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Fibrinogen Ledyard (A alpha Arg16----Cys): biochemical and physiologic characterization
M H Lee1, E Kaczmarek, D T Chin
1Department of Pathology, Beth Israel Hospital, Boston, MA 02215.
Blood
|October 1, 1991
Summary
Fibrinogen Ledyard, a congenital fibrinogen defect, involves a mutation where arginine at position 16 is replaced by cysteine. This structural change impairs thrombin binding and fibrin polymerization, leading to bleeding disorders.
Area of Science:
- Hematology
- Molecular Biology
- Biochemistry
Background:
- Congenital fibrinogen defects are rare inherited bleeding disorders.
- Fibrinogen Ledyard presents as a mild bleeding tendency in affected individuals.
- The condition is inherited in an autosomal heterozygous pattern.
Observation:
- Plasma fibrinogen Ledyard showed normal immunological levels but severely reduced functional activity.
- Purified fibrinogen Ledyard exhibited prolonged polymerization, partially corrected by calcium ions.
- Thrombin-mediated release of fibrinopeptide A (FPA) and fibrinopeptide B (FPB) was analyzed using HPLC.
Findings:
- HPLC analysis revealed normal release of FPA and FPB, with corrected kinetic parameters for FPA release, suggesting thrombin's catalytic site is unaffected.
- Amino-terminal sequencing of the A alpha chain identified an Arg16 to Cys16 substitution in abnormal fibrinogen molecules.
- Fibrinogen Ledyard appears to be a mixture of normal and abnormal homodimers, with abnormal molecules potentially forming disulfide bonds via Cys16.
Implications:
- The Arg16Cys substitution likely alters fibrinogen structure, hindering thrombin interaction and fibrin polymerization.
- Abnormal fibrinogen molecules may inhibit the growth of fibrin protofibrils by interacting with normal fibrin monomers.
- Despite polymerization defects, fibrinogen Ledyard supports normal adenosine diphosphate-induced platelet aggregation.