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Antiphospholipid Syndrome

Antiphospholipid syndrome (APS, also known as Hughes Syndrome) is a systemic autoimmune condition. It is five times more common in women than in men, and many of those women will suffer multiple fetal and obstetric complications due to the disease.1 The other hallmark symptom is venous and arterial thromboses, with deep vein thrombosis and stroke or transient ischemic attacks, respectively, leading the list of symptoms.2 Some symptoms, such as epilepsy and headache, can date back to childhood.3

APS can be difficult for healthcare providers to diagnose. Often the more clinically recognizable symptoms of APS such as migraines, arthritic symptoms, livedo reticularis, and thrombocytopenia, can be attributable to other immune conditions as well, making the diagnosis of APS that much more critical.3

Persistent antiphospholipid antibodies (aPL) are at the core of both the pathogenesis and diagnosis of APS. Elevated titers of any of three possible aPL tests, along with the presence of at least one clinical and one laboratory criterion, can confirm a provider’s diagnosis and advance patients to the phase of disease management.4

Testing aids in the diagnosis of APS

APS is a condition potentially underlying other conditions.5,6 Identifying APS, whether as a singular condition or one among a constellation of autoimmune diseases, means patients are able to receive a diagnosis earlier in the course of the disease and providers are able to implement the appropriate management in time to reverse or prevent its symptoms.7

Triple positivity, defined by these three tests has high specificity for APS.9

The diagnosis of APS can be confirmed through elevated aPL titers. One or more of the following aPL test results must be positive on two or more occasions at least 12 weeks apart:8

  • Lupus anticoagulant
  • Anticardiolipin antibodies (IgG and/or IgM)
  • Anti-β2-glycoprotein I antibodies (IgG and/or IgM)

Beta-2-glycoprotein I (β2GPI) is a multifunctional protein with key roles in the clotting pathway. β2GPI is considered to be the predominant antigen in APS and antibodies against β2GPI (anti-β2GPI) play a major role in the management of APS patients because of their high specificity for diagnosing the disease, despite their relatively poor sensitivity compared to (aCL) antibodies.9(10) A high level of specificity plays an important role in a clinician's diagnosis of APS, due to the wide clinical and serological spectrum of the syndrome—better enabling clinicians to prescribe appropriate treatment and referrals to best manage a patient's personal manifestation of the disease.

Data continues to build for testing the IgA anti-β2GPI isotype as well the IgG and IgM forms. Currently, it is recommended to test for IgA anti-β2GPI in patients with negative IgG and IgM anti-β2GPI and in whom APS is still suspected. In addition, a number of studies have shown the presence of IgA anti-β2GPI has a correlation with arterial thrombosis, but not venous thrombosis in patients meeting the clinical criteria for APS. A significantly different prevalence for IgA anti-β2GPI among patients with primary APS compared with secondary APS associated autoimmune disease has also been shown. These findings may indicate a variable role for IgA anti-β2GPI in different pathogenic pathways of APS.10

aCL is considered to be of significant diagnostic relevance, as a correlation has been found with a greater tendency increased incidence of venous/arterial thromboses, thrombocytopenia, habitual abortion, and neurological manifestations in aCL/LA positive patients. Elevated levels of ACA / LA may also be found in patients with cerebrovascular insufficiency or myocardial infarction. Although aCL antibodies of the IgA isotype are not part of the classification criteria, they are considered as to be associated with APS. IgA aCL are associated with skin ulcers, thrombocytopenia, and vasculitis in connective tissue disease patients. Increased prevalence of aCL antibodies occurs in patients of African genetic ancestry.11

Fortunately, testing for APS is simple, specific, and reliable and can help expedite a provider’s diagnosis, which can help get patients the treatment they need sooner.

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Continued testing and monitoring

Patients with autoimmune diseases are inherently more likely to develop additional or related autoimmune conditions, so it’s important that a long-term management plan be tailored to the signs and symptoms presented at the time. Cross screening is a useful strategy to identify the possibility of an undiagnosed associated disorder in an individual who has not yet displayed signs or symptoms. This is particularly important with overlap syndrome, which may cause manifestations due to multiple syndromes or diseases.

Due to the wide clinical and serological spectrum of the syndrome, there remains no standard practice for treating aPL-positive patients, and each patient must be treated and managed on an extremely individualized basis.7

  1. Myers B, Pavord S. Diagnosis and management of antiphospholipid syndrome in pregnancy. Obstetrician Gynaecologist. 2011;13:15-21.
  2. Asherson RA, Cervera R. The antiphospholipid syndrome: multiple faces beyond the classical presentation. Autoimmun Rev. 2003;2:140-151.
  3. Hughes RV. Put Hughes Syndrome on Your Radar. The Rheumatologist. 2007. http://www.the-rheumatologist.org/article/put-hughes-syndrome-on-your-radar/. Accessed November 2017.
  4. Chaturvedi S, McCrae KR. The antiphospholipid syndrome: still an enigma. Hematology Am Soc of Hematol Educ Program. 2015;2015:53-60. 
  5. 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;4:295-306.
  6. Chighizola CB, Ubiali T, Meroni PL. Treatment of thrombotic antiphospholipid syndrome: the rationale of current management—an insight into future approaches. J Immunol Res. 2015;2015:951424.
  7. Ortel TL. Antiphospholipid Syndrome Laboratory Testing and Diagnostic Strategies. Am J Hematol. 2012;87(Suppl 1):S75-S81.
  8. Pericleous C, Ripoll VM, Giles I, et al. Laboratory tests for the antiphospholipid syndrome. Methods Mol Biol. 2014;1134:221-235. 
  9. Meroni LP, Chighizola CB, Rovelli F, et al. Antiphospholipid syndrome in 2014: more clinical manifestations, novel pathogenic players and emerging biomarkers. Arthritis Res Ther. 2014; 16:209.  
  10. Devreese KMJ, Pierangeli SS, De Laat B, et al. Testing for Antiphospholipid Antibodies with Solid Phase Assays: guidance from the SSC of the ISTH. J Thromb Haemost. 2014;12:792-5.