Fibrinogen Bbeta14 Arg-->Cys: further evidence for a role in thrombosis.
A single base substitution (C-->T) in exon II of the Bbeta fibrinogen gene resulting in an Arg14-->Cys replacement was identified in a young woman with a history of recurrent thrombotic stroke. The patient's plasma showed 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 history of venous and arterial thrombosis. Fibrin monomer polymerization with thrombin, 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 degrees C. Plasma viscosity in the affected individuals was normal. Flow cytometric analysis of platelets from the proband and another affected member showed no increase in surface bound fibrinogen. Euglobulin clot lysis time was normal. The same point mutation has been described previously in individuals with thrombosis. This family adds further to the genotype-phenotype correlation of the dysfibrinogenaemias and provides strong evidence for a genuine association of fibrinogen BbetaArg14Cys with thrombosis. The mechanism underlying a causal relationship with the increased incidence of thrombosis remains obscure but a review of related dysfibrinogens suggests that the addition of a free thiol group rather than the loss of the thrombin cleavage site may be important.
Vakalopoulou
S
S
Department of Haematology, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Mille-Baker
B
B
Mumford
A
A
Manning
R
R
Laffan
M
M
D000328:Adult; D001120:Arginine / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D006801:Humans; D008297:Male; D017354:Point Mutation; D013927:Thrombosis / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology
D005340:Fibrinogen; D001120:Arginine; D003545:Cysteine