title: Use of global assays to understand clinical phenotype in congenital factor VII deficiency.
abstract: Congenital factor VII (FVII) deficiency is characterized by genotypic variability and phenotypic heterogeneity. Traditional screening and factor assays are unable to reliably predict clinical bleeding phenotype and guide haemorrhage prevention strategy. Global assays of coagulation and fibrinolysis may better characterize overall haemostatic balance and aid in haemorrhagic risk assessment. We evaluated the ability of novel global assays to better understand clinical bleeding severity in congenital FVII deficiency. Subjects underwent central determination of factor VII activity (FVII:C) as well as clot formation and lysis (CloFAL) and simultaneous thrombin and plasmin generation (STP) global assay analysis. A bleeding score was assigned to each subject through medical chart review. Global assay parameters were analysed with respect to bleeding score and FVII:C. Subgroup analyses were performed on paediatric subjects and subjects with FVII ≥ 1 IU dL(-1). CloFAL fibrinolytic index (FI2 ) inversely correlated with FVII:C while CloFAL maximum amplitude (MA) and STP maximum velocity of thrombin generation (VT max) varied directly with FVII:C. CloFAL FI2 directly correlated with bleeding score among subjects in both the total cohort and paediatric subcohort, but not among subjects with FVII ≥ 1 IU dL(-1) . Among subjects with FVII ≥ 1 IU dL(-1), STP time to maximum velocity of thrombin generation and time to maximum velocity of plasmin generation inversely correlated with bleeding score. These preliminary findings suggest a novel potential link between a hyperfibrinolytic state in bleeding severity and congenital FVII deficiency, an observation that should be further explored.
authors.affiliation: Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA. greenel@email.chop.edu
authors.forename: L A
authors.initials: LA
authors.lastname: Greene
authors.forename: N A
authors.initials: NA
authors.lastname: Goldenberg
authors.forename: M L
authors.initials: ML
authors.lastname: Simpson
authors.forename: E
authors.initials: E
authors.lastname: Villalobos-Menuey
authors.forename: C
authors.initials: C
authors.lastname: Bombardier
authors.forename: S S
authors.initials: SS
authors.lastname: Acharya
authors.forename: P J
authors.initials: PJ
authors.lastname: Santiago-Borrero
authors.forename: A
authors.initials: A
authors.lastname: Cambara
authors.forename: D M
authors.initials: DM
authors.lastname: DiMichele
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005168:Factor VII Deficiency / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D005342:Fibrinolysis; D006470:Hemorrhage / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics; D006801:Humans; D008297:Male; D010641:Phenotype; D011446:Prospective Studies; D055815:Young Adult
keywords: clot formation; factor VII deficiency; fibrinolysis; global assay; plasmin generation; thrombin generation