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The antiphospholipid syndrome (APS) is characterised by venous and arterial thrombosis, recurrent fetal loss, and by the presence of antiphospholipid antibodies (aPL).1 aPL are also present in 2% of the healthy population,2,3 and, with the exception of those with high titres of aPL, there is no clear evidence of an increased incidence of thrombosis throughout the follow up.2–4 Thus, one of the key questions is: What causes the development of thrombosis in patients with APS? We suggest that in APS, a persistent procoagulant state,5,6 a continuous endothelial and platelet activation is present, and this may be detected by raised levels of soluble adhesion molecules.
METHODS AND RESULTS
We prospectively studied the following groups of subjects: (a) 20 patients with APS,7 10 with primary disease and 10 associated with systemic lupus erythematosus; all had presented an arterial or venous thrombotic episode, or both; (b) 20 subjects with aPL but without any clinical finding (aPL WCF); in these subjects aPL were determined by the unexplained presence of an activated partial thromboplastin time inhibitor; (c) 20 healthy controls (HC).
Lupus anticoagulant was analysed by screening tests (dilute Russell viper venom time, dilute one stage prothrombin time, and sensitised partial thromboplastin time) and confirmed by the viper venom time with phospholipid excess and platelet neutralisation tests.8 Standardised enzyme linked immunosorbent assays (ELISAs) were used to measure serum levels of anticardiolipin antibodies (Orgentec Diagnostika, Mainz, Germany)9; immunoglobulin G anti-β2-glycoprotein I (anti-β2GPI) (IMMCO Diagnostic, Buffalo NY, USA)10; and platelet (P-selectin) and endothelial (E-selectin and intercellular cell adhesion molecule-1, ICAM-1) adhesion molecules (R&D, Minneapolis, USA). In patients with APS, soluble adhesion molecules were measured at the time of the second determination of aPL (8 weeks after thrombosis or after parturition).
At least the lupus anticoagulant or increased serum levels of one of the isotypes of anticardiolipin antibodies was detected in all subjects with APS or aPL WCF. Serum concentrations of anti-β2GPI above the normal range were detected in all patients with APS and in 30% of the subjects with aPL WCF.
Those subjects with APS and with aPL WCF all showed increased concentrations of E-selectin, in comparison with HC. P-selectin levels were only significantly increased in patients with APS. ICAM-1 concentrations were similar in each of the groups (table 1). Patients with primary or secondary APS showed similar concentrations of the adhesion molecules. There was no difference between patients with arterial or venous thrombosis or abortions in respect of these measures (data not shown).
All the patients with APS were treated with dicumarin, maintaining an international normalised ratio of more than 3. During a follow up of 18 months, no significant clinical event was noted. Likewise, no significant change was detectable in the percentage of positivity or in the mean titres of aPL or adhesion molecules.
These results demonstrate that the presence of aPL, with or without clinical findings, is linked to increased levels of P-selectin, a marker of endothelial activation; however, serum concentration of ICAM-1, a molecule that mediates the firm adhesion of circulating cells, was normal. Owing to the absence of clinical events during the follow up, we cannot rule out the possibility of an increased expression of ICAM-1 in relation to the appearance of new thrombi.
The presence of simultaneously increased levels of P-selectin in patients with APS supports the suggestion of a platelet activation state as the explanation for the clinical findings in this disease. The persistence of raised levels of adhesion molecules rules out an increased expression of these antigens as a consequence of the recent thrombosis or abortions.
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