The clinical benefit of aprotinin with respect to improved hemostasis, plat
elet function, and inflammatory response to cardiopulmonary bypass (CPB) su
rgery has been well documented, but these benefits have been overshadowed b
y the concern that such a potently hemostatic agent might also be prothromb
otic. In this article, we discuss recent advances in the understanding of t
he basic mechanism of aprotinin that have led to the identification of new
antiinflammatory targets and the discovery that aprotinin is, in fact, anti
thrombotic with respect to platelets. Its antithrombotic action is mediated
by the selective blocking of the major thrombin receptor, the protease-act
ivated receptor 1 (PAR1), but not other receptors of platelet activation (i
e, collagen, adenosine diphosphate [ADP], or epinephrine receptors). The se
lective targeting of PARI enables aprotinin to protect platelets from unwan
ted activation by thrombin generated during CPB surgery (consistent with a
role in platelet-preservation), while permitting the participation of plate
lets in the formation of hemostatic plugs at wound and suture sites, where
collagen, ADP, and epinephrine are most likely to be expressed. Aprotinin t
herefore exerts a subtle hemostatic yet antithrombotic mechanism of action,
which, when allied with its multitiered antiinflammatory effect, makes thi
s drug a valuable companion to cardiac surgery. (C) 2001 by The Society of
Thoracic Surgeons.