Pathophysiological mechanisms in antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by recurrent thrombosis and fetal loss in the presence of persistently positive antiphospholipid (aPL) antibodies (Abs) including lupus anticoagulant (LAC), IgG/IgM anticardiolipin (aCL) Abs and anti-b2glycoprotein I (b 2 GPI) Abs [1–3]. aPL Abs are a heterogenous group of autoantibodies that react to phospholipids (PLs), PL-binding proteins and PL–protein complexes. aPL Abs mainly target the antigen b 2 GPI and along with Abs acting against prothrombin (PT) account for more than 90% of the Ab-binding activity in APS patients [4–6]. While many aPL Abs exhibit specificity for a single antigen, purified aPL Abs from some patients bind multiple proteins involved in coagulation, suggesting a single aPL Ab clone can induce multiple changes in coagulation and cell activity resulting in thrombosis or fetal loss [7]. Presence of aPL Abs per se does not guarantee a patient will develop APS as only 8.1% of patients with aPL Abs without a history of clinical thrombosis developed thrombosis during a 5-year follow-up period, suggesting that a patient needs an additional insult to develop the clinical disease [8]. Supporting this ‘two-hit’ hypothesis, comorbidities that have been identified as significant risk factors for thrombosis in APS include hypertension, presence of an autoimmune disease, hypercholesterolemia, presence of antidsDNA Abs or medium-to-high titer aCL Abs [8]. Risk factors particularly for arterial thrombosis include hypertension, hyperhomocysteinemia and use of hormone-replacement therapy or oral contraceptives [9]. By contrast, venous thrombosis was associated with presence of hypertriglyceridemia, presence of a hereditary thrombophilia or aCL IgG more than 40 IU [9]. Antiphospholipid syndrome causes significant morbidity with positive LAC and/or aPL Abs conferring an increased risk of thrombosis with an odds ratio ranging from 3.1 to 9.4 [10,11]. The risk of recurrent thrombosis in APS over 5 years is 16.6% despite the use of anticoagulants and/or aspirin. APS is also associated with a 5-year mortality of 5.3% with most deaths occurring within the first year of diagnosis, with the leading causes of death being bacterial infections, myocardial infarction, stroke and cerebral hemorrhage [12]. Catastrophic APS – multiple simultaneous arterial or venous thromboses in the presence of aPL Abs – is a much-feared, albeit rare complication occurring in 0.9% of patients with APS. Despite aggressive treatment, mortality rates still range between 44 and 55.6% [12,13]. These data underscore the need for development of more effective therapies that target the pathologic processes involved in APS without the toxicities associated with chronic anticoagulation.