A CORRELATION BETWEEN THROMBOTIC DISEASE AND A SPECIFIC FIBRINOGEN ABNORMALITY (A-ALPHA 554 ARG-]CYS) IN 2 UNRELATED KINDRED, DUSART AND CHAPEL-HILL-III

For the first time, a correlation between a specific fibrinogen abnorm ality and the clinical symptoms of thrombosis has been found in unrela ted families. These abnormal fibrinogens have been designated Dusart a nd Chapel Hill III. The abnormal fibrinogen Chapel Hill III was identi fied previously in a patient with thrombotic disease. We purified fibr inogen from smalt aliquots of patient and normal plasmas by a simple, rapid procedure. Coomassie stained sodium dodecyl sulfate-polyacrylami de gel electrophoresis (SDS-PAGE) analysis demonstrated that fibrinoge n Chapel Hill III contained several high molecular weight forms in add ition to the two forms seen with normal fibrinogen. Immunoblot analysi s of Chapel Hill III fibrinogen demonstrated that essentially all the high molecular weight forms react with antiserum to albumin. Immunoblo t analysis of plasmin digests of Chapel Hill III fibrinogen demonstrat ed that albumin is linked to the C-terminus of the A alpha chain. Usin g DNA analysis, we found that the patient is heterozygous for a single base change, resulting in the substitution A alpha Arg 554 --> Cys. T his is the same change identified in fibrinogen Dusart. The Dusart fam ily members who are heterozygous for this substitution also suffer fro m recurrent thrombotic disorders. (C) 1994 by The American Society of Hematology.