Document Detail

Lupus anticoagulants, thrombosis and the protein C system.
MedLine Citation:
PMID:  10329924     Owner:  NLM     Status:  MEDLINE    
Although lupus anticoagulants (LAs) are immunoglobulins that inhibit procoagulant reactions in vitro, these molecules are associated with thrombosis in vivo. We and others have hypothesized that this may be due to selective targeting of the activated protein C (APC) anticoagulant pathway. Populations of antibodies that interact with protein C or protein S in ways that inhibit their activity are obvious candidates for such pathological molecules. However, it is less clear how populations that appear to bind to membrane surfaces might target the APC anticoagulant complex selectively. Studies now show that the membrane requirements of the APC anticoagulant complex are significantly different from those of the procoagulant reactions. The most dramatic difference is the requirement for the presence of phosphatidylethanolamine (PE) in the membrane for optimal APC function. The inhibitory activity of at least some LAs is enhanced by the presence of PE, but the anti-APC activity is enhanced even more, resulting in the plasma from these patients clotting faster than normal when APC is present. Structure-function studies have been undertaken to understand the PE dependence of this reaction better. Chimeric proteins in which all or part of the Gla domain of protein C has been replaced by the homologous region of prothrombin have been prepared. Unexpectedly, the PE dependence resides primarily in the C-terminal half 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 chains are required for optimal inactivation of factor Va. It is hoped that a better understanding of the biochemistry of these reactions, combined with the use of the chimeric proteins described, will permit us to design better assays for the identification of pathologic LAs.
N L Esmon; M D Smirnov; O Safa; C T Esmon
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.; Review    
Journal Detail:
Title:  Haematologica     Volume:  84     ISSN:  0390-6078     ISO Abbreviation:  Haematologica     Publication Date:  1999 May 
Date Detail:
Created Date:  1999-08-03     Completed Date:  1999-08-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  ITALY    
Other Details:
Languages:  eng     Pagination:  446-51     Citation Subset:  IM    
Oklahoma Medical Research Institute, Cardiovascular Biology, Research Program, 825 N.E.13th Street, Oklahoma City, Oklahoma 73104, USA.
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MeSH Terms
Lupus Coagulation Inhibitor / immunology*
Protein C / metabolism*
Structure-Activity Relationship
Thrombosis / immunology*
Grant Support
Reg. No./Substance:
0/Lupus Coagulation Inhibitor; 0/Protein C

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