Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation.
P-selectin inhibition has been shown to decrease thrombogenesis in multiple animal species. In this study, we show that a novel oral small-molecule inhibitor of P-selectin, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Experimental groups consisted of the following: 1) primates receiving a single oral dose of PSI-697 (30 mg/kg) daily starting three days pre-iliac vein balloon occlusion, and continued for six days; 2) primates receiving a single treatment dose of a low-molecular-weight-heparin (LMWH) (1.5 mg/kg) daily starting one day pre-iliac balloon occlusion, and continued for six days; and 3) primates receiving a single oral dose of a vehicle control daily starting three days pre-iliac vein balloon occlusion, and continued for six days. Animals receiving PSI-697, although thrombosed after balloon deflation, demonstrated greater than 80% vein lumen opening over time, with no opening (0%) for vehicle control (p < 0.01). LMWH opening evident after balloon deflation slightly deteriorated over time compared to PSI-697. PSI-697 therapy also significantly decreased vein wall inflammation determined by magnetic resonance venography (MRV). Importantly, this beneficial opening occurred without measured anticoagulation. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus LMWH and control animals six hours post thrombus induction (p < 0.01). This study is the first to demonstrate the effectiveness of oral P-selectin inhibition to modify venous thrombogenesis, increase vein lumen opening, and decrease inflammation in a large animal model.
Myers
Daniel D
DD
Jobst Vascular Research Laboratories, Section of Vascular Surgery, 2Unit for Laboratory Animal Medicine and 3Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0654, USA. ddmyers@umich.edu
Wrobleski
Shirley K
SK
Longo
Chris
C
Bedard
Patricia W
PW
Kaila
Neelu
N
Shaw
George D
GD
Londy
Frank J
FJ
Rohrer
Suzan E
SE
Fex
Beverly A
BA
Zajkowski
Paul J
PJ
Meier
Thomas R
TR
Hawley
Angela E
AE
Farris
Diana M
DM
Ballard
Nicole E
NE
Henke
Peter K
PK
Schaub
Robert G
RG
Wakefield
Thomas W
TW
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D000925:Anticoagulants / Q000008:administration & dosage; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D002404:Catheterization; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage; D006912:Hydroxyquinolines / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D007084:Iliac Vein / Q000601:surgery; D007279:Injections, Subcutaneous; D018810:Magnetic Resonance Angiography; D008297:Male; D019007:P-Selectin / Q000187:drug effects*; D048530:Papio anubis; D013997:Time Factors; D018615:Ultrasonography, Doppler, Color; D014654:Vascular Patency / Q000187:drug effects; D020246:Venous Thrombosis / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D005338:Fibrin Fibrinogen Degradation Products; D006495:Heparin, Low-Molecular-Weight; D006912:Hydroxyquinolines; D019007:P-Selectin; C036309:fibrin fragment D; C514191:2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo(H)quinoline-4-carboxylic acid