centres use it again for high-risk bypass patients under a registry.
?Why was it withdrawn?
The BART trial found more deaths within 30 days with aprotinin than with tranexamic acid or aminocaproic acid, on top of earlier observational signals for kidney failure and death.
?Why can a second dose be dangerous?
It is a cow protein, so the immune system can form antibodies after the first exposure. In one large series, reactions were 0.09% on first exposure and 1.5% on re-exposure, with all severe ones within six months.
?Is it the same as tranexamic acid?
No. Tranexamic acid and aminocaproic acid are small synthetic molecules that block clot breakdown; aprotinin is a protein that blocks several enzymes, and in BART it carried more deaths.
?Does a smaller dose avoid the problems?
Not clearly. A 1996 trial found low and high doses cut bleeding about equally, and European registry data found less re-operation for bleeding with the full dose but more early kidney injury in people with kidney disease.
References
- [clinical-trial] Royston D, et al. "Effect of aprotinin on need for blood transfusion after repeat open-heart surgery." Lancet, 1987;2(8571):1289-91. PMID: 2446091.
- [clinical-trial] Lemmer JH Jr, et al. "Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens." Ann Thorac Surg, 1996;62(6):1659-67; discussion 1667-8. PMID: 8957369.
- [pubmed] Levy JH, et al. "Pharmacokinetics of aprotinin in preoperative cardiac surgical patients." Anesthesiology, 1994;80(5):1013-8. PMID: 7517106.
- [clinical-trial] Lentschener C, et al. "Aprotinin reduces blood loss in patients undergoing elective liver resection." Anesth Analg, 1997;84(4):875-81. PMID: 9085974.
- [clinical-trial] Tabuchi N, et al. "Monitoring of anticoagulation in aprotinin-treated patients during heart operation." Ann Thorac Surg, 1994;58(3):774-7. PMID: 7524456.
- [pubmed] Mangano DT, et al. "The risk associated with aprotinin in cardiac surgery." N Engl J Med, 2006;354(4):353-65. PMID: 16436767.
- [pubmed] Mangano DT, et al. "Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery." JAMA, 2007;297(5):471-9. PMID: 17284697.
- [pubmed] Karkouti K, et al. "A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery." Transfusion, 2006;46(3):327-38. PMID: 16533273.
- [pubmed] Schneeweiss S, et al. "Aprotinin during coronary-artery bypass grafting and risk of death." N Engl J Med, 2008;358(8):771-83. PMID: 18287600.
- [pubmed] Shaw AD, et al. "The effect of aprotinin on outcome after coronary-artery bypass grafting." N Engl J Med, 2008;358(8):784-93. PMID: 18287601.
- [clinical-trial] Fergusson DA, et al. "A comparison of aprotinin and lysine analogues in high-risk cardiac surgery." N Engl J Med, 2008;358(22):2319-31. PMID: 18480196.
- [review] Gagne JJ, et al. "Aprotinin and the risk of death and renal dysfunction in patients undergoing cardiac surgery: a meta-analysis of epidemiologic studies." Pharmacoepidemiol Drug Saf, 2009;18(4):259-68. PMID: 19185048.
- [review] Meybohm P, et al. "Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and ε-aminocaproic acid -- a meta-analysis of randomised and observational trials of over 30.000 patients." PLoS One, 2013;8(3):e58009. PMID: 23483965.
- [pubmed] Dietrich W, et al. "Aprotinin and anaphylaxis: analysis of 12,403 exposures to aprotinin in cardiac surgery." Ann Thorac Surg, 2007;84(4):1144-50. PMID: 17888960.
- [pubmed] Siehr S, et al. "Hypersensitivity reactions to aprotinin re-exposure in paediatric surgery." Eur J Cardiothorac Surg, 2010;37(2):307-11. PMID: 19767215.
- [review] Atasever AG, et al. "Efficacy and safety of aprotinin in paediatric cardiac surgery: A systematic review and meta-analysis." Eur J Anaesthesiol, 2022;39(4):352-367. PMID: 34783684.
- [pubmed] De Hert S, et al. "Use and safety of aprotinin in routine clinical practice: A European postauthorisation safety study conducted in patients undergoing cardiac surgery." Eur J Anaesthesiol, 2022;39(8):685-694. PMID: 35766393.
- [pubmed] Colson PH, et al. "Half-Dose versus Full Dose of Aprotinin in Cardiac Surgery: A Post-hoc Analysis of the Aprotinin European Registry." Eur J Cardiothorac Surg, 2025;67(9). PMID: 40802524.
- [clinical-trial] Ebrahim Soltani Z, et al. "Safety and efficacy of aprotinin versus tranexamic acid for reducing absolute blood loss and transfusion in pediatric patients undergoing craniosynostosis surgery: a randomized, double-blind, three-arm controlled trial." J Neurosurg Pediatr, 2022;29(5):551-559. PMID: 35148511.
- [review] Kristeller JL, et al. "Benefits and risks of aprotinin use during cardiac surgery." Pharmacotherapy, 2008;28(1):112-24. PMID: 18154481.
- [review] Vanglabeke LLW, et al. "Platelet-sparing properties of aprotinin: A scoping review on mechanisms and clinical effects." Eur J Anaesthesiol, 2025;42(1):36-43. PMID: 39628415.
- [fda] Drugs@FDA (openFDA): BLA020304, TRASYLOL (aprotinin), Bayer Healthcare; original approval December 29, 1993; marketing status Discontinued. Read October 28, 2026.
- [other] UniProt P00974 (BPT1_BOVIN), mature chain residues 36-93, pancreatic trypsin inhibitor; read October 28, 2026. https://www.uniprot.org/uniprotkb/P00974/entry
- [other] PubChem CID 16130295, Pancreatic trypsin inhibitor (aprotinin): formula C284H432N84O79S7, molecular weight 6511. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/16130295
- [fda-pi] Trasylol (aprotinin injection) US prescribing information, Bayer, revised November 2006. Drugs@FDA, application 020304, supplement 22: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020304s022lbl.pdf (not on DailyMed: no longer marketed). Read October 28, 2026.
- [fda] US FDA, Aprotinin injection (marketed as Trasylol) information page: Bayer suspended marketing in November 2007; update of May 14, 2008 on removal of remaining supplies and investigational access. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aprotinin-injection-marketed-trasylol-information. Read October 28, 2026.
Sources & Citations
Studies were read from their PubMed abstracts; doses, half-life and warnings from the last US Trasylol label on Drugs@FDA (revised November 2006); the market history from FDA's aprotinin information page and Drugs@FDA, read October 28, 2026.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.