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, 25–75th 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.

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment

“…Recently, an algorithm to aid in the diagnosis of patients with a bleeding tendency has been published . Three studies have demonstrated that patients with UBD have evidence of fibrionlytic abnormalities with evidence of hyperfibrinolysis and fibrinolytic regulators . This may explain the efficacy of TxA that we observed at the time of haemostatic challenges.…”

High proportion of patients with bleeding of unknown cause in persons with a mild‐to‐moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB)

“…These high numbers underline the urgent need of studies on novel pathophysiological mechanisms to understand the bleeding tendency in these patients. In a recent study, we investigated increased fibrinolysis as a possible cause for the bleeding tendency in patients with BUC and identified a potential aetiological role of this mechanism at least in some of the patients . One hundred ninety‐six of these patients are included in the present analyses.…”

Preoperative screening for bleeding disorders: A comprehensive laboratory assessment of clinical practice

“…These include platelet storage pool diseases,29, 38 and some vWD types 39. We did not perform repeated measures, which is usually performed in the diagnostic work‐up of bleeding disorders, as many variables such as stress and circadian variation influence hemostatic measurements 7, 40, 41. Furthermore, the definition of a “hemostatic abnormality” is subject to debate.…”