title: The fibrinogen Aalpha R16C mutation results in fibrinolytic resistance.
abstract: The fibrinogen Aalpha R16C mutation is a common cause of dysfibrinogenaemia and has been previously associated with both bleeding and thrombosis. However, the mechanism underlying the thrombotic phenotype has not yet been elucidated. This report characterises the defect in fibrinolysis seen as a result of the Aalpha R16C mutation. A young patient with dysfibrinogenaemia (fibrinogen Hershey III) was found to be heterozygous for the Aalpha R16C mutation. Functional assays were performed on the purified fibrinogen to characterise clot formation and lysis with plasmin and trypsin. Consistent with previous results, clot formation was diminished. Unexpectedly, fibrinolysis was also delayed. Plasminogen activation was normal, ruling out decreased plasmin generation as the mechanism behind the fibrinolytic resistance. Western blot analysis showed no difference in the amount of bound alpha2-antiplasmin or albumin. When clot lysis was assayed with trypsin substituted for plasminogen, a significant delay was also observed, indicating that defective binding to plasminogen could not explain the fibrinolytic resistance. These results suggest that the defective fibrinolysis is due to increased proteolytic resistance, most likely reflecting changes in clot structure.
authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239-3098, USA.
authors.forename: Veronica H
authors.initials: VH
authors.lastname: Flood
authors.forename: Hamid A
authors.initials: HA
authors.lastname: Al-Mondhiry
authors.forename: David H
authors.initials: DH
authors.lastname: Farrell
mesh_terms: D002675:Child, Preschool; D020147:Coagulation Protein Disorders / Q000097:blood / Q000235:genetics*; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000235:genetics*; D015241:Fibrinogens, Abnormal / Q000235:genetics*; D005342:Fibrinolysis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation
chemical_list: D015241:Fibrinogens, Abnormal; C464794:fibrinogen Aalpha; D005337:Fibrin; D005340:Fibrinogen