Nature Clinical Practice Rheumatology. Published online: 19 February 2008. doi:10.1038/ncprheum0740 Received 6 September 2007. Accepted 4 December 2007. Conclusion and future directions: APS is still seen as a rather obscure disease despite extensive research; this view is mainly the result of the unreliability of the current assays for detecting the presence of antiphospholipid antibodies. The consequences are a poor correlation between serological markers and clinical manifestations, and a lack of clarity about the pathogenetic mechanism causing the syndrome. As mentioned above, we found that the presence of LA-inducing anti-beta2 GPI antibodies (with an affinity for domain I) correlates almost uniformly with the occurrence of thrombosis.21, 23 Our next aim is to investigate whether the presence of anti-domain I antibodies correlates with recurrent fetal loss. Research focused specifically on anti-domain I antibodies will hopefully provide information about the mechanism that causes APS. We have found that these antibodies cause increased (factor V Leiden-independent) APC resistance, increased resistance against the anticoagulant properties of annexin A5 and increased levels of activated von Willebrand factor (Figure 3).39, 42, 46 It is anticipated that this population is also involved in disease-causing mechanisms other than thrombosis in APS. It seems strange that new roles for a protein with no previous clear function come to light in the presence of an autoantibody. Perhaps native beta2 GPI already possesses these functions, but requires activation (such as a conformational change) before it can perform them. Native beta2 GPI could potentially already exhibit these actions at sites of cellular damage.47 Under apoptotic conditions, the antigen would be concentrated on the anionic phospholipids of the exposed cellular membranes and inhibit the unwanted consequences of the exposure of negatively-charged surfaces to components of the circulating bloodstream. In the presence of anti-beta2 GPI antibodies, the active conformation of the beta2 GPI protein is stabilized and its function is no longer limited to sites of damage. The consequence would be an imbalance in the hemostatic system, resulting in thrombosis at any vascular site in the body. In the future, more insight is needed into whether there are more antibody subpopulations that can cause the (specific) clinical manifestations that are observed in APS. Future investigations into the pathology should be performed with antibody populations with precisely defined epitopes.

Recommended therapeutic international normalized ratios (INRs) for oral anticoagulation in patients with lupus anticoagulants who sustain a thromboembolic event are controversial. Patients with lupus anticoagulants often have a prolonged prothrombin time, which may complicate management of anticoagulant therapy.

Volume 86, Issue 10, pp. 3685-3691, 11/15/1995 Copyright © 1995 by The American Society of Hematology