Tissue factor pathway inhibitor is the main determinant of thrombin generation in haemophilic patients

Abstract

The thrombin generation (TG) assay evaluates haemostatic balance, which is influenced by the levels of many coagulation factors and inhibitors. Our objective was to identify the determinant factors of TG in haemophilia A (HA) and haemophilia B (HB) patients and to compare them to those in healthy controls. Coagulation factor and inhibitor levels, and TG, were measured in platelet‐poor plasma from 40 patients with HA, 32 patients with HB and 40 healthy subjects. Data were analysed using multiple regression models. In HA patients, factor VIII was a positive determinant of endogenous thrombin potential (ETP) and peak, whereas tissue factor pathway inhibitor (TFPI) and factor V were negative determinants of ETP and peak. In HB patients, FIX was a positive determinant of ETP and peak, FVII being a positive determinant of peak. Antithrombin and protein S (PS) were negative determinants of ETP while FX was a negative determinant of peak. Above all, in HB patients, TFPI was a negative determinant of ETP and peak. In healthy subjects, FVIII was a positive determinant of ETP and peak, whereas FX and protein S were negative determinants of these parameters. TFPI was not a negative determinant of either peak or ETP. In haemophilic patients, the determinant factors of TG are all implicated in FXa generation and inhibition, the crucial determinant factor being TFPI whatever the type of haemophilia, A or B. These findings contribute to the rationale that recently place TFPI as a target for innovative therapies of haemophilia.

Measurement of plasma and platelet tissue factor pathway inhibitor, factor V and Protein S in people with haemophilia

“…There were no differences in plasma total TFPI or TFPIα concentrations between people with haemophilia A or haemophilia B. This finding is in agreement with recent publications by Fosbury and Chelle and colleagues, who examined a combined 91 people with haemophilia A and 45 with haemophilia B and also found no differences in the plasma concentrations of TFPI. However, they are in contrast to a study of 30 people with haemophilia A and 21 with haemophilia B by Tardy‐Poncet and colleagues, who found decreased plasma free‐TFPI in people with haemophilia B vs those with haemophilia A.…”

Thrombin generation abnormalities in Quebec platelet disorder

“…As TXA did not improve TG by plasminogen-deficient plasma, we suggest that TXA improves TG by reducing plasmin generation during ex vivo assessments of TG. We noted that TFPI (which has emerged to be an important determinant of TG 3,4,31 ) is normal in QPD plasma and platelets and that plasma TFPI showed association to the lag time for QPD PRP samples. The QPD TFPI findings are interesting as plasma FV serves as a carrier for TFPI and FV-TFPI binding inhibits FV activation and prothrombinase activity.…”

“…and bleeding. [3][4][5] We postulated that using CAT to study TG and measuring TFPI levels in Quebec platelet disorder (QPD) might provide new insights on a disorder with unique fibrinolytic abnormalities and platelet but not plasma factor V (FV) deficiency.…”

Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas

“…Marstacimab would presumably inhibit endothelial cell TFPI given its binding to the TFPI K2 domain. Recent studies, however, confirm the importance of plasma TFPI as a major negative determinant of thrombin generation in haemophilic patient plasmas …”