title: The impact of factor Xa inhibition on axial dependent arterial thrombus formation triggered by a tissue factor rich surface.
abstract: This study was designed to assess the effect of Factor Xa antagonists on thrombus formation at various axial positions on a tissue factor rich surface under arterial blood flow conditions. Non-anticoagulated, flowing human blood, drawn directly from an antecubital vein, was perfused over a tissue factor coated cover slip in a parallel-plate perfusion chamber. Thrombus surface coverage, thrombus mean height and fibrin surface coverage were measured at six different axial positions by confocal microscopy. Both thrombus surface coverage and mean height decreased along the cover slip axis whereas the fibrin surface coverage increased. Pre-chamber treatment of blood with the direct Factor Xa inhibitors Razaxaban and 813893 resulted in significantly reduced thrombus and fibrin formation at all axial positions investigated (P < 0.05). Thrombus and fibrin deposition in a laminar flow chamber changed with axial position with surface coverage measurements being more reproducible than thrombus mean height. Data were more reproducible towards the centre of the flow chamber than at the extremities. Razaxaban and 813893 inhibited thrombus and fibrin formation at the highest concentrations tested. No difference in drug effect was apparent at different axial positions. In conclusion, axial position influences the degree of thrombus and fibrin deposition with measurements being less reproducible at the extremities of the flow chamber. This technique may prove useful for analysing anti-thrombotic drug effects before progression to clinical trials.
authors: Department of Biochemistry, University of Cambridge, Cambridge CB1 2QW, UK. np306@cam.ac.uk
authors: Nicholas
authors: N
authors: Pugh
authors: Gavin E
authors: GE
authors: Jarvis
authors: Annelize
authors: A
authors: Koch
authors: Kjell S
authors: KS
authors: Sakariassen
authors: Bill
authors: B
authors: Davis
authors: Richard W
authors: RW
authors: Farndale
mesh_terms: D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010477:Perfusion / Q000295:instrumentation / Q000379:methods*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D013499:Surface Properties / Q000187:drug effects; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism* / Q000517:prevention & control; D055815:Young Adult
chemical_list: D065427:Factor Xa Inhibitors; D007555:Isoxazoles; D011720:Pyrazoles; C500057:razaxaban; D013925:Thromboplastin; D015951:Factor Xa