Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis.
BACKGROUND
Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus and local thrombotic and inflammatory mechanisms. We hypothesized that inhibition of vein wall injury through reduction of thrombotic and inflammatory events with P-selectin inhibition and/or low-molecular-weight heparin (LMWH) occurs independently of thrombus resolution in a rat model of venous thrombosis.


METHODS
Male rats underwent inferior vena cava (IVC) stenosis (94.4% +/- 0.5% reduction in IVC diameter) to induce thrombosis. Rats were treated from 2 days after thrombosis until they were killed 7 days later. Groups consisted of (1) PSI-697, a P-selectin inhibitor (30 mg/kg; oral gavage daily); (2) LMWH-Lovenox (LOV; enoxaparin) 3 mg/kg subcutaneously daily; (3) PSI-697 (30 mg/kg; oral gavage daily) plus LOV 3 mg/kg subcutaneously daily (PSI + LOV); (4) and untreated controls. Evaluations included thrombus mass, vein wall tensiometry (stiffness [inverse of compliance]), intimal thickness scoring by light microscopy, vein wall inflammatory mediators by enzyme-linked immunosorbent assay, and vein wall inflammatory cells by histologic evaluation.


RESULTS
Thrombus mass was not reduced by any treatment. Animals treated with PSI-697 alone, LOV alone, or PSI + LOV demonstrated significant decreases in vein wall stiffness when compared with controls. The vein wall stiffness of the PSI-697-treated groups was also significantly lower than in the LOV-only group. Animals treated with PSI-697 showed a significantly decreased intimal thickness score when compared with vehicle control IVCs. Vein wall intimal thickening was also significantly decreased in animals treated with PSI-697 vs LOV. The PSI-697 and PSI + LOV groups manifested significant decreases in the immunoregulatory and inflammatory cytokine interleukin 13 as compared with controls and LOV. Vein wall monocyte chemotactic protein 1 levels were also significantly reduced in the PSI-697 and PSI + LOV groups vs control. Only PSI-697 significantly decreased vein wall levels of platelet-derived growth factor betabeta. Both the LOV and PSI + LOV groups had significant increases in vein wall monocytes and total inflammatory cells vs controls.


CONCLUSIONS
These data suggest that both LMWH and PSI-697 inhibit vein wall injury independently of thrombus mass. P-selectin inhibition seemed superior to LMWH in measured parameters of injury and mediator inhibition.
Myers
Daniel D
DD
Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, 48109-0654, USA. ddmyers@umich.edu
Henke
Peter K
PK
Bedard
Patricia W
PW
Wrobleski
Shirley K
SK
Kaila
Neelu
N
Shaw
Gray
G
Meier
Thomas R
TR
Hawley
Angela E
AE
Schaub
Robert G
RG
Wakefield
Thomas W
TW
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D017984:Enoxaparin / Q000627:therapeutic use; D005355:Fibrosis; D006912:Hydroxyquinolines; D007962:Leukocytes / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology*; D019007:P-Selectin; D051381:Rats; D017207:Rats, Sprague-Dawley; D019087:Selectins; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D014682:Vena Cava, Inferior / Q000473:pathology*; D020246:Venous Thrombosis / Q000473:pathology*
D000925:Anticoagulants; D017984:Enoxaparin; D006912:Hydroxyquinolines; D018945:Monocyte Chemoattractant Proteins; D009930:Organic Chemicals; D019007:P-Selectin; D019087:Selectins; C514191:2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo(H)quinoline-4-carboxylic acid