Fibrinogen B beta 14 Arg -> Cys: further evidence for a role in thrombosis

A single base substitution (C --> T) in exon II of the B beta fibrinogen ge ne resulting in an Arg14 --> Cys replacement was identified in a young woma n with a history of recurrent thrombotic stroke. The patient's plasma showe d prolongation of the thrombin and Reptilase times, and plasma fibrinogen, which was low when determined by chronometric assay (Clauss technique) was normal by clot weight. Dysfibrinogenaemia associated with the same mutation was identified in eight family members including two siblings with a histo ry of venous and arterial thrombosis. Fibrin monomer polymerization with th rombin, Reptilase and Agkistrodon contortrix contortrix venom was defective . Polymerization studies revealed a reduced rate of polymerization compared with normal plasma, which improved on cooling from 37 degrees C to 20 degr ees C. Plasma viscosity in the affected individuals was normal. Flow cytome tric analysis of platelets from the proband and another affected member sho wed no increase in surface bound fibrinogen. Euglobulin clot lysis time was normal. The same point mutation has been described previously in individua ls with thrombosis. This family adds further to the genotype-phenotype corr elation of the dysfibrinogenaemias and provides strong evidence for a genui ne association of fibrinogen B beta Arg14Cys with thrombosis. The mechanism underlying a causal relationship with the increased incidence of thrombosi s remains obscure but a review of related dysfibrinogens suggests that the addition of a free thiol group rather than the loss of the thrombin cleavag e site may be important. (C) 1999 Lippincott Williams Wilkins.