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Abstract Number: 2865

The Cellular Effects of ANTI-Factor Xa Antibodies Isolated from Patients with Antiphospholipid Syndrome ARE Inhibited By Factorxa Inhibitors, Hydroxychloroquine and Fluvastatin

Bahar Artim-Esen1, Natalia Smoktunowicz2, Vera M. Ripoll3, Charis Pericleous4, Rachel Chambers2, Ian Mackie5, David Isenberg6, Anisur Rahman7, Yiannis Ioannou6 and Ian Giles4, 1Department of Internal Medicine, Division of Rheumatology, Rheumatology Division, Department of Internal Medicine, Istanbul Faculty of Medicine,Istanbul University, Istanbul, Turkey, 2Rayne Institute, 1st floor, Respiratory Research Unit, University College London, London, United Kingdom, 3Centre for Rheumatology, Rayne Institute, 4th floor, Centre for Rheumatology, University College London, London, United Kingdom, 4Centre for Rheumatology, Division of Medicine, Centre for Rheumatology, University College London, London, United Kingdom, 5Haemostasis Research Unit, 1st Floor, 51 Chenies Mews, Haemostasis Research Unit, University College London, London, United Kingdom, 6Centre for Rheumatology Research, University College Hospital London, London, United Kingdom, 7Centre for Rheumatology Research, University College London, London, United Kingdom

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: antiphospholipid syndrome

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Session Information

Session Title: Antiphospholipid Syndrome

Session Type: Abstract Submissions (ACR)

Background/Purpose

Recently we showed that FXa reactive IgG in patients with the antiphospholipid syndrome (APS) displayed higher avidity binding to FXa and had greater functional effects upon the coagulant functions of FXa compared to patients with anti-FXa IgG isolated from patients with systemic lupus erythematosus (SLE) without APS. FXa signalling has been observed in many cell types via activation of protease-activated receptors (PAR) which stimulate an increase in intracellular calcium (Ca2+) levels. Given that cellular responses elicited through activation of PARs are important in influencing pathways responsible for inflammation, tissue repair and haemostasis, FXa-reactive IgG may be important in the pathogenesis of SLE and APS. Therefore, we characterised the interaction between FXa and human umbilical vein endothelial cells (HUVEC) and the cellular effects of anti-FXa IgG isolated from patients with APS and SLE without APS.

Methods

IgG was purified from patients with APS (n=14) and SLE/no APS (n=14) who had medium or high serum levels of anti-FXa IgG and healthy controls (HC) (n=8). The effect of IgGs on FXa-mediated intracellular calcium release was measured using the fluorescent image plate reader (FLIPR). HUVECs were seeded in 96-well plates, for 48 hours until confluent and then incubated with Fluo-4AM calcium binding dye for one hour. Alterations in intracellular calcium release were monitored for 10 minutes following stimulation with α-Thrombin (Thr) or FXa +/- IgGs. PAR inhibitors, agonist peptides (AP), hydroxychloroquine (HCQ), fluvastatin and desensitisation experiments were also performed to characterise responses. Results

We observed a dose-dependent induction of Ca2+ transients by FXa in HUVEC. FXa was a weaker agonist than Thr but the kinetics of response was different with a longer lag-time and duration. APS IgG significantly potentiated the FXa-induced Ca2+ release compared to SLE/no APS IgG (p=0.04), HC IgG (p<0.05) and FXa alone (p<0.05). FXa-mediated Ca2+ release was significantly reduced by PAR-1 inhibitors. When PAR-1 receptors were desensitised by Thr (10 nM) and cells were stimulated by PAR-2 AP, PAR-2 response was reduced by 47.5%. When Thr-desensitised cells were stimulated by FXa, response was reduced by 66% and residual response was not inhibited by PAR-1 or completely by 2 inhibitors. When cells were treated with: Antistasin, a specific FXa inhibitor; Hydroxychloroquine; or fluvastatin – FXa induced and IgG potentiated intracellular Ca2+ release was significantly reduced.

Conclusion

We confirmed FXa stimulation of HUVEC to be mediated mainly via PAR1 and 2 dependent signalling mechanisms that may be acting as a unit and this effect was enhanced by FXa-reactive APS-IgG. These effects were blocked by a FXa inhibitor which raises the exciting prospect that anti-FXa IgG positivity may be used as a novel biomarker to predict response to treatment with FXa inhibitors in patients with APS. Despite the need for the specificity to be investigated further, results also suggest that HCQ and fluvastatin may be beneficial in patients with APS.


Disclosure:

B. Artim-Esen,
None;

N. Smoktunowicz,
None;

V. M. Ripoll,
None;

C. Pericleous,
None;

R. Chambers,
None;

I. Mackie,
None;

D. Isenberg,
None;

A. Rahman,
None;

Y. Ioannou,
None;

I. Giles,
None.

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