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.1 Laboratory 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.1
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.9
Although the prevailing evidence links specific bacterial infections, viral infections, and vaccination to the development of APS, such associations are not clear-cut. As reported by Mendoza-Pinto and colleagues, a case-control study found no association between pandemic influenza vaccination and development of APS, perhaps a reflection of aPL heterogeneity and the lack of complete understanding of APS pathophysiology.4 However, given the evidence for molecular mimicry, the increased risk for infection-induced aPL, and the suggestion to systematically assess anticardiolipin in patients with Q fever,4 it may be reasonable to speculate that until further studies are done to better understand the association among infection, vaccination, and the risk for APS, routine assessment of aPL should be standard practice in patients receiving vaccination.
A routine assessment of aPL in patients with infectious diseases or who are receiving a vaccination is not straightforward, as stated by Ricard Cervera, MD, PhD, FRCP, Department of Autoimmune Diseases, Hospital Clínic in Barcelona, Catalonia, Spain. “The aPL have been detected in some patients with several infectious diseases but, usually, in low titers and without association to thrombotic events,” said Dr Cervera, adding “therefore, until more information becomes available, the routine assessment of aPL in patients having infections or receiving a vaccination is not advised.” Conversely, thrombotic manifestations of APS develop in some patients — even its catastrophic variant, CAPS — after an infection. “It is hypothesized that infection was a triggering factor in a patient already having an immunological/genetic/hormonal background for this syndrome,” said Dr Cervera, adding “the search for aPL in patients who [have] a thrombotic event after an infection is strongly advised.”
While the majority of elevated aPL cases are transient, persistently elevated cases have been reported, particularly those associated with hepatitis C infection, and those that manifest as APS can have fatal consequences. Given that aPL is not systematically assessed in many disease states and that routine assessment of aPL is generally not advised, it is important that physicians be able to promptly recognize the clinical features of APS in patients with viral and bacterial infections and initiate an appropriate management strategy.
- Negrini S, Pappalardo F, Murdaca G, Indiveri F, Puppo F. The antiphospholipid syndrome: from pathophysiology to treatment. Clin Exp Med. 2017;17(3):257-267.
- Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306.
- Shoenfeld Y, Blank M, Cervera R, Font J, Raschi E, Meroni PL. Infectious origin of the antiphospholipid syndrome. Ann Rheum Dis. 2006;65(1):2-6.
- Mendoza-Pinto C, García-Carrasco M, Cervera R. Role of infectious diseases in the antiphospholipid syndrome (including its catastrophic variant). Curr Rheumatol Rep. 2018;20(10):62.
- Lim W. Antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2013;2013:675-680.
- Willis R, Gonzalez EB. Pathogenetic mechanisms of antiphospholipid antibody production in antiphospholipid syndrome. World J Rheumatol. 2015; 5(2): 59-68.
- Hancer VS. Genetics of antiphospholipid syndrome [published online September 30, 2011]. Human Genet Embryol. doi:10.4172/2161-0436.1000e103
- Espinosa G, Cervera R, Asherson RA. Catastrophic antiphospholipid syndrome and sepsis. A common link? J Rheumatol. 2007;34(5):923-926.
- Dimitrijević L, Živković I, Stojanović M, Petrušić V, Živančević-Simonović S. Vaccine model of antiphospholipid syndrome induced by tetanus vaccine. Lupus. 2012;21(2):195-202.
This article originally appeared on Rheumatology Advisor