title: Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency.
abstract: Severe factor V (FV) deficiency is associated with mild to severe bleeding diathesis, but many patients with FV levels lower than 1% bleed less than anticipated. We used calibrated automated thrombography to screen patients with severe FV deficiency for protective procoagulant defects. Thrombin generation in FV-deficient plasma was only measurable at high tissue factor concentrations. Upon reconstitution of FV-deficient plasma with purified FV, thrombin generation increased steeply with FV concentration, reaching a plateau at approximately 10% FV. FV-deficient plasma reconstituted with 100% FV generated severalfold more thrombin than normal plasma, especially at low tissue factor concentrations (1.36 pM) or in the presence of activated protein C, suggesting reduced tissue factor pathway inhibitor (TFPI) levels in FV-deficient plasma. Plasma TFPI antigen and activity levels were indeed lower (P < .001) in FV-deficient patients (n = 11; 4.0 +/- 1.0 ng/mL free TFPI) than in controls (n = 20; 11.5 +/- 4.8 ng/mL), while persons with partial FV deficiency had inter-mediate levels (n = 16; 7.9 +/- 2.5 ng/mL). FV immunodepletion experiments in normal plasma and surface plasmon resonance analysis provided evidence for the existence of a FV/TFPI complex, possibly affecting TFPI stability/clearance in vivo. Low TFPI levels decreased the FV requirement for minimal thrombin generation in FV-deficient plasma to less than 1% and might therefore protect FV-deficient patients from severe bleeding.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Connie
authors.initials: C
authors.lastname: Duckers
authors.forename: Paolo
authors.initials: P
authors.lastname: Simioni
authors.forename: Luca
authors.initials: L
authors.lastname: Spiezia
authors.forename: Claudia
authors.initials: C
authors.lastname: Radu
authors.forename: Sabrina
authors.initials: S
authors.lastname: Gavasso
authors.forename: Jan
authors.initials: J
authors.lastname: Rosing
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Castoldi
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D005165:Factor V / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005166:Factor V Deficiency / Q000097:blood* / Q000150:complications / Q000151:congenital / Q000235:genetics; D005260:Female; D006467:Hemophilia A / Q000097:blood; D006474:Hemorrhagic Disorders / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D008074:Lipoproteins / Q000097:blood* / Q000737:chemistry / Q000235:genetics; D008297:Male; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000097:blood; D009154:Mutation; D020349:Surface Plasmon Resonance; D013917:Thrombin / Q000096:biosynthesis
chemical_list: D008074:Lipoproteins; D046912:Multiprotein Complexes; C051928:lipoprotein-associated coagulation inhibitor; D005165:Factor V; D004247:DNA; D013917:Thrombin