title: Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy.
abstract: Thrombomodulin-associated coagulopathy (TM-AC) is a newly recognized dominant bleeding disorder in which a p.Cys537Stop variant in the thrombomodulin (TM) geneTHBD, results in high plasma TM levels and protein C-mediated suppression of thrombin generation. Thrombin in complex with TM also activates thrombin-activatable fibrinolysis inhibitor (TAFI). However, the effect of the high plasma TM on fibrinolysis in TM-AC is unknown. Plasma from TM-AC cases and high-TM model control samples spiked with recombinant soluble TM showed reduced tissue factor-induced thrombin generation. Lysis of plasma clots from TM-AC cases was significantly delayed compared with controls but was completely restored when TM/thrombin-mediated TAFI activation was inhibited. Clots formed in blood from TM-AC cases had the same viscoelastic strength as controls but also showed a TAFI-dependent delay in fibrinolysis. Delayed fibrinolysis was reproduced in high-TM model plasma and blood samples. Partial restoration of thrombin generation with recombinant activated factor VII or activated prothrombin complex concentrate did not alter the delayed fibrinolysis in high-TM model blood. Our finding of a previously unrecognized fibrinolytic phenotype indicates that bleeding in TM-AC has a complex pathogenesis and highlights the pivotal role of TM as a regulator of hemostasis.
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Burley
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Whyte
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Westbury
authors.affiliation: Department of Haematology, University Hospitals Bristol National Health Service Foundation Trust, Bristol, United Kingdom.
authors.forename: Mary
authors.initials: M
authors.lastname: Walker
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.|National Institute for Health Research BioResource - Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Stirrups
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.|National Institute for Health Research BioResource - Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom.|Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom; and.
authors.forename: Ernest
authors.initials: E
authors.lastname: Turro
authors.affiliation: Department of Haematology, University Hospitals Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom.
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Chapman
authors.affiliation: Department of Haematology, University Hospitals Bristol National Health Service Foundation Trust, Bristol, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Reilly-Stitt
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Mutch
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mumford
mesh_terms: D000328:Adult; D001778:Blood Coagulation Disorders / Q000378:metabolism*; D015942:Factor VIIa / Q000494:pharmacology; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D011516:Prothrombin / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D018180:Thrombomodulin; D011516:Prothrombin; D015942:Factor VIIa; D013917:Thrombin