Synthetic FXII Inhibitor Safely Reduces Risk of Thrombosis

Researchers from the Ecole Polytechnique Federale De Lausanne have developed a coagulation factor XII (FXII) inhibitor that reduces the risk of thrombosis and does not cause bleeding side effects.

According to Christian Heinis, senior author of a paper published in Nature Communications today, their synthetic inhibitor of FXII has high potency, high selectivity, and is highly stable, with a plasma half-life of over 120 hours.

"The FXII inhibitor is a variation of a cyclic peptide that we identified in a pool of more than a billion different peptides, using a technique named phage display," says Heinis. The researchers then improved the inhibitor by painstakingly replacing several of its natural amino acids with synthetic ones. "This wasn't a quick task; it took over six years and two generations of PhD students and post-docs to complete."

When the team evaluated the FXII inhibitor in actual disease models, they were able to show that the inhibitor efficiently blocks coagulation in a thrombosis model without increasing the bleeding risk. They also assessed the inhibitor's pharmacokinetic properties. "Our collaboration found that it is possible to achieve bleeding-free anti-coagulation with a synthetic inhibitor," says Heinis.

"The new FXII inhibitor is a promising candidate for safe thromboprotection in artificial lungs, which are used to bridge the time between lung failure and lung transplantation," says Heinis. "In these devices, contact of blood proteins with artificial surfaces such as the membrane of the oxygenator or tubing can cause blood clotting." Known as 'contact activation', this can lead to severe complications or even death and limits the use of artificial lungs for longer than a few days or weeks.

When the team tested the inhibitor in an artificial lung model, they found that it efficiently reduced blood clotting, all without any bleeding side-effects.

The only problem is that the inhibitor has a relatively short retention time in the body: it's too small and the kidneys would filter it out. In the context of artificial lungs, this would mean constant infusion, since suppressing blood clotting for several days, weeks or months requires a long circulation time. But Heinis is optimistic: "We're fixing this; we're currently engineering variants of the FXII inhibitor with a longer retention time."