1. Thrombin generation and its inhibition: a review of the scientific basis and mechanism of action of anticoagulant therapies 
C.P.R. Walker, D. Royston 
British Journal of Anaesthesia 
Volume 88, Issue 6, Pages (June 2002)
DOI: /bja/
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

2. Fig 1
Diagrammatic representation of secondary structures of coagulation factor VII, IX, and X to show N‐terminal of increased negativity (shown as circled area on factor VII). Protrusions from surface represent gamma‐carboxy glutamic acid residues.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

3. Fig 2
(a) Factor Xa and prothrombin without co‐factor V. The shaded discs represent the negatively charged platelet surface. The multiple bars at the lower pole of each molecule represent the gamma‐carboxy glutamic acid residues with filled circles on the lower extensions representing positively charged calcium ions to allow the negative glutamate residues to approach the platelet surface. Xa cannot release constraint around the active site of prothrombin (to release thrombin) as prothrombin is not correctly aligned. The bar protruding from the middle of the prothrombin molecule represents a portion of the molecule which gives steric hindrance and is intended to prevent unwanted activation by other proteolytic enzymes. (b) The role of factor V (two thick bars in V shape) which acts as a co‐factor to hold factor Xa and prothrombin in exact configuration so they have no choice but to have a productive interaction and allow thrombin generation.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

4. Fig 3
Diagrammatic representation of the organization and generation of active coagulation factors on the cell surface. The lipid bilayer is typically a platelet membrane; the rectangle filled with diagonal lines is substrate or zymogen: the oval filled with vertical lines is a co‐factor; and the scissors represent an active serine protease. Factor VIII, X, IXa is termed the tenase and V, II, Xa the prothrombinase complex.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

5. Fig 4
Proteolytic activation of factor X or IX (FX or FIX) at cell surface by factor VIIa. TF has an intracellular and transmembrane domain to ensure the reaction occurs at the cell surface and the extracellular domain holds factor VII or VIIa and factor X in correct conformation. Factor VII circulates as active and partially activated enzyme.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

6. Fig 5
Schematic representation of thrombin molecule to show proteolytic site with three substrate binding sites (marked as S) and two anion‐binding exosites. The exosite adjacent to the proteolytic area plays a considerable part in the binding of the C‐terminal polypeptide of hirudin. The second area, away from the proteolytic site, is important in the enhanced effectiveness of ATIII complexed to heparin with more than 18 saccharides to inhibit thrombin.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

7. Fig 6
Diagram to show how thrombin is bound to surface thrombomodulin in a way that exposes the cleavage site. This will cleave protein C to give aPC. aPC slows coagulation by interfering with co‐factors V and VIII thus converting procoagulant thrombin to an anticoagulant.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

8. Fig 7
Sites of inhibition of thrombin generation by antithrombin III, shown as an open cross‐shaped box. Weight of line represents inhibitor capacity, with inhibition of thrombin strongest and that of factor IXa relatively weak. Activated protein C is shown overlapping factor V and VIII as the hexagonal symbol, and tissue factor pathway inhibitor by a moiety with three domains filled by horizontal lines. This moiety prevents proper interaction between VIIa and X. It is easy to appreciate that a natural inhibitor controls each phase of the process of thrombin generation. It is also apparent why this balance can be disturbed by relative lack of any of the inhibitors. Examples include reduction of protein C concentration with warfarin therapy and of AT III by consumption following prolonged heparin administration.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

9. Fig 8
Action of heparin to activate ATIII and enhance ATIII activity against thrombin. Row 1 shows pentasaccharide sequence binding to ATIII leading to conformational change in the molecule. This molecule can approach and attach to thrombin but the configuration of molecules is not controlled and the active site positive charge may inhibit binding to the active site on thrombin. The active site charge is neutralized by heparin with a pentasaccharide sequence of up to 18 sugars via attachment to a binding site on ATIII, which approaches the active centre pole. This is shown in row 2. Row 3 shows that heparin molecules with more than 18 saccharide residues allows three mechanisms of (1) conformational change, (2) neutralization of ATIII charge, and (3) ‘approximation’ with heparin binding to the anion exosite on thrombin to allow the thrombin molecule to be held in an optimum configuration for inhibition by ATIII.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

10. Fig 9
Inhibition of thrombin by hirudin and direct thrombin inhibitors based on TAME (tosyl‐arginine methyl ester). Hirudin is able to complex the C‐terminal of its structure with the exosite of the thrombin molecule to enhance agonist activity. Enhanced activity of TAME derivatives is related to small size, allowing maximum penetration of the proteolytic site, and the design of molecule, which enhances attachment to substrate binding sites on the thrombin molecule.
British Journal of Anaesthesia  , DOI: ( /bja/ )
Copyright © 2002 British Journal of Anaesthesia Terms and Conditions