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Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):562-572
Seronegative antiphospholipid syndrome: refining the value of “non-criteria” antibodies for diagnosis and clinical management
Pasquale Pignatelli,1,2* Evaristo Ettorre,3* Danilo Menichelli,1 Arianna Pani,4,5 Francesco Violi,1,2** and Daniele Pastori1**
1I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome; 2Mediterranea Cardiocentro, Naples; 3Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Division of Gerontology, Sapienza University, Rome; 4Department of Oncology and Onco- Hematology, University of Milan, Milan and 5Clinical Pharmacology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
*PP and EE contributed equally to this work.
**FV and DP contributed equally to this work as co-senior authors.
ABSTRACT
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombotic manifestations and/or pregnancy-related complications in patients with persistently high antiphospholipid antibodies (aPL), the most common being represent- ed by anticardiolipin antibodies (aCL), anti-beta 2 glycoprotein-I (aβ2GPI), and lupus anticoagulant (LAC). A growing number of studies have showed that, in some cases, patients may present with clinical features of APS but with temporary positive or persistently negative titers of aPL. For these patients, the definition of seronegative APS (SN-APS) has been proposed. Nevertheless, the negativity to classic aPL criteria does not imply that other antibodies may be present or involved in the onset of thrombosis. The diag- nosis of SN-APS is usually made by exclusion, but its recognition is impor- tant to adopt the most appropriate anti-thrombotic strategy to reduce the rate of recurrences. This research is in continuous development as the clin- ical relevance of these antibodies is far from being completely clarified. The most studied antibodies are those against phosphatidylethanolamine, phos- phatidic acid, phosphatidylserine, phosphatidylinositol, vimentin/cardi- olipin complex, and annexin A5. Moreover, the assays to measure the levels of these antibodies have not yet been standardized. In this review, we will summarize the evidence on the most studied non-criteria aPL, their poten- tial clinical relevance, and the antithrombotic therapeutic strategies avail- able in the setting of APS and SN-APS.
Introduction
The prevalence of antiphospholipid antibodies (aPL) in the general population is difficult to estimate due to the lack of population-based studies. The most fre- quently detectable aPL are anticardiolipin antibodies (aCL), antiβ2-glycoprotein I antibodies (anti-β2-GPI), and lupus anticoagulant (LAC).1 A large review of the lit- erature in 2013 estimated that the prevalence of aPL positivity is 6% among women with pregnancy complications, 10% among patients with deep venous thrombosis (DVT), 11% among patients with myocardial infarction, and 17% among patients with juvenile stroke (<50 years of age). As acknowledged by the Authors, this prevalence should be considered with caution, because 60% of the papers were published before 2000, all three criteria aPL tests were performed in only 11% of the papers, and 36% of papers used a low-titer aCL cut off.2
Subjects carrying aPL who develop thrombotic complications are diagnosed with the antiphospholipid syndrome (APS), which was first described in 1983 by Hughes, who initially defined it as “anticardiolipin syndrome”.3 This definition was derived from clinical observation of recurrent miscarriages, central nervous system
Correspondence:
PASQUALE PIGNATELLI
pasquale.pignatelli@uniroma1.it.
Received: June 10, 2019. Accepted: December 18, 2019. Pre-published: January 30, 2020.
doi:10.3324/haematol.2019.221945
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