The current place of aprotinin in the management of bleeding

Abstract

SummaryThere is a considerable difference between the mechanism of action of the lysine analogues, tranexamic acid and epsilon-aminocaproic acid, and the serine protease inhibitor aprotinin. Aprotinin acts to inactivate free plasmin, but with little effect on bound plasmin, whereas the lysine analogues are designed to prevent excessive plasmin formation by fitting into plasminogen's lysine-binding site to prevent the binding of plasminogen to fibrin. Aprotinin is associated with a reduction in bleeding and transfusion requirements following major surgery, and has a dose-response profile, compared with no dose-response effect in the one study investigating tranexamic acid in cardiac surgical patients. Following its withdrawal in 2007, which is explained in detail in this review, the regulators have now licensed aprotinin for myocardial revascularisation only, which is relatively low-risk for bleeding.

Major transfusions remain frequent despite the generalized use of tranexamic acid: an audit of 3322 patients undergoing cardiac surgery

“…44 Consequently, the suspension of the license for aprotinin was lifted in Canada and in Europe for this specific indication, which is relatively low risk for bleeding. 45 This indication is based on the randomized controlled trials that led to approval of the drug. Nevertheless, most clinicians would argue that, since primary, elective CABG surgery is not associated with major bleeding, they would tend to use aprotinin in major cardiac cases such as those that were included in BART: "high-risk cardiac surgical procedures for which cardiopulmonary bypass [is] required: repeat cardiac surgery, isolated mitral-valve replacement, combined valve and CABG surgery, multiple valve replacement or repair, and surgery of the ascending aorta or aortic arch."…”

TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections

“…The non-specific nature of those inhibitors may cause unpredictable side effects. For instance, the Food and Drug Administration (FDA) has found that aprotinin increases the risks of kidney failure, heart disease and stroke, resulting in banned or restricted status of the drug in some countries [80]. Therefore, it is necessary to develop inhibitors that specifically target TMPRSS2.…”

Purification and characterization of tenerplasminin-1, a serine peptidase inhibitor with antiplasmin activity from the coral snake ( Micrurus tener tener ) venom

“…The results suggested that the TP1 induces an anti-fibrinolytic mechanism similar to aprotinin, a plasmin non-competitive inhibitor and a plasminogen activation competitive inhibitor, however, aprotinin is associated with acute renal failure, myocardial infarction, stroke, encephalopathy and increased risk of death (Longstaff, 1994; Karkouti, et al, 2004; Levy and Sypniewski, 2004; Royston, 2015). Its mechanism of action may be through the formation of stable complex made of TP1:enzyme (Fig.…”