Aprotinin is a naturally occurring protein that functions as an enzyme inhibitor. Discovered in 1930, it was initially identified as a kallikrein inactivator in bovine lymph nodes and later as a trypsin inhibitor in bovine pancreas. Also known as bovine pancreatic trypsin inhibitor (BPTI), it is found in various bovine tissues, including the lungs, from which it was purified in 1964. Aprotinin plays a role in regulating enzymatic activity.
What are Proteases and Protease Inhibitors
Proteases are enzymes that break down proteins into smaller polypeptides or individual amino acids through a process called hydrolysis. These enzymes are involved in numerous biological pathways throughout the body. For instance, they play roles in the digestion of ingested proteins, the breakdown of old proteins (catabolism), and various cell signaling processes. Proteases are also involved in highly regulated cascades, such as the blood-clotting system and immune responses.
Protease inhibitors, also known as antiproteases, are molecules that counteract the activity of proteases. They function by blocking the active site of proteases, thereby preventing them from cleaving peptide bonds. Many naturally occurring protease inhibitors are proteins themselves, acting as a regulatory mechanism within the body. These inhibitors can bind to proteases either reversibly or irreversibly, depending on their specific mechanism.
Aprotinin’s Mechanism of Action
Aprotinin specifically functions as a competitive inhibitor of several serine proteases. It works by forming a stable, reversible complex with the active site of these enzymes, thus preventing them from performing their usual protein-cleaving actions. This inhibitory action extends to a range of serine proteases, including trypsin, chymotrypsin, and plasmin, at 125,000 kallikrein inactivator units per milliliter (KIU/mL).
Aprotinin more strongly inhibits kallikrein. This inhibition reduces factor XIIa formation, which in turn inhibits the intrinsic pathway of coagulation. Aprotinin also directly slows down fibrinolysis, the process responsible for breaking down blood clots, through its action on plasmin. Beyond its effects on coagulation, aprotinin modulates systemic inflammatory responses by attenuating pro-inflammatory cytokine release and maintaining glycoprotein homeostasis.
Historical and Current Medical Uses
Aprotinin was initially used in the treatment of acute pancreatitis, a condition where the pancreas is thought to be damaged by its own enzymes. Its application in major surgery began in the 1960s, primarily to reduce blood loss and the need for blood transfusions. It was particularly used during complex procedures like heart and liver surgery, where significant blood loss is a concern.
Its main benefit in these surgical contexts was to slow down fibrinolysis, the process that dissolves blood clots, which helped reduce blood loss. Aprotinin was approved in the United States in 1993 for use in high-risk patients undergoing coronary artery bypass graft (CABG) surgery. Following safety concerns and withdrawal, aprotinin’s use is now limited to specific high-risk scenarios, such as isolated coronary artery bypass graft surgery for patients with substantial risk of major blood loss.
Safety Concerns and Withdrawal
Safety concerns emerged regarding aprotinin, leading to its withdrawal from the market in many countries. Observational studies in 2006 indicated that aprotinin use was associated with serious adverse events. These findings suggested an increased risk of perioperative renal dysfunction and failure requiring dialysis in patients undergoing coronary artery surgeries.
Further studies indicated an increased risk of myocardial infarction or heart failure. There was also an increased risk of stroke or encephalopathy. In October 2007, a large randomized controlled trial, the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), was stopped early due to preliminary analysis showing a trend towards increased all-cause 30-day mortality in patients receiving aprotinin. This led to the manufacturer temporarily suspending marketing and shipment of the drug worldwide.
Modern Alternatives and Future Outlook
Following aprotinin’s withdrawal, alternative antifibrinolytic agents largely replaced its use for blood conservation during surgery. These alternatives include tranexamic acid and aminocaproic acid, which have been shown to be effective in reducing the need for blood transfusions. Neither tranexamic acid nor aminocaproic acid has been associated with the increased risks of renal, cardiac, or cerebral events linked to aprotinin.
Aprotinin’s current regulatory status is highly restricted. While it was removed from the worldwide market in 2007, its marketing in Canada and Europe was permitted again in 2011 after re-evaluation of the BART study data. However, its use is now limited to adult patients undergoing isolated coronary artery bypass graft surgery who are at high risk of major blood loss. Aprotinin remains unavailable for use in the United States.