Lupus anticoagulants, thrombosis and the protein C system

Although lupus anticoagulants (LAs) are immunoglobulins that inhibit procoa gulant reactions in vitro, these molecules are associated with thrombosis i n vivo. We and others have hypothesized that this may be due to selective t argeting of the activated protein C (APC) anticoagulant pathway. Population s of antibodies that interact with protein C or protein S in ways that inhi bit their activity are obvious candidates for such pathological molecules. However, it is less clear how populations that appear to bind to membrane s urfaces might target the APC anticoagulant complex selectively. Studies now show that the membrane requirements of the APC anticoagulant complex are s ignificantly different from those of the procoagulant reactions. The most d ramatic difference is the requirement for the presence of phosphatidylethan olamine (PE) in the membrane for optimal APC function. The inhibitory activ ity of at least some LAs is enhanced by the presence of PE, but the anti-AP C activity is enhanced even more, resulting in the plasma from these patien ts clotting faster than normal when APC is present. Structure-function stud ies have been undertaken to understand the PE dependence of this reaction b etter. Chimeric proteins in which all or part of the Gla domain of protein C has been replaced by the homologous region of prothrombin have been prepa red. Unexpectedly, the PE dependence resides primarily in the C-terminal ha lf of the Gla domain. Using liposomes of various composition, we found both the presence of the PE head group and unsaturation of the fatty acid chain s are required for optimal inactivation of factor Va. It is hoped that a be tter understanding of the biochemistry of these reactions, combined with th e use of the chimeric proteins described, will permit us to design better a ssays for the identification of pathologic LAs. (C)1999, Ferrata Storti Fou ndation.