Effect of vascular injury on inhibition of venous thrombosis with ZK-807834, a direct inhibitor of factor Xa.
Inhibition of factor Xa with the small molecule inhibitor ZK-807834 (Mr 527 Da, Ki 0.11 nM) attenuates progression of thrombosis, but the ED50 is substantially lower for venous compared with arterial thrombosis in experimental animals. To determine whether this reflects differences in the extent of vascular injury, we compared the dose-response of ZK-807834 for inhibition of venous thrombosis induced with a cotton thread and copper wire device in the presence and absence of balloon catheter-induced injury to the vena cava in rabbits. ZK-807834 administration over 2 h (total dosages of 0.0023-2.3 micro mol kg-1, n = 6/group) resulted in dose-dependent reductions in clot weight compared with vehicle controls, but the ED50 was 0.03 micro mol kg-1 for non-injured veins and 0.42 micro mol kg-1 for injured veins. We conclude that vascular injury invokes a tissue factor-mediated response that increases the dose requirements for inhibition of venous thrombosis with ZK-807834.
Abendschein
D R
DR
Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MO 63110, USA. dabendsc@imgate.wustl.edu
Baum
P K
PK
Light
D R
DR
Morser
J
J
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001780:Blood Coagulation Tests; D002404:Catheterization / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000293:injuries*; D065427:Factor Xa Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D015912:Thrombolytic Therapy; D014684:Venae Cavae / Q000473:pathology; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000209:etiology*
D000578:Amidines; D065427:Factor Xa Inhibitors; D011725:Pyridines; C114592:Fidexaban