Aprotinin (Trasylol): cuts bleeding during heart surgery
A cow-derived protein dripped into a vein during open-heart surgery to reduce blood loss; pulled from the market in 2007 over safety concerns and later allowed back in Europe for limited use, check current status in your country.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Aprotinin (sold as Trasylol) is a small bovine protein, given by intravenous infusion to reduce surgical bleeding — primarily in adults undergoing coronary artery bypass graft (CABG) surgery. It is a 58-amino-acid serine protease inhibitor originally purified from cow tissue, and it works by blocking the body's bleeding-promoting enzymes during the artificial-circulation phase of heart surgery. The drug has had a turbulent regulatory history: widely used from the late 1980s onward, withdrawn worldwide in 2007–2008 over safety concerns, and reinstated in the European Union in 2012–2013 for a restricted indication after the data behind the withdrawal were re-evaluated.
The stored 58-residue sequence is the mature bovine pancreatic trypsin inhibitor (BPTI) backbone. Aprotinin is a Kunitz-type fold stabilised by three disulfide bonds (Cys5–Cys55, Cys14–Cys38, Cys30–Cys51 in the canonical BPTI numbering); those bridges are not visible in the linear single-letter sequence but are essential to the inhibitor's compact pear-shaped structure and its ability to engage active-site serines.
History
Aprotinin was first identified in the 1930s as a bovine inhibitor of trypsin- and kallikrein-like enzymes, and the protein was thoroughly characterised through the 1950s–1970s as bovine pancreatic trypsin inhibitor (BPTI). It became one of the most intensively studied small proteins in structural biology — one of the earliest protein crystal structures solved — and is the archetypal member of the Kunitz protease-inhibitor family.
The drug's modern clinical career began with a landmark 1987 trial: Royston and colleagues at the Royal Brompton Hospital reported that high-dose aprotinin reduced mean blood loss from about 1,500 mL to under 300 mL in 22 patients undergoing repeat open-heart surgery, with parallel reductions in transfusion requirement (Royston et al., The Lancet, 1987). That trial transformed aprotinin (marketed by Bayer as Trasylol) into a routine intra-operative agent in cardiac surgery worldwide over the next two decades, and a 1987 mechanistic paper documented its effects on the hemostatic disturbances of cardiopulmonary bypass (van Oeveren et al., Annals of Thoracic Surgery, 1987).
The story turned in 2006 when Mangano and colleagues published an observational analysis in The New England Journal of Medicine reporting that aprotinin use was associated with renal failure, myocardial events, stroke and encephalopathy compared with lysine antifibrinolytics or no antifibrinolytic (Mangano et al., NEJM, 2006), followed by a 2007 JAMA study reporting increased five-year mortality after CABG in aprotinin-exposed patients (Mangano, JAMA, 2007). The Canadian BART trial — a randomized comparison of aprotinin against tranexamic acid and aminocaproic acid in high-risk cardiac surgery — was halted early in 2008 after an interim analysis showed a higher 30-day mortality rate in the aprotinin arm (6.0% vs ~4%) despite a modest bleeding advantage (Fergusson et al., NEJM, 2008; commentary Ray, NEJM 2008). Bayer suspended marketing worldwide that year.
A subsequent re-analysis judged the BART results unreliable; the European Medicines Agency lifted its suspension in February 2012, and the European Commission formally reinstated marketing authorisation in 2013 for a restricted indication. Royston's 2014 review in Anaesthesia summarised the post-reinstatement evidence and the renewed clinical case for aprotinin in selected patients (Royston, Anaesthesia, 2014).
What it does
In the context of heart surgery on cardiopulmonary bypass, aprotinin blunts the surge of clot-dissolving and inflammatory enzyme activity that the artificial circuit triggers, and the result is less postoperative bleeding and a lower need for donor-blood transfusion. The original 1987 trial showed roughly a five-fold reduction in mean blood loss in repeat heart surgery (Royston 1987); subsequent work extended this to specific high-bleeding-risk populations including patients on clopidogrel presenting for CABG (van der Linden et al., Circulation, 2005) and to profoundly hypothermic perfusion (Westaby et al., European Journal of Cardio-Thoracic Surgery, 1994).
Beyond the antifibrinolytic effect, aprotinin has documented anti-inflammatory actions on the bypass-induced systemic response — Royston reviewed the role of aprotinin and other protease inhibitors in preventing the inflammatory response to open-heart surgery (Royston, International Journal of Cardiology, 1996) — and it preserves coronary bypass-graft vascular reactivity in animal models of cardiac surgery (Allen et al., Journal of Thoracic and Cardiovascular Surgery, 1997).
Mechanism
Aprotinin is a broad-spectrum serine protease inhibitor of the Kunitz family. Its compact, disulfide-stabilised fold presents a "canonical loop" that occupies the active site of target serine proteases as a pseudo-substrate, blocking catalysis. Clinically the most relevant targets are plasmin (the fibrinolytic enzyme that breaks down clots) and plasma kallikrein (the contact-system enzyme that drives kinin generation and contributes to the inflammatory response to cardiopulmonary bypass). The 2014 Royston review draws a sharp mechanistic contrast with the lysine analogues tranexamic acid and ε-aminocaproic acid: those drugs prevent plasminogen from binding fibrin (so they block plasmin formation), whereas aprotinin inactivates free plasmin that has already been generated — a different point of intervention in the same cascade (Royston, Anaesthesia, 2014).
Pharmacokinetically, aprotinin is administered intravenously during surgery; a weight-related dosing regimen has been evaluated for producing more predictable and constant plasma concentrations than fixed dosing (Royston et al., Anesthesia & Analgesia, 2001).
Evidence
- Human (efficacy on bleeding and transfusion): Multiple randomized and observational studies established that aprotinin reduces perioperative blood loss and transfusion need in cardiac surgery — the original Royston 1987 Lancet trial in repeat open-heart surgery; the van der Linden 2005 Circulation study in clopidogrel-treated CABG patients; the Westaby 1994 trial in hypothermic perfusion; and the BART trial itself confirmed a reduction in massive bleeding (74/781 aprotinin vs 93–94/~770 in each lysine-analogue arm) (Fergusson et al., NEJM, 2008).
- Human (safety controversy): Mangano's 2006 NEJM observational analysis and 2007 JAMA five-year mortality follow-up reported safety signals against aprotinin in CABG; BART showed a 30-day mortality difference; Henry and colleagues' 2009 CMAJ meta-analysis of aprotinin versus lysine-derived antifibrinolytics quantified the comparative safety profile (Henry et al., CMAJ, 2009); Takagi and colleagues' meta-analysis of head-to-head randomized trials reported increased mortality with aprotinin compared with tranexamic acid (Takagi et al., Interactive CardioVascular and Thoracic Surgery, 2009). Re-analyses and editorial responses contested these conclusions (Bizouarn, Annales Françaises d'Anesthésie et de Réanimation, 2006; Bremerich et al., Der Anaesthesist, 2006; Immer et al., Heart Surgery Forum, 2008; Augoustides, Drug Safety, 2008; Pagano et al., Journal of Thoracic and Cardiovascular Surgery, 2008), and the EMA review that underpinned reinstatement concluded the BART results were unreliable.
- Cognitive outcomes: Postoperative cognitive dysfunction in aprotinin-exposed cardiac surgery patients has been examined as a separate question from mortality (Murkin, Canadian Journal of Anesthesia, 2004).
Known effects
- Reduced perioperative blood loss in cardiac surgery — consistently demonstrated since Royston 1987; mechanism is plasmin and kallikrein inhibition.
- Reduced allogeneic blood transfusion requirement in CABG — including in patients on antiplatelet therapy (van der Linden 2005).
- Modulation of the systemic inflammatory response to cardiopulmonary bypass — protease-inhibition–mediated, reviewed by Royston 1996.
Safety signals
The published safety record is the central element of aprotinin's regulatory history. Mangano and colleagues' observational NEJM 2006 study reported increased rates of renal dysfunction, myocardial infarction and cerebrovascular events in aprotinin-treated CABG patients compared with controls (Mangano et al., NEJM, 2006), and Mangano's JAMA 2007 follow-up reported a higher five-year all-cause mortality in the aprotinin-exposed cohort (Mangano, JAMA, 2007). The BART randomized trial reported a 30-day all-cause mortality of 6.0% in the aprotinin arm versus 3.9% with tranexamic acid and 4.0% with aminocaproic acid (Fergusson et al., NEJM, 2008). Henry and colleagues' CMAJ 2009 meta-analysis and the Takagi 2009 head-to-head meta-analysis quantified comparative risk relative to lysine analogues (Henry et al., CMAJ, 2009; Takagi et al., Interactive CardioVascular and Thoracic Surgery, 2009).
These findings drove the worldwide marketing suspension in 2007–2008. The subsequent EMA re-review (concluding in February 2012) judged the BART analysis unreliable and supported reinstatement for a restricted population — adults at high risk of major blood loss in isolated CABG — and the Royston 2014 Anaesthesia review summarises the post-reinstatement landscape, including the differing mechanisms and safety profiles of aprotinin and the lysine analogues (Royston, Anaesthesia, 2014).
Regulatory status
- EU: EMA marketing authorisation reinstated by CHMP recommendation in February 2012 and formally reinstated by the European Commission in 2013, for adults at high risk of major blood loss undergoing isolated CABG. A European post-authorisation safety registry (NAPaR) was established as a condition of reinstatement.
- US: FDA-approved historically as Trasylol. Bayer suspended US marketing in November 2007 and permanently withdrew the regular marketing authorisation in May 2008 following the BART results. Aprotinin remained accessible in the US only under a restricted, investigational pathway after that point.
- WADA: Not listed as a prohibited substance — aprotinin is a surgical antifibrinolytic, not a performance-enhancing agent.
Common questions
Is aprotinin still used today? In the European Union and several other jurisdictions, yes — for adults at high bleeding risk undergoing isolated coronary artery bypass surgery, following the EMA's 2012 reinstatement and the European Commission's 2013 decision. In the United States, the regular marketing authorisation has not been restored after the 2008 withdrawal.
Why was aprotinin withdrawn in 2007–2008? Because two observational studies (Mangano 2006 NEJM; Mangano 2007 JAMA) and a randomized trial (BART, Fergusson 2008 NEJM) reported increased mortality and adverse cardiovascular and renal events in aprotinin-treated cardiac surgery patients compared with lysine-analogue antifibrinolytics or no antifibrinolytic.
Why was the European withdrawal reversed? The EMA's 2012 review concluded that the BART trial's mortality result was unreliable on re-analysis, and that the benefit–risk balance favoured aprotinin in a defined high-risk CABG population. The European Commission formally reinstated marketing authorisation in 2013 with a registry requirement (NAPaR) to monitor real-world use.
How is aprotinin different from tranexamic acid? Both reduce surgical bleeding but they intervene at different points in the fibrinolytic cascade. Tranexamic acid (and ε-aminocaproic acid) are lysine analogues that block plasminogen's lysine-binding site so plasmin cannot form efficiently. Aprotinin directly inactivates free plasmin that has already been generated, and also inhibits plasma kallikrein, contributing an anti-inflammatory effect on the cardiopulmonary-bypass response (Royston, Anaesthesia, 2014).
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
If aprotinin is so tough and compact that it survives almost anything, could scientists attach a tissue-homing signal to it so it only blocks destructive enzymes where they are actually causing disease?
If true, doctors could use aprotinin-like drugs for chronic diseases, not just surgery, because the drug would go exactly where needed instead of affecting the whole body. Patients with inflammatory diseases or slow-healing wounds could benefit without systemic side effects.
If aprotinin works by blocking bleeding enzymes during heart surgery, could it do the same during liver transplants or after major injuries without causing more harm than existing drugs?
If true, surgeons would have a stronger option to control heavy bleeding in operations where current medicines fall short. Patients facing high blood loss could recover faster and need fewer transfusions.
If aprotinin blocks destructive enzymes in the blood, could breathing it in at very low doses protect the lungs during severe pneumonia or ARDS without causing blood clots elsewhere?
If true, hospitals would have a new way to treat life-threatening lung failure using an existing medicine, potentially saving lives during flu seasons or pandemics when ventilators are not enough.
If the tail end of aprotinin touches different bleeding enzymes in different ways, could changing that tail make the drug stop bleeding without the side effects that got it banned?
If true, doctors could use a safer, customized version of an existing drug instead of inventing an entirely new one. Patients would face lower risks of kidney damage or dangerous clots after surgery.
▸3-letter notation
▸citationbibtex
@peptide{pep04443,
sequence = {RPDFCLEPPYTGPCKARIIRYFYNAKAGLCQTFVYGGCRAKRNNFKSAEDCMRTCGGA},
target = {},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}