Fibrinogen Birmingham: a heterozygous dysfibrinogenemia (A alpha 16 Arg- ---His) containing heterodimeric molecules

KR Siebenlist, JT Prchal, MW Mosesson


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.