Fibrinogens Bern IV, Bern V and Milano XI: three dysfunctional variants with amino acid substitutions in the thrombin cleavage site of the Aalpha-chain.
Thrombin-induced cleavage of fibrinopeptide A is the initial step in the conversion of fibrinogen to fibrin. Three dysfunctional fibrinogen variants are described with an amino acid substitution at position 16 of the Aalpha-chain: the fibrinogen variants Bern IV and Milano XI having an Arg-->His substitution and the variant Bern V having an Arg-->Cys substitution. Routine coagulation studies revealed prolonged plasma thrombin and reptilase clotting times in all patients, and a discrepancy between the plasma levels of fibrinogen determined by the clotting assay and electroimmunoassay. The defect was localized by high-performance liquid chromatography analysis of fibrinopeptide release and confirmed by polymerase chain reaction and sequencing of exon 2 of the Aalpha-chain. Immunoblotting analysis with a rabbit antiserum against human serum albumin indicated that albumin was linked to the additional sulfhydryl group of fibrinogen Bern V. The assay of tissue-plasminogen-activator-induced plasmic degradation revealed that the fibrinolysis of fibrin Bern V was delayed, whereas fibrin Bern IV was digested in the same way as normal fibrin.
Stucki
B
B
Central Hematology Laboratory, Inselspital, University Hospital of Bern, Switzerland.
Zenhäusern
R
R
Biedermann
B
B
Baudo
F
F
Redaelli
R
R
Lämmle
B
B
Furlan
M
M
D000328:Adult; D019943:Amino Acid Substitution; D001665:Binding Sites; D001778:Blood Coagulation Disorders / Q000097:blood / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D005260:Female; D015241:Fibrinogens, Abnormal / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D005344:Fibrinopeptide A / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010958:Plasminogen / Q000378:metabolism / Q000494:pharmacology; D012709:Serum Albumin / Q000276:immunology / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D013918:Thrombin Time; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology
D015241:Fibrinogens, Abnormal; D012709:Serum Albumin; D005344:Fibrinopeptide A; D010958:Plasminogen; D013917:Thrombin; D010959:Tissue Plasminogen Activator