Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause

Johanna Gebhart,Stefanie Hofer,Christine Mannhalter,Peter Quehenberger,Ernst Eigenbauer,Alisa S Wolberg,Helmuth Haslacher,Sylvia Kepa,Alexandra Kaider,Ingrid Pabinger,Simon Panzer,Silvia Koder

doi:10.1007/s00277-016-2893-6

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, 25–75th percentile 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.

Highlights

In the majority of adult patients with a mild-to-moderate bleeding tendency, no diagnosis can be established and the cause for the bleeding symptoms remains elusive [1]
We investigated a broad panel of parameters with pro- and anti-fibrinolytic capacity to get a clearer picture about the involvement of fibrinolysis in bleeding tendencies of unknown cause (BUC)
We found significantly increased Tissue plasminogen activator (tPA) activity, lower levels of tPA-plasminogen activator inhibitor type-1 (PAI-1) complexes, and slightly but significantly increased levels of TAFI, α2-antiplasmin, and fibrinogen in our patients with BUC compared to the group of healthy controls

Summary

Introduction

In the majority of adult patients with a mild-to-moderate bleeding tendency, no diagnosis can be established and the cause for the bleeding symptoms remains elusive [1]. This lack of a diagnosis subsequently hinders targeted therapy and causes high psychological strain in affected individuals and treating physicians, especially in situations with increased bleeding risk, such as surgery. Our study aimed to investigate fibrinolysis in a cohort of patients with a mild-to-moderate bleeding tendency in whom no diagnosis could be established despite thorough investigation of hemostatic parameters. Gastrointestinal (GI) bleeds due to pathologies in the GI tract or intracerebral bleeding due to aneurysm were not regarded as spontaneous bleeding

Patients and methods

Results

Discussion

Compliance with ethical standards