Fibrinogen Bellingham: A gamma-chain R275C substitution and a beta-promoter polymorphism in a thrombotic member of an asymptomatic family

Congenital dysfibrinogenemia is a rare cause of unexplained thrombosis. How ever, most individuals with dysfibrinogenemia are asymptomatic, suggesting that co-morbid factors contribute to thrombo-embolic events. The potential roles of additional genetic or acquired prothrombotic risk factors are poor ly understood because detailed family studies are lacking. Herein, we descr ibe a family whose propositus was a young Caucasian man with recurrent veno us thrombo-emboli and dysfibrinogenemia due to heterozygosity for an Arg--> Cys substitution at residue 275 in the gamma-chain., The only additional th rombophilic abnormality found in the proband was heterozygosity for a G/A t ransition at position -455 in the fibrinogen beta-chain promoter; a genotyp e associated with high acute phase levels of fibrinogen. The proband's fath er, who died of a cerebral artery thrombosis, carried the gamma R275C subst itution but not the beta-promoter -455 variant. Among 14 living relatives, eight were heterozygous for one or the other mutation and only one, a 21-ye ar-old niece, was dually affected. None had suffered bleeding or thrombosis . In vitro studies of the proband's purified fibrinogen revealed markedly a bnormal thrombin-catatyzed polymerization and delayed fibrin clot lysis by tPA-activated plasmin, We hypothesize that the gamma R275C substitution pre disposes to thrombosis by generating clots that are relatively resistant to fibrinolysis. The clinical risk is low, however, in the absence of an addi tional thrombophilic mutation. The beta-promoter variant could, theoretical ly, contribute to this risk by augmenting expression of the dysfibrinogen u nder conditions of stress. Like the common hereditary thrombophilias, heter ozygous familial dysfibrinogenemia induces thrombosis in the setting of mul tiple prothrombotic influences. Am. J, Hematol. 64:242-250, 2000. (C) 2000 Wiley-Liss, Inc.