Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model.
OBJECTIVE
Antiphospholipid antibodies (aPL) have thrombogenic properties in vivo, through their interactions with soluble coagulation factors and their ability to modulate the functions of cells involved in coagulation homeostasis. These antibodies have also been shown to enhance the adhesion of leukocytes to endothelial cells (ECs) in vivo. New lipophilic statins such as fluvastatin have antiinflammatory and antithrombogenic effects. This study uses an in vivo mouse model to investigate whether fluvastatin has an effect on decreasing both the adhesion of leukocytes to ECs and the thrombus formation induced by aPL.


METHODS
Two groups of CD-1 male mice, each comprising approximately 18 mice, were fed either normal saline solution or 15 mg/kg fluvastatin for 15 days. Each of the 2 groups was further subdivided to receive either purified IgG from patients with the antiphospholipid syndrome (IgG-APS) or normal IgG from healthy subjects. Analysis of thrombus dynamics was performed in treated and control mice, using a standardized thrombogenic injury procedure, and the area (size) of the thrombus was measured. Adhesion of leukocytes to ECs was analyzed with a microcirculation model of exposed cremaster muscle. Baseline and posttreatment soluble intercellular adhesion molecule 1 (sICAM-1) levels were determined by enzyme-linked immunosorbent assay.


RESULTS
IgG-APS mice treated with fluvastatin showed significantly smaller thrombi, a reduced number of adherent leukocytes, and decreased levels of sICAM-1 compared with IgG-APS animals treated with placebo.


CONCLUSIONS
These findings indicate that fluvastatin significantly diminishes aPL-mediated thrombosis and EC activation in vivo. These results may have important implications for the design of new treatment strategies aimed at preventing recurrent thrombosis in patients with APS.
Ferrara
Dardo E
DE
Morehouse School of Medicine, Atlanta, Georgia 30310-1495, USA.
Liu
Xiaowei
X
Espinola
Ricardo G
RG
Meroni
Pier Luigi
PL
Abukhalaf
Imad
I
Harris
E Nigel
EN
Pierangeli
Silvia S
SS
D000284:Administration, Oral; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000494:pharmacology*; D016736:Antiphospholipid Syndrome / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000627:therapeutic use*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply; D013927:Thrombosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
D017152:Antibodies, Antiphospholipid; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D018799:Intercellular Adhesion Molecule-1; D000077340:Fluvastatin