Review and application of serine protease inhibition in coronary artery bypass graft surgery

Abstract

Purpose: Current pharmacologic agents, aprotinin, epsilon aminocaproic acid, and tranexamic acid, used to decrease blood loss and transfusion requirements during coronary artery bypass graft (CABG) surgery are discussed. Aprotinin is the only agent that also modulates the systemic inflammatory responses that are generated by contact activation during CABG surgery. These responses are largely mediated by serine proteases such as kallikrein, thrombin, and plasmin.

Summary: Aprotinin is a naturally occurring polypeptide that has a concentration-dependent effect to inhibit serine proteases. Two aprotinin dosing regimens are indicated in the United States (U.S.) for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass (CPB) during the course of CABG surgery. Serum concentrations achieved with the full-dose regimen inhibit both kallikrein and plasmin activity resulting in attenuation of the systemic inflammatory response to bypass, whereas serum concentrations achieved with the half-dose regimen only inhibit plasmin activity. The efficacy and safety of aprotinin have been studied in randomized controlled trials in over 5,000 patients. Aprotinin is well tolerated compared to placebo. Treatment-emergent adverse events are similar to those associated with CPB surgery. However, because aprotinin is a bovine protein, there is a small, but manageable risk of hypersensitivity reactions. Epsilon aminocaproic acid and tranexamic acid are lysine analogs that reduce bleeding by inhibiting the conversion of plasminogen to plasmin, a serine protease responsible for breaking down fibrinogen to fibrin. Although they are commonly used to decrease bleeding associated with CABG surgery with CPB, they are not currently approved by the U.S. Food and Drug Administration (FDA) for CABG surgery.

Conclusion: Aprotinin is the only agent that has an FDA indication to prevent blood loss and transfusion during CABG surgery, and the additional benefit of attenuating the systemic inflammatory response associated with CABG with CPB.