Examining links between Factor Xa, endothelial dysfunction, adverse pregnancy outcomes and cardiovascular disease in Lupus
Citation:MURPHY, CLAIRE-LOUISE MARIE, Examining links between Factor Xa, endothelial dysfunction, adverse pregnancy outcomes and cardiovascular disease in Lupus, Trinity College Dublin.School of Medicine, 2018
MD thesis-13.12.18.pdf (PhD thesis, final) 10.60Mb
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune rheumatic disease (ARD) associated with significant morbidity and mortality, which presents mainly in women of childbearing age. Women with SLE have a 5-10-fold increased risk of developing cardiovascular disease (CVD) compared to age and sex-matched controls. Increased CVD risk in SLE is not fully explained by traditional risk factors and other factors such as persistent inflammation, autoantibodies and microparticles (MPs) have been implicated. Women with SLE and previous adverse pregnancy outcomes (APO) are at increased risk of CVD. Other co-morbidities in women with SLE include low bone mineral density (LBMD), which is also linked with CVD. Increasing interest has focused on the involvement of serine proteases (SP) such as anti-Factor Xa (FXa) and anti-Thrombin (Thr) in atherosclerotic plaque formation. These SP are of further interest because they are known to have extended cellular/inflammatory effects beyond coagulation through their activation of protease activated receptors (PARs) and antibodies (IgG) directed against them have been identified in patients with SLE. To examine the importance of these risk factors in CVD pathogenesis in SLE, I studied a cohort of 100 patients with SLE who had undergone detailed vascular imaging via carotid and femoral ultrasound scans. These patients had no clinical diagnosis of CVD prior to scanning and were subdivided by the presence of subclinical CVD (n=36) and absence of CVD (n=64). I explored associations between atherosclerotic plaque and the presence of anti-FXa and/or anti-Thr IgG by ELISA. Plasma was analysed for presence of endothelial and platelet microparticles (EMPs and PMPs). Samples were stained with Annexin V, CD42a, CD31, CD105 and CD144 and measured using flow cytometry. Furthermore, I carried out retrospective analysis of the pregnancy experience of 95 women with SLE focusing on APO and CV risk. I then correlated bone density results with CV status. Finally, I carried out a systematic review to determine whether fertility and parity are reduced in patients with SLE. Of the cohort 95% were female with a mean age of 45.2 (range 20-66; SD 12.4) years. Anti-FXa IgG positivity was found in 33/64 (52%) of patients without plaque and 11/36 (31%) of patients with plaque (p=0.04). PMPs were higher in patients with SLE compared to healthy controls (p=0.025). Strikingly, almost half the women (45%) with SLE had no children, more than double one would expect in UK women of the same mean age. A total of 61% had APO and rates of miscarriage were higher (31%) than in the general population (15-20%). My systematic review showed an overall reduction in fertility and parity in women with SLE. Of this lupus cohort, 81% had available bone density scans and 65% had LBMD. This work demonstrates for the first time that anti-FXa IgG may be atheroprotective in patients with SLE. PMPs are higher in patients with lupus, likely due to overall disease burden. APO and miscarriage rates were high which is in keeping with other studies. My study identified much higher rates of nulliparity in women with SLE than in the general population. Reasons underlying this difference are likely to be multifactorial. The systematic review revealed reduced fertility and parity in women with SLE, although this was confounded by differences in design and outcome measures of studies selected for inclusion. Although there was no correlation between lupus and CVD with low BMD, my work has highlighted the importance of screening for osteoporosis in lupus. Overall, the work produced in my thesis has contributed to the identification of risk factors for CVD in patients with SLE. Further research is now required to elucidate the mechanisms involved in SLE CVD progression.
Author: MURPHY, CLAIRE-LOUISE MARIE
Publisher:Trinity College Dublin. School of Medicine. Discipline of Clinical Medicine
Type of material:Thesis
Availability:Full text available