Abnormalities of factor VIII and/or von Willebrand factor (vWF) structure and concentration occur not only in inherited coagulation disorders such as vWF disease and hemophilia A but in acquired disorders including renal dysfunction, disseminated intravascular coagulation, heart disease, and pregnancy. To elucidate the relationship between aberrant factor VIII/vWF forms and disease states we propose to: 1) Develop new immunological probes and electrophoretic techniques to examine factor VIII antigen (VIII:CAg) and vWF in small samples of whole plasma. Peptide analogues of the amino- and carboxy-terminal ends, and thrombin sensitive regions of factor VIII, will be synthesized. Monoclonal antibodies made to these peptides, and antibodies from other sources, will be used to locate factor VIII related polypeptides separated by electrophoretic methods. Improved analytical techniques will help to establish correlations between VIII:CAg forms and VIII:C coagulant activity. New procedures will also help to define the temporal association between vWF and various polypeptide segments released from factor VIII undergoing proteolysis. 2) Examine VIII:CAg proteolytically modified by thrombin, plasmin, activated protein C, factor IXa, factor X, and calcium activated protease. With this information, hypotheses can be formulated about enzyme activity, disease etiology and abnormal VIII:CAg fragments. 3) Synthesize and examine the properties of a polypeptide, the sequence of which corresponds to the hydrophilicity maximum of factor VIII. From empirical and theoretical considerations this segment may be part of the determinant recognized by many human anti factor VIII antibodies. Investigated will be the interaction of the peptide with these human antibodies, as well as the interaction of factor VIII and monoclonal antibodies raised against the peptide. 4) Determine the cause and effect of VIII:CAg/vWF modifications in atypical plasma, particularly that from patients with renal dysfunction, disseminated intravascular coagulation, heart disease, bone marrow transplantation, and pregnancy. This information may ultimately have diagnostic value in predicting the severity of a disease based on the appearance of abnormal VIII:CAg/vWF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL022355-09
Application #
3336845
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1978-04-01
Project End
1991-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
9
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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