title: The profibrinolytic effect of plasma thrombomodulin in factor XI deficiency and its implications in hemostasis.
abstract: Bleeding tendency in factor (F)XI deficiency may result from premature clot lysis due to insufficient thrombin activatable fibrinolysis inhibitor (TAFI) activation. Thrombomodulin (TM), upon binding to thrombin, is capable of modulating TAFI activation. In this study, we investigated the effects of plasma TM on fibrinolysis in FXI-deficient patients. A clot lysis assay showed the defective down-regulation of fibrinolysis in FXI-deficient patients as compared with normal controls. To evaluate the effects of plasma TM on fibrinolysis, a monoclonal anti-TM IgG was preincubated with plasma for 30 min. The presence of anti-TM IgG significantly prolonged the clot lysis times both in the FXI-deficient and normal plasma, indicating that plasma TM stimulated fibrinolysis. Furthermore, the presence of anti-TM IgG not only reduced protein C activation, but also increased thrombin generation and TAFI activation. The profibrinolytic effect of plasma TM was inhibited in the assay by including either a monoclonal anti-TAFI IgG or a specific TAFI inhibitor--carboxypeptidase inhibitor (CPI). Our results indicate that the impaired thrombin generation in FXI-deficient patients leads to the defective down-regulation of fibrinolysis, and that plasma TM stimulates fibrinolysis through APC pathway which inhibits TAFI activation. The profibrinolytic effect of plasma TM may contribute to the bleeding tendency observed in some FXI-deficient patients.
authors.affiliation: The Haemophilia Reference Center, Center for Haemostasis and Thrombosis, St. Thomas' Hospital, London, UK. Letian.Dai@gstt.sthames.nhs.uk
authors.forename: L
authors.initials: L
authors.lastname: Dai
authors.forename: M
authors.initials: M
authors.lastname: Mitchell
authors.forename: G
authors.initials: G
authors.lastname: Savidge
authors.forename: A
authors.initials: A
authors.lastname: Alhaq
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001778:Blood Coagulation Disorders / Q000628:therapy*; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D002648:Child; D005173:Factor XI Deficiency / Q000097:blood* / Q000628:therapy*; D005260:Female; D005342:Fibrinolysis; D006470:Hemorrhage; D006487:Hemostasis; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D046911:Macromolecular Substances / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000737:chemistry; D018180:Thrombomodulin / Q000097:blood* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007074:Immunoglobulin G; D046911:Macromolecular Substances; D011486:Protein C; D011994:Recombinant Proteins; D018180:Thrombomodulin; D002268:Carboxypeptidases