The Tissue Factor-TFPI Pathway as a Therapeutic Target in Bleeding Disorders of Unknown Cause

Bleeding disorders of unknown cause (BDUC) comprise a heterogeneous group of conditions characterized by clinically significant bleeding despite normal results on standard haemostatic investigations.

To investigate tissue factor (TF)-dependent coagulation in patients with BDUC and to evaluate the in vitro ability of concizumab and recombinant activated factor VII (rFVIIa) to restore thrombin generation.

Thrombin generation was assessed using an assay designed to isolate TF-dependent coagulation by inhibiting contact pathway activation with corn trypsin inhibitor (CTI). A subgroup of patients with BDUC exhibited impaired thrombin generation under these conditions. Reduced thrombin generation was frequently associated with increased tissue factor pathway inhibitor (TFPI) activity, suggesting that excessive inhibition of TF-mediated coagulation contributes to the bleeding phenotype in a subset of patients. In vitro addition of concizumab or rFVIIa restored thrombin generation, indicating that defects in TF-dependent coagulation can be pharmacologically corrected.

These findings identify dysregulation of the TF-TFPI axis as a potential pathophysiological mechanism underlying bleeding in a subset of patients with BDUC and highlight TFPI inhibition and rFVIIa administration as potential therapeutic approaches. However, the absence of abnormalities in all patients supports the concept that BDUC represents a biologically heterogeneous group of disorders with multiple underlying mechanisms.