Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with reduced tissue factor activity.
BACKGROUND
Plaque disruption and exposure of subendothelial procoagulants such as tissue factor (TF) to circulating factor VII/VIIa (FVII/VIIa) lead to intravascular thrombosis. Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of TF-induced coagulation that binds to factor Xa and the TF-FVIIa catalytic complex in a two-step process. The aim of this study was to determine the expression of TFPI within human atherosclerotic plaque and its role in modulation of TF activity.


RESULTS
We measured the level of TFPI antigen in human carotid plaque and determined the relationship between TFPI and TF activity within plaque. Furthermore, we examined the biological activity and immunolocalization patterns of TFPI within carotid plaque. TFPI was detectable (TFPI+ group) in 22 of 34 specimens (mean+/-SEM, 404. 4+/-91.8 pg/mg) and undetectable (TFPI- group) in 12 of 34 specimens. In the TFPI- group, normalized TF activity was significantly greater than that in the TFPI+ group (0.28+/-0.04 vs 0.14+/-0.02 U/pg, P=0.002). Furthermore, neutralization of TFPI activity using a polyclonal antibody resulted in an 8-fold increase in TF activity in the TFPI+ group (P=0.001) but had no effect in the TFPI- group. Immunostaining for TFPI showed localization to endothelial cells, vascular smooth muscle cells within the fibrous cap region of the plaque, and macrophages within the shoulder region of the plaque.


CONCLUSIONS
Taken together, these data suggest that biologically active TFPI is present within human atherosclerotic plaque and is associated with attenuated TF activity.
Caplice
N M
NM
From the Divisions of Cardiovascular Diseases (N.M.C.) and Biochemistry and Molecular Biology, Molecular Medicine Program, Mayo Clinic and Foundation, Rochester, Minn, USA.
Mueske
C S
CS
Kleppe
L S
LS
Simari
R D
RD
D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002339:Carotid Arteries / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016894:Endarterectomy, Carotid; D004797:Enzyme-Linked Immunosorbent Assay; D005167:Factor VII / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008074:Lipoproteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009500:Neutralization Tests; D015842:Serine Proteinase Inhibitors / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D017539:Tunica Intima / Q000737:chemistry / Q000378:metabolism / Q000473:pathology
D000906:Antibodies; D008074:Lipoproteins; D015842:Serine Proteinase Inhibitors; C051928:lipoprotein-associated coagulation inhibitor; D005167:Factor VII