SERONEGATIVE ANTIPHOSPHOLIPID SYNDROME

Seronegative antiphospholipid syndrome (seronegative APS) has remained an enigma and the concept is controversial. A small group of APS patients remain persistently negative for routine assays of antiphospholipid (aPL) antibodies. The clinical features are well defi ned, and include the tendency to both arterial and venous thrombosis, to recurrent miscarriages, and to occasional thrombocytopenia. Patients with clinical manifestations highly suggestive of APS but persistently negative conventional aPLs are classifi ed as having seronegative APS.

The antiphospholipid syndrome (APS) was described in 1983. The antiphospholipid syndrome is an autoimmune disease characterised by arterial and/or venous thromboses, recurrent abortions or foetal loss, and circulating antiphospholipid (aPL) antibodies (1-5).
However, as always in real clinical practice, there are often discrepancies between antibody levels and clinical disease expression. It is universally recognized that the routine screening tests -the anti-cardiolipin (aCL) antibodies and lupus anticoagulant, may miss some cases. A small group of APS patients remain persistently negative for routine assays of aPL (3-8).
Cases of aCL negativity but with positive antiβ 2 -glycoprotein 1 (anti-β 2 -GP1) antibodies were exceptionally rare. According to the classifi cation criteria, diagnosis of APS requires the combination of at least one clinical and one laboratory criterion (4-7). As awareness increases, and the number of patients with APS grows, it comes as no surprise that seronegative APS provides the focus of day to day clinical discussion -the patient with migraine, stroke, several previous miscarriages, thrombocytopenia, and livedo reticularis, whose aPL tests are doggedly negative. Pathological livedo reticularis may therefore be a clinical marker of the seronegative APS (2-4).
Livedo reticularis was included in the original clinical description of the APS (Figure 1). Frances et al reported signifi cant associations between pathological livedo reticularis and cerebral or ocular ischemic arterial events, seizures, heart valve abnormalities, hypertension and Raynaud's phenomenon in patients with APS. As with APS, livedo reticularis in the absence of aPL antibodies has been associated with pregnancy morbidity. Livedo reticularis shares a number of features with APS such as pregnancy loss, arterial thrombosis, heart valve abnormalities and seizures and indeed it is the most common cutaneous manifestation of APS. Livedoid vasculopathy is a rare condition which predominantly affects young women. It is characterized by intense painful purpuric maculae in the legs, ankles and feet, due to thrombosis of the small and medium-sized dermal vessels, in the absence of vasculitis. Livedoid vasculopathy has been frequently associated with hypercoagulable states and APS. Tests for aPL antibodies were repeatedly negative (6-10).
In the clinical practice it is possible to fi nd patients with clinical signs suggestive of APS, who are persistently negative for the laboratory criteria of APS, that is, aCL antibodies, anti-β 2 -GP1 antibodies and lupus anticoagulant. Therefore, it was proposed for these cases the term of seronegative APS (7-11).
Three possible explanations for the existence of such seronegative cases have been proposed: either the diagnosis is wrong, or that previously positive aPL tests have become negative, or, as seems most likely, the current range of tests is inadequate (8-15).
Antibodies may be directed for example against other phospholipids such as phosphatidylethanolamine, or against components of the protein C pathway or annexin V (18).
Is it possible that previously positive aPL titres become negative-either acutely by consumption during an acute thrombotic episode, or slowly, over time (19,20).
In conclusion, a syndrome in which antiphospholipid antibodies are not detected is called seronegative APS. The entity of seronegative APS, where patients have characteristic clinical manifestations of APS but lack conventional serological markers, has also been given consideration in classifi cation criteria for APS. These fi ndings suggest that in sera from patients with seronegative APS, antibodies may be detected using new antigenic targets or methodological approaches different from traditional techniques. Seronegative APS represents a mosaic, in which antibodies against different antigenic targets may be detected.

Competing interests
The authors declare that they have no competing interests.
Author's contribution IMC and MMC equally contributed to this paper.