Anticoagulant Protein TFPI Crucial to Bleeding Severity Profile of Hemophilia Patients, Study Says

A natural anticoagulant protein called tissue factor pathway inhibitor (TFPI) is critical for defining the bleeding severity profiles of people with hemophilia A and B, researchers in France report.

This discovery, which was found not to hold for healthy individuals, adds support to TFPI as an important element for hemophilia-related bleeding, and one that could represent a new target for treatment.

The study “Tissue factor pathway inhibitor is the main determinant of thrombin generation in haemophilic patients” was published in the journal Haemophilia.

Clinicians often use the thrombin generation (TG) test to assess blood clotting potential, identifying people prone to excessive bleeding and their level of hemophilia severity. The TG test evaluates the overall balance between procoagulant and anticoagulant forces.

TG assay results can be influenced by the levels of many coagulation factors and inhibitors. In patients with hemophilia A and B, a low TG potential is known to associate with the level of deficiency in coagulation factors VIII and IX, respectively.

Hemophilia patients with a similar coagulation factor deficiency, however, can still have different bleeding profiles.

A team led by researchers from the University of Lyon set up a study to explore which blood coagulation factors might contribute to profile differences among patients, and to compare these factors to those of healthy people.

Their study enrolled 40 hemophilia A and 32 hemophilia B patients, as well as 40 healthy volunteers.

All three groups showed similar values of 12 main blood clotting factors and inhibitors. The proportion of variability in these elements was also comparable between healthy participants (16% variability) and patients (18% variability) regardless of hemophilia type.

Antithrombin was the inhibitor that showed the lowest variation (10%) between individuals, while TFPI levels had the highest variation (38%). Hemophiliac patients also had significantly higher fibrinogen levels than healthy participants.

Using the TG assay, the researchers as expected found that healthy individuals had significantly higher endogenous thrombin potential (ETP) and peak — the two parameters evaluated by the test — compared to those with hemophilia A and B. No differences in these parameters were seen among patients with hemophilia A or B, regardless of  disease severity.

Additional analysis revealed that higher levels of factor VIII and factor IX were directly linked to higher ETP and peak values in hemophilia A and B samples, as expected. In contrast, the team found that free TFPI levels were a strong negative determinant of both ETP and peak in these patients. This means that TFPI is responsible for low thrombin generation in these patients, and also  inhibits (blocks) the production of coagulation factors.

Other clotting factors and inhibitors also found to have an impact, though weaker, on TG results include factor V and fibrinogen in hemophilia A patients; and free protein S, factor X, antithrombin, and fibrinogen in hemophilia B patients.

A similar analysis of blood samples from healthy individual showed that factor X and free protein S were negative determinants of both ETP and peak, while TFPI levels showed no association with TG test results.

“The TG determinants in [hemophilia A and B] patients differ somewhat from those in healthy individuals,” with TFPI being the major determinant of TG results in hemophilia patients, the study noted.

“The finding that TFPI plays a much more important role in TG in haemophilic patients than in healthy subjects is of major interest,” the researchers wrote. “As the crucial determinant of peak and ETP in haemophilic patients, TFPI could be considered as the best target for the treatment of haemophilia irrespective of its type and irrespective of the severity of factor VIII or IX deficiency.”

They concluded, “[o]ur findings corroborate the current interest in TFPI that appears a highly relevant target to be neutralized” in treating people with hemophilia.