Anti-tissue factor pathway inhibitor activity in subjects with antiphospholipid syndrome is associated with increased thrombin generation.
OBJECTIVE
Immunoglobulin G (IgG) fractions from subjects with antiphospholipid syndrome (aPS) have previously been demonstrated to have inhibitory activity against tissue factor pathway inhibitor (TFPI). This may contribute to the development of a prothrombotic state by impaired regulation of the tissue factor (TF) pathway. This study investigated the effect that IgG fractions from aPS subjects containing anti-TFPI activity have on in vitro TF-induced thrombin generation.


METHODS
TFPI and anti-TFPI activities were determined in normal controls (n=29) and aPS subjects (n=57). TFPI activity was determined using an amidolytic assay based on the generation of factor Xa. Anti-TFPI activity was determined after incubating IgG isolated from a control or subject plasma with pooled normal plasma, using the TFPI activity assay. The influence of IgG fractions from controls (n=10) and subjects (n=23) on TF-induced in vitro thrombin generation was determined using a chromogenic assay of thrombin activity.


RESULTS
TFPI activity in controls (1.13+/-0.25 U/mL) was significantly lower than in subjects (1.30+/-0.42 U/mL) (p < 0.05). Anti-TFPI activity was significantly higher in subjects than controls (p = 0.0001). TF-induced thrombin generation was positively associated with anti-TFPI activity (r = 0.356; p > 0.05), with increased levels of each demonstrated in 5 subjects.


CONCLUSIONS
Anti-TFPI activity was confirmed in 65% of aPS subjects. IgG fractions demonstrated a variable ability to interfere with TFPI function and TF-induced thrombin generation. Cross-reacting antiphospholipid antibodies and/or other entities may interfere with TFPI function, resulting in a net increase in thrombin generation and an increased thrombotic risk.
Adams
Murray
M
School of Biomedical Sciences, Curtin University of Technology, GPO Box U 1987, Perth WA 6845, Australia. m.adams@curtin.edu.au
Breckler
Liza
L
Stevens
Paul
P
Thom
Jim
J
Baker
Ross
R
Oostryck
Robert
R
D000328:Adult; D016736:Antiphospholipid Syndrome / Q000097:blood* / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D008074:Lipoproteins / Q000097:blood* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D013917:Thrombin / Q000378:metabolism*
D007074:Immunoglobulin G; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D013917:Thrombin