1. The antithrombotic and antiinflammatory mechanisms of action of aprotinin 
R.Clive Landis, PhD, George Asimakopoulos, Mike Poullis, Dorian O. Haskard, Kenneth M. Taylor 
The Annals of Thoracic Surgery 
Volume 72, Issue 6, Pages (December 2001)
DOI: /S (01)

2. Fig 1
The proteolytic activation mechanism of the thrombin receptor PAR1. Thrombin initially binds to a hirudin-like motif on PAR1 before cleaving the receptor at arginine 41. Cleavage unmasks a “tethered ligand” sequence in the ectodomain, which is now available to dock within the ligand-binding pocket located between extracellular loops 2 and 3 of the transmembrane domain. Cleavage occurs via the serine protease activity of thrombin in conjunction with other “cofactors,” some of which are serine proteases that may themselves be targets of aprotinin. Proteolytic activation of PAR1 is followed by translocation of heterotrimeric G protein signals, Ca2+ fluxing and downstream activation events, such as platelet aggregation and serotonin secretion. (For a good review on protease-activating receptors, see the article by Coughlin [16].)
The Annals of Thoracic Surgery  , DOI: ( /S (01) )

3. Fig 2
Selective blocking of PAR1-mediated activation of platelets by aprotinin. This schematic summarizes the effect of aprotinin on platelet activation in response to proteolysis-dependent agonists (ie. thrombin and trypsin) versus proteolysis-independent agonists (ie, collagen, ADP or epinephrine). Aprotinin selectively blocks proteolysis-dependent modes of activation mediated via the PAR1 receptor, but not proteolysis-independent modes, which are mediated via the collagen, ADP, or epinephrine receptors (after Poullis and associates [20]).
The Annals of Thoracic Surgery  , DOI: ( /S (01) )

4. Fig 3
The leukocyte–endothelial cell adhesion cascade. The three main phases of the adhesion cascade are shown: 1. leukocyte rolling, 2. firm adhesion, and 3. extravasation. Also indicated are the points at which the major categories of adhesion molecules and proteases play a role. The initial tethering and rolling phase under hydrodynamic shear flow is mediated by the selectin family of adhesion molecules, E-, P- and L-selectin, which are characterized by rapid on:off rates for their lectin-type ligands. The firm adhesion step is mediated by the integrins, such as Mac-1, LFA-1 and VLA-4, which have evolved as conditional adhesion molecules on leukocytes that require prior activation, usually via a chemokine, before they can mediate adherence to endothelium. Endothelial counterligands for the integrins are members of the immunoglobulin supergene family and include ICAM-1, ICAM-2, and CD31. Chemokines are generated from within the tissues and are transported to the apical side of the blood vessel where they are “presented” on the glycocalyx to rolling leukocytes looking for signs of underlying tissue injury or infection. The extravasation and tissue migration steps involve further contributions from proteases of the elastase and metalloproteinase families, which are secreted at the leading edge of leukocytes, where they digest cell:cell junctions or subendothelial matrix components ahead of the migrating cell. (For a good review of the leukocyte–endothelial cell adhesion cascade, see Frenette and Wagner [46].)
The Annals of Thoracic Surgery  , DOI: ( /S (01) )