Antiphospholipid syndrome (APS) occurs only in a small percentage of individuals with positive antiphospholipid antibodies (aPL). The wide heterogeneity of aPL presents a syndrome that is difficult to differentially diagnose with a pathophysiology that is difficult to elucidate. The prevalence has been challenging to quantify with any degree of accuracy, although a range of between 1% and 5% has been reported.1Laboratory criteria for APS include lupus anticoagulant, anticardiolipin, immunoglobulin isotype G (IgG) and M (IgM) as well as IgG and IgM anti-b2 glycoprotein-I.2 The clinical manifestations of APS are wide-ranging and include increased risk for blood clots that can lead to life-threatening systemic complications. Vascular thrombosis and pregnancy-related morbidity are the most common presenting hallmarks of APS; however, other clinical manifestations that are thought to be related to APS include thrombocytopenia, arthritis, livedo reticularis, migraine, and thickening of the heart valve. To a lesser degree, APS has been reported to be associated with renal involvement and neurologic manifestations.
The management of APL is challenging because not all cases of elevated aPL are pathogenic. The differentiation of pathogenic from nonpathogenic aPL is critical to optimal management, particularly given that catastrophic APS (CAPS), a variant of APS first defined in 1992, is the most severe form of APS. CAPS is reported to occur in approximately 1% of patients with aPL and is associated with rapid development of microvascular thrombosis that can result in multiorgan failure.1,3,4
Patients with APS and CAPS have a high risk for recurrent thrombosis that can occur despite anticoagulant therapy.5 Although the precise etiology of APS is unknown, a combination of genetic and environmental factors are thought to play a role. Trigger factors, particularly for CAPS, are commonly viral and bacterial infections, although trauma, including surgical procedures, anticoagulation withdrawal, parasitic and fungal infections, and a variety of malignancies, have been implicated in the disease etiology.4,6 Studies on animal models as well as human familial and population studies provide some evidence for the influence of genetic and environmental influences, including bacterial and viral agents, in the development of APS.4 Viral infections that have been reported to be associated with aPL and APS primarily include HIV and hepatitis B and C viruses. Bacterial infections associated with APS include Mycoplasma pneumonia, Streptococci, Mycobacterium leprae, Mycobacterium tuberculosis, and Coxiella burnetii. Oher infectious agents with less robust evidence for their role in the development of APS include Borrelia burgdorferi and Helicobacter pylori.4 The most common bacteria associated with CAPS include Shigella, Escherichia coli, Klebsiella, Salmonella, Streptococcus, and Staphylococcus; commonly associated viruses include hepatitis C and herpes.4 Recently, Chikungunya virus has also been implicated in some cases of CAPS.
Despite extensive investigations, the precise genetic association of aPL has been challenging to identify with certainty.6,7 “Molecular mimicry” between the pathogen and specific host molecular entities has been suggested as a potential explanation for the development of APS.8 This suggestion is based on several factors, including a correlation between APS clinical manifestations and the presence of infectious agents and the strong sequence homology between specific viral and bacterial proteins and β2-glycoprotein I.3,8 Support for molecular mimicry was provided in 2 non-autoimmune prone mouse models, BALB/c and C57BL/6, in which APS was successfully induced by tetanus toxoid hyperimmunization, suggesting that vaccination may induce APS. It has been documented that there is evidence that links the development of APS with exposure to microbial antigens, either during infection or vaccination.9 In these models, molecular mimicry and polyclonal B-cell activation occur in APS induction; molecular mimicry effects were dominant in BALB/c mice and polyclonal cell activation was dominant in C57BL/6 mice.