Lupus anticoagulants and thrombosis: the role of phospholipids

Lupus anticoagulants (LAs) are loosely defined as immunoglobulins that inhibit phospholipid dependent coagulation assays. Antiphospholipid antibodies (APAs) are those immunoglobulins that are observed to bind to phospholipids, usually cardiolipin, in ELISA type assays. Interest in these antibody populations derives from the observation that rather than being associated with bleeding disorders as would be expected, they correlate with an increased risk of thrombosis. Many mechanisms have been proposed to account for the prothrombotic activity of some LAs and APAs. These mechanisms are as diverse as inhibition of the production of endothelial prostacyclin synthesis or impaired fibrinolysis to interaction with beta 2-glycoprotein 1 or prothrombin bound to phospholipids. For the purposes of this review, we would like to focus on a potential mechanism that has been proposed by several labs in addition to our own, namely inhibition of the protein C anticoagulant pathway.

The authors have been working in this field and contributing original papers. In addition, the material examined in the present paper includes articles published in journals covered by the Science Citation Index and Medline.

In general, correlation of phospholipid specificity and thrombosis has not been performed on a large scale. We were therefore led to ask two questions. Are the membrane requirements of the protein C anticoagulant pathway really the same as those for the procoagulant complexes? Secondly, if they are not, do the membrane requirements of the anticoagulant complexes mimic those of the thrombotic LAs? The membrane requirements for the activated protein C anticoagulant complex differ from those of the prothrombinase complex. These requirements, i.e. the need for phosphatidylethanolamine for optimal activity, mimic the lipid requirements for at least a population of lupus anticoagulants associated with thrombosis. These observations may provide both the specificity and the link between the activated protein C pathway, lupus anticoagulants and thrombosis. Of course, no conclusion is ever that black and white. Only future studies into the fine specificity of lupus anticoagulants and anti-phospholipid antibodies associated with thrombosis will bear out the hypothesis that those directed towards the activated protein C pathway will be predictive of thrombotic risk.