The effects of tissue factor pathway inhibitor and anti-beta-2-glycoprotein-I IgG on thrombin generation.
OBJECTIVE
Recent evidence suggests that autoantibodies to tissue factor pathway inhibitor (TFPI) and/or antiphospholipid antibodies (aPL) may contribute to upregulation of the tissue factor (TF) pathway of blood coagulation and the development of thrombotic complications in the antiphospholipid syndrome (aPS). The aim of this study was to determine the influence of aPL e.g. anti-beta-2-glycoprotein-I (anti-beta2GPI) and anti-prothrombin, on in vitro TF-induced thrombin generation in the presence and absence of TFPI.


METHODS
IgG fractions were collected from subjects with aPL (n=21) and normal controls (n=36). Anti-TFPI activity was determined after incubation of IgG isolated from control or subject plasma with pooled normal plasma using an amidolytic assay for TFPI. The influence of IgG fractions and purified aPL (anti-beta2GPI and anti-prothrombin) on TF-induced in vitro thrombin generation was determined using a chromogenic assay of thrombin activity.


RESULTS
Patients with aPL had significantly elevated thrombin generation (median [interquartile range]) compared to normal controls (112.0 [104.0-124.0]% vs 89.9 [85.7-100.9]%, respectively; p<0.001). Thrombin generation was significantly correlated with anti-TFPI activity in patients with aPL (r(s)=0.452; p=0.039). It was also demonstrated that anti-beta2GPI, but not anti-prothrombin IgG antibodies, significantly enhanced TF-induced thrombin generation in the presence of TFPI, using both purified and patients' samples.


CONCLUSIONS
Our findings support the hypothesis that anti-beta2GPI IgG antibodies accelerate thrombin generation in the presence of TFPI and may contribute to hypercoagulability in patients with aPS.
Lean
Sim Yee
SY
Western Australian Biomedical Research Institute, School of Biomedical Sciences Curtin University of Technology, GPO Box U 1987, Perth, WA 6845 Australia.
Ellery
Paul
P
Ivey
Leesa
L
Thom
Jim
J
Oostryck
Robert
R
Leahy
Michael
M
Baker
Ross
R
Adams
Murray
M
D000328:Adult; D000368:Aged; D000818:Animals; D065427:Factor Xa Inhibitors; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000502:physiology*; D008074:Lipoproteins / Q000097:blood / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000096:biosynthesis*; D013918:Thrombin Time; D053482:beta 2-Glycoprotein I / Q000097:blood / Q000276:immunology*
D065427:Factor Xa Inhibitors; D007074:Immunoglobulin G; D008074:Lipoproteins; D053482:beta 2-Glycoprotein I; C051928:lipoprotein-associated coagulation inhibitor; D013917:Thrombin