Tissue factor pathway inhibitor is a potential modifier of bleeding risk in factor XI deficiency

• Published in: Journal of thrombosis and haemostasis Vol. 21; no. 3; pp. 467 - 479
• Main Authors: Reitsma, Stéphanie E., Holle, Lori A., Bouck, Emma G., Monroe, Dougald M., Mast, Alan E., Burthem, John, Bolton-Maggs, Paula H.B., Gidley, Gillian N., Wolberg, Alisa S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.03.2023
• Subjects: Blood Coagulation; factor XI; Factor XI - metabolism; Factor XI Deficiency; fibrin; fibrinolysis; Hemorrhage - etiology; Humans; TFPI; Thrombin - metabolism; tissue factor pathway inhibitor; fibrinolysis; tissue factor pathway inhibitor; factor XI; fibrin; TFPI
• ISSN: 1538-7836; 1538-7933; 1538-7836
• DOI: 10.1016/j.jtha.2022.10.005

Factor (F) XI deficiency is associated with increased bleeding risk in some individuals. Neither FXI levels nor clinical clotting assays predict the bleeding risk. Compared with controls, FXI-deficient bleeders have reduced clot formation, decreased fibrin network density, and increased susceptibility to fibrinolysis. Tissue factor pathway inhibitor (TFPI) was recently implicated as a modifying factor in individuals with bleeding of unknown cause. To determine the potential of TFPI in modifying the bleeding risk in FXI-deficient individuals. The effects of TFPI on thrombin generation and clot formation, structure, and fibrinolysis in FXI-deficient plasma were measured in vitro in the absence or presence of inhibitory anti-TFPI antibody or exogenous recombinant TFPIα. Total plasma TFPI concentration was measured in 2 independent cohorts of controls and FXI-deficient individuals classified as bleeders or nonbleeders (cohort 1: 10 controls and 16 FXI-deficient individuals; cohort 2: 48 controls and 57 FXI-deficient individuals) and correlated with ex vivo plasma clot formation and fibrinolysis parameters associated with bleeding risk. In an in vitro FXI deficiency model, inhibition of TFPI enhanced thrombin generation and clot formation, increased the network density, and decreased fibrinolysis, whereas an increase in TFPI had the opposite effects. Compared with controls, plasma from FXI-deficient bleeders had higher TFPI concentration. Total plasma TFPI concentrations correlated with parameters from ex vivo clotting and fibrinolysis assays that differentiate FXI-deficient bleeders and nonbleeders. Coagulation and fibrinolysis parameters that differentiate FXI-deficient nonbleeders and bleeders were altered by plasma TFPIα. Total plasma TFPI was increased in FXI-deficient bleeders. TFPI may modify the bleeding risk in FXI-deficient individuals. •Bleeding risk in factor (F) XI deficiency is variable and correlates poorly with FXI:C.•We studied the effects of tissue factor pathway inhibitor (TFPI) on thrombin generation and clotting in FXI-deficient plasma.•In an experimental model, TFPI alters thrombin generation, clot formation, structure, and lysis.•In clinical samples, TFPI correlates with parameters that distinguish bleeders from nonbleeders.