A team of researchers from the École Polytechnique Fédérale De Lausanne (EPFL) and collaborators say they developed the first synthetic inhibitor of coagulation factor XII (FXII). The inhibitor reportedly has high potency and selectivity, and is highly stable, with a plasma half-life of over 120 hours.

Several years ago a study was carried out on mice that had been genetically modified to be deficient in FXII, which normally helps blood clot. The mice without the enzyme had a reduced risk of thrombosis without having bleeding side-effects. The discovery triggered a race for FXII inhibitors.

“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 Christian Heinis, PhD, who heads the Laboratory of Therapeutic Proteins and Peptides at EPFL. 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 year and two generations of PhD students and post-docs to complete,” adds Heinis.

With a potent FXII inhibitor in hand, Heinis’s group wanted to evaluate it in actual disease models. To do this, they teamed up with experts in blood and disease-modeling at the University Hospital of Bern (Inselspital) and the University of Bern. Working with the group of Anne Angellillo-Scherrer, MD (Inselspital), they showed that the inhibitor blocks coagulation in a thrombosis model without increasing the bleeding risk. Then they assessed the inhibitor’s pharmacokinetic properties with the group of Robert Rieben, PhD (University of Bern). “Our collaboration found that it is possible to achieve bleeding-free anti-coagulation with a synthetic inhibitor,” notes Heinis.

The team published its research “Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs” in Nature Communications.

“Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with sub-nanomolar activity (Ki=370±40pM) and a high stability (t1/2>5 days in plasma), allowing for the preclinical evaluation of a first synthetic FXIIa inhibitor. This 1899 Da molecule, termed FXII900, efficiently blocks FXIIa in mice, rabbits, and pigs,” write the investigators.

“We found that it reduces ferric-chloride-induced experimental thrombosis in mice and suppresses blood coagulation in an extracorporeal membrane oxygenation (ECMO) setting in rabbits, all without increasing the bleeding risk. This shows that FXIIa activity is controllable in vivo with a synthetic inhibitor, and that the inhibitor FXII900 is a promising candidate for safe thromboprotection in acute medical conditions.”

This includes applications in “artificial lungs, which are used to bridge the time between lung failure and lung transplantation,” explains 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.

To test the effectiveness of the FXII inhibitor in artificial lungs, Heinis’s group turned to Keith Cook, PhD, at Carnegie Mellon University, an expert for artificial lung system engineering. Cook’s group tested the inhibitor in an artificial lung model, and 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.”

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