Thrombophilia in Systemic Lupus Erythematosus: A Review of Multiple Mechanisms and Resultant Clinical Outcomes

Abstract

cardiovascular disease and clotting, the multiple mechanisms for hypercoagulability in SLE, and discuss the complexity of this problem in this population.Pregnancy Thrombophilia -The Unsuspected Risk Premature cardiovascular diseaseLupus-specific thrombophilic factors contribute to premature cardiac disease and atherosclerosis in this population. These lupus specific factors can affect the endothelium resulting in premature arterial vascular disease contributing to the accelerated/premature atherosclerosis observed in SLE [24]. Atheroma formation is initiated when oxidized low density lipoprotein (LDL) is taken up by foam cells in vascular endothelium [24][25]. High density lipoprotein (HDL) and Apo-A1 are protective factors against atherosclerosis. β-2 glycoprotein-1 binding to oxidized LDL facilitates uptake by foam cells [26]. Patients with SLE have antibodies to LDL/ β-2 glycoprotein-1 complexes, HDL, and Apo -A1 [26][27]. Antibodies to HDL and Apo A-1 cross react with cardiolipin and prevent HDL and Apo-1 protection against atherosclerosis. Antibodies to oxidized LDL may cross react with β-2 glycoprotein-1 and may enhance uptake, thus promoting plaque formation [25][26][27][28]. Anticardiolipin antibody binding exposes immunogenic and normally hidden (or cryptic) epitopes on β-2 glycoprotein-1, which can bind to anti-β-2 glycoprotein-1 antibodies. These antibodies bind to adhered β-2 glycoprotein-1 on endothelial cells which causes endothelial activation and subsequent up regulation of inflammatory and procoagulant factors [24][25][26]. In addition, adhered β-2 glycoprotein-1 on oxidized LDL promotes LDL uptake by macrophages, thus facilitating plaque formation [24][25][26]28]. During the acute phase response, HDL can be converted to pro-inflammatory molecules which promote LDL oxidation. Chronic inflammation can cause HDL dysfunction in SLE. HDL has been found to be pro-inflammatory in women with SLE and is termed pro-inflammatory HDL or piHDL [25][26]28]. More than 85% patients with SLE and carotid plaques had piHDL vs. 40% in those without plaques [27]. Pro-inflammatory HDL is an independent risk factor for atherosclerosis in rheumatoid arthritis and antiphospholipid antibody syndrome [26,28]. The prevalence of moderate to severe atherosclerosis in SLE at autopsy is 52% [29]. There is a higher prevalence of coronary artery disease in SLE than general population which is not predicted by traditional risk factors or increase in lupus activity alone [30][31][32][33][34][35][36][37][38][39]. Mortality studies show coronary artery disease (CAD) /myocardial infarction (MI) is a frequent cause of death in SLE and occurs in 11-48% of SLE patients [3,[30][31][32][33][34][35]. Death from CAD in SLE is disproportionately larger in late disease, with CAD/MI being the leading cause of death in SLE survivors. This accounts for the late peak in mortality in SLE [36][37][38]. Although there are a greater number of CAD risk factors (hypertension, diabetes mellitus, dyslipidemia, sedentary life style) in SLE patients than ...