Fibrinogen Kumamoto with an Aα Arg-19 to Gly Substitution Has Reduced Affinity for Thrombin Possible Relevance to Thrombosis

Abstract

A heterozygous dysfibrinogen, fibrinogen Kumamoto, derived from a 29-year-old woman with episodes of recurrent blurred vision accompanied by weakness of the ipsilateral lower extremity was found to have an Arg-19 to Gly substitution. Both the thrombin and ancrod times were prolonged, and fibrin monomer polymerization profiles were abnormal with a slightly prolonged lag phase and a moderately reduced amplitude. When analyzed by sodium dodecylsulfate polyacrylamide gel electrophoresis, thrombin-catalyzed cleavage of both fibrinopeptides A and B was only minimally delayed and factor XIIIa-catalyzed cross-linking of the fibrin γ-chains was obviously altered. Nevertheless, that of the fibrinogen γ-chains was identical with the normal control in the early stage of the reaction, but was substantially delayed in the later stage. These results may imply that the initial contact between two adjacent D domains of different fibrinogen molecules took place normally, but that the molecular realignment of partially cross-linked single-stranded fibrinogen oligomers to create double-strands was perturbed. In addition to these dysfunctions, decreased adsorption of thrombin to fibrin gels was observed. This finding suggests that immobilization of thrombin onto fibrin clots is incomplete, and thus thrombin action on fibrinogen and platelets in blood circulation is seemingly potentiated, accounting for the transient ischemic attacks in the patient. This type of amino acid substitution has been shown in two dysfibrinogens, Aarhus and Mannheim I, and a transient ischemia was observed in fibrinogen Aarhus I as well.