title: Fibrinogen γ' increases the sensitivity to activated protein C in normal and factor V Leiden plasma.
abstract: Activated protein C (APC) resistance, often associated with the factor V (FV) Leiden mutation, is the most common risk factor for venous thrombosis. We observed increased APC resistance in carriers of fibrinogen γ gene (FGG) haplotype 2, which is associated with reduced levels of the alternatively spliced fibrinogen γ' chain. This finding prompted us to study the effects of fibrinogen and its γ' chain on APC resistance. Fibrinogen, and particularly the γA/γ' isoform, improved the response of plasma to added APC in the thrombin generation-based assay. Similarly, a synthetic peptide mimicking the C-terminus of the fibrinogen γ' chain, which binds thrombin and inhibits its activities, greatly increased the APC sensitivity of normal and FV Leiden plasma, likely due to its ability to inhibit thrombin-mediated activation of FV and FVIII. Although the fibrinogen γ' peptide also inhibited protein C activation by the thrombin/thrombomodulin complex, it still increased the sensitivity of plasma to endogenously formed APC when thrombin generation was measured in the presence of soluble thrombomodulin. We conclude that fibrinogen, and particularly fibrinogen γ', increases plasma APC sensitivity. The fibrinogen γ' peptide might form the basis for pharmacologic interventions to counteract APC resistance.
authors.affiliation: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands;
authors.forename: Farida
authors.initials: F
authors.lastname: Omarova
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors.forename: Shirley
authors.initials: S
authors.lastname: Uitte de Willige
authors.affiliation: Department of Cardiologic, Thoracic and Vascular Sciences, and Department of Medicine, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Simioni
authors.affiliation: Theme Thrombosis, Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds, United Kingdom; and.
authors.forename: Robert A S
authors.initials: RA
authors.lastname: Ariëns
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Bertina
authors.affiliation: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands;
authors.forename: Jan
authors.initials: J
authors.lastname: Rosing
authors.affiliation: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Castoldi
mesh_terms: D020016:Activated Protein C Resistance / Q000097:blood / Q000150:complications / Q000235:genetics; D000328:Adult; D000595:Amino Acid Sequence; D005165:Factor V / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015241:Fibrinogens, Abnormal / Q000235:genetics / Q000378:metabolism*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011486:Protein C / Q000378:metabolism*; D012307:Risk Factors; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000097:blood; D020246:Venous Thrombosis / Q000097:blood / Q000209:etiology / Q000235:genetics
chemical_list: D015241:Fibrinogens, Abnormal; D011486:Protein C; C546931:THBD protein, human; D018180:Thrombomodulin; C095381:factor V Leiden; C527521:fibrinogen gamma'; D005165:Factor V; D013917:Thrombin