title: Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause.
abstract: In more than 50% of patients with a mild-to-moderate bleeding tendency, no underlying cause can be identified (bleeding of unknown cause, BUC). Data on parameters of fibrinolysis in BUC are scarce in the literature and reveal discrepant results. It was the aim of this study to investigate increased fibrinolysis as a possible mechanism of BUC. We included 270 patients (227 females, median age 44 years, 25-75thpercentile 32-58) with BUC and 98 healthy controls (65 females, median age 47 years, 25-75thpercentile 39-55). Tissue plasminogen activator (tPA-) antigen and activity, plasminogen activator inhibitor type-1 (PAI-1), tPA-PAI-1 complexes, thrombin activatable fibrinolysis inhibitor (TAFI), α2-antiplasmin, and D-dimer were determined. While PAI-1 deficiency was equally frequent in patients with BUC and controls (91/270, 34%, and 33/98, 34%, p = 0.996), tPA activity levels were more often above the detection limit in patients than in controls (103/213, 48%, and 23/98, 23%, p < 0.0001). We found lower levels of tPA-PAI-1 complexes (6.86 (3.99-10.00) and 9.11 (7.17-13.12), p < 0.001) and higher activity of TAFI (18.61 (15.80-22.58) and 17.03 (14.02-20.02), p < 0.001) and α2-antiplasmin (102 (94-109) and 98 (90-106], p = 0.003) in patients compared to controls. Detectable tPA activity (OR 3.02, 95%CI 1.75-5.23, p < 0.0001), higher levels of TAFI (OR 2.57, 95%CI 1.48-4.46, p = 0.0008) and α2-antiplasmin (OR 1.03, 95%CI 1.01-1.05, p = 0.011), and lower levels of tPA-PAI-1 complexes (OR 0.90, 95%CI 0.86-0.95, p < 0.0001) were independently associated with BUC in sex-adjusted logistic regression analyses. We conclude that the fibrinolytic system can play an etiological role for bleeding in patients with BUC.
authors.affiliation: Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
authors.forename: Johanna
authors.initials: J
authors.lastname: Gebhart
authors.affiliation: Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kepa
authors.affiliation: Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hofer
authors.affiliation: Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Koder
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Vienna, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kaider
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599-7525, USA.
authors.forename: Alisa S
authors.initials: AS
authors.lastname: Wolberg
authors.affiliation: Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria.
authors.forename: Helmuth
authors.initials: H
authors.lastname: Haslacher
authors.affiliation: Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Quehenberger
authors.affiliation: IT-Systems and Communications, Medical University Vienna, Vienna, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Eigenbauer
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine, Medical University Vienna, Vienna, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Panzer
authors.affiliation: Department of Laboratory Medicine, Division of Molecular Biology, Medical University Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
authors.affiliation: Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. ingrid.pabinger@meduniwien.ac.at.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pabinger
mesh_terms: D000328:Adult; D001778:Blood Coagulation Disorders / Q000097:blood* / Q000175:diagnosis*; D015331:Cohort Studies; D005260:Female; D005342:Fibrinolysis / Q000502:physiology*; D006470:Hemorrhage / Q000097:blood* / Q000175:diagnosis*; D006801:Humans; D008297:Male; D008875:Middle Aged
keywords: Alpha2-antiplasmin; Bleeding of unknown cause; Hyperfibrinolysis; Plasminogen activator inhibitor-1 deficiency; Thrombin activatable fibrinolysis inhibitor; Tissue plasminogen activator