Molecular basis of factor VIII inhibition by human antibodies: antibodies that bind to the factor VIII light chain prevent the interaction of factor VIII with phospholipid

Most antibodies to factor VIII have recently been shown to react with discrete regions of the factor VIII light chain (within the C2 domain) and/or the factor VIII heavy chain (within the amino-terminal segment of the A2 domain). The mechanism by which these antibodies, usually designated "fact...

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Bibliographic Details
Published in:The Journal of clinical investigation 1989-06, Vol.83 (6), p.1978-1984
Main Authors: ARAI, M, SCANDELLA, D, HOYER, L. W
Format: Article
Language:English
Subjects:
Antigens - immunology
Antigens - metabolism
Autoantibodies - analysis
Autoantibodies - physiology
Binding Sites, Antibody
Binding, Competitive
Biological and medical sciences
Blood Coagulation Tests
Blood coagulation. Blood cells
Coagulation factors
Enzyme-Linked Immunosorbent Assay
Factor VIII - immunology
Factor VIII - metabolism
Fundamental and applied biological sciences. Psychology
Humans
Immunoblotting
Isoantibodies - analysis
Isoantibodies - physiology
Macromolecular Substances
Molecular and cellular biology
Phosphatidylserines - metabolism
Phospholipids - metabolism
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Summary:Most antibodies to factor VIII have recently been shown to react with discrete regions of the factor VIII light chain (within the C2 domain) and/or the factor VIII heavy chain (within the amino-terminal segment of the A2 domain). The mechanism by which these antibodies, usually designated "factor VIII inhibitors," interfere with factor VIII function has been examined by determining their effect on factor VIII binding to a phospholipid. Factor VIII-phosphatidylserine binding was prevented by all seven factor VIII inhibitors that had strong factor VIII light chain reactivity and reduced by two inhibitors with weak anti-light chain reactivity. None of four inhibitors with heavy chain reactivity prevented factor VIII-phosphatidylserine interaction, though a partial reduction (less than 50%) was noted for the intact IgG preparations. However, when Fab' fragments were substituted, no detectable reduction in factor VIII-phosphatidylserine binding was noted for the anti-heavy chain inhibitors and complete inhibition was retained by the anti-light chain inhibitors. These data suggest that a subset of factor VIII inhibitors, those that bind to light chain determinants, inactivate factor VIII by preventing its effective interaction with phospholipid.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI114107