Fibrinogen Birmingham: a heterozygous dysfibrinogenemia (A alpha 16 Arg-
---His) containing heterodimeric molecules
KR Siebenlist, JT Prchal and MW Mosesson
Mount Sinai Medical Center, University of Wisconsin Medical School,
Milwaukee 53233.
Fibrinogen was isolated from the plasma of a 25-year-old female with a
history of mild bleeding and several recent moderate to severe hemorrhagic
episodes. Coagulability with thrombin approached 100% and varied directly
with the time of incubation with the enzyme. High- performance liquid
chromatography analysis of thrombin-induced fibrinopeptide release
demonstrated retarded fibrinopeptide A (FPA) and fibrinopeptide B (FPB)
release and the presence of an abnormal A peptide (FPA) amounting to 50% of
the total. The same biochemical abnormalities were found in her
asymptomatic father. Amino acid analysis and carboxypeptidase digestion of
FPA demonstrated the substitution of His for Arg at A alpha 16. In contrast
to the thrombin- and reptilase-sensitive Arg-Gly bond in the normal A alpha
chain, the abnormal A alpha chain (A alpha) sequence is resistant to
reptilase attack but is slowly cleaved by thrombin. To evaluate whether
Birmingham A alpha and A alpha chains had been assembled nonselectively
into heterodimeric (ie, 50% A alpha, A alpha) and homodimeric (ie, 25% A
alpha, A alpha; 25% A alpha, A alpha) species, the clot and the clot liquor
resulting from reptilase treatment of normal or Birmingham fibrinogen were
separated, and each was then further incubated with thrombin to release
remaining fibrinopeptides. Assuming that fibrinogen Birmingham contained
heterodimeric molecules and that these and the normal molecules were
completely incorporated into a reptilase clot, the expected coagulability
would be 75%. In addition, subsequent thrombin treatment of the reptilase
clot would release 50% of the total FPA and 75% of the total FPB present in
the original sample. On the other hand, if only homodimeric fibrinogen
species (50% A alpha, A alpha; 50% A alpha, A alpha) existed, the maximum
reptilase coagulability would be 50%, and after thrombin treatment, 50% of
the total FPB and no FPA would be recovered from the reptilase clot. We
found the propositus's fibrinogen to be 68% coagulable, and we recovered
45% of the FPA and 70% of the FPB from the reptilase clot. Essentially the
same coagulability and distribution of fibrinopeptides was found in the
reptilase clot from her father's fibrinogen. We therefore conclude that
fibrinogen Birmingham contains heterodimeric species (A alpha, A alpha)
amounting to approximately 50% of the circulating fibrinogen molecules. The
existence of heterodimers is consistent with a nonselective intracellular
process of constituent chain assembly of dimeric plasma fibrinogen
molecules.
Volume 71,
Issue 3,
pp. 613-618,
03/01/1988
Copyright © 1988 by The American Society of Hematology
