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Synthetic inhibitors – Bleeding free anticoagulation

     Do you know blood thinners can cause bleeding side effects? Yes, for the patients who are suffering from thrombosis, pulmonary embolism or stroke are usually administered with some drugs to help their blood flow smoothly. Those drugs are the ‘blood thinners’ or otherwise called anticoagulants, which can stop blood clots from forming or getting bigger. Moreover, it helps people to recover from heart defects and also prevent further complications. It also causes bleeding side effects.

How did blood thinners work?                  

     Blood thinners usually block an enzyme that helps to stop bleeding after an injury. Because of this, every blood thinner can lead to severe, and also life-threatening bleeding after an injury.

Synthetic inhibitors – Bleeding free anticoagulation

Study on genetically modified mice with a lack of enzyme

     The problem remained unresolved over the years. But, a few years back, researchers conducted a study on genetically modified mice with a deficiency in an enzyme responsible for blood clotting. Coagulation factor XII (FXII) is the name of the enzyme. Moreover, the mice with the lack of enzyme had shown a highly reduced risk of thrombosis without bleeding side-effects. Furthermore, this research triggered a race for finding FXII inhibitors.


GM mice

The first synthetic inhibitor of FXII

    Christian Heinis, a professor of the Laboratory of Therapeutic Proteins and Peptides at EPFL, developed the first FXII synthetic inhibitor. The inhibitor has a half-life of over 120 hours. Also, it has a high selectivity, high potency, and is highly stable. Nature Communications published the study results along with three other labs in Switzerland and the United States.

How FXII inhibitor developed?

     Heinis said that they used a technique named phage display to identify the FXII inhibitor. Moreover, it is a variation of a cyclic peptide identified around a pool of more than a billion different peptides. Then the researchers replaced several natural amino acids in the inhibitor with synthetic ones and improved its quality. He also added that this was not a quick task, and it also took over six years and two generations of post-docs and Ph.D. students to complete it.


Evaluation of FXII inhibitor in disease models

     After developing a potent FXII inhibitor, Heinis’s group decided to evaluate it in actual disease models. And so they tied up with experts in blood and disease-modeling at the University Hospital of Bern (Inselspital) and the University of Bern.

     Initially, they worked with the group of Professor Anne Angelillo-Scherrer (Inselspital). In that study, they showed that the inhibitor blocks coagulation in a thrombosis model very efficiently. Moreover, it does not increase the risk of bleeding side-effects. Additionally, they assessed the pharmacokinetic properties of the inhibitor with the group of Professor Robert Rieben (University of Bern). Heinis said that with the help of their collaboration, it is possible to develop bleeding-free anticoagulation with a synthetic inhibitor.

Synthetic inhibitors and Artificial lungs

     Heinis said that the new synthetic FXII inhibitor is a promising candidate for a safe thrombo-protection in artificial lungs. The artificial lungs are used to bridge the time between lung failure and lung transplantation.

     Do you know what is ‘contact activation?’ In the people who are using artificial lungs, the blood proteins, when it comes in contact with the plastic surfaces, causes blood clotting. Also known as contact activation. The membrane of the oxygenator or tubing is an example of synthetic surfaces. Moreover, this can lead to severe complications or even death. Furthermore, it limits the use of artificial lungs for longer than a few days or weeks.

     Heinis’s group tied up with Professor Keith Cook at Carnegie Mellon University (US), to test the effectiveness of the FXII inhibitor in artificial lungs. Cook is an expert in artificial lung system engineering. Cook’s group tested the inhibitor in a plastic lung model and found that it reduced blood clotting very efficiently. Moreover, it does not cause any bleeding side-effects.

Synthetic inhibitors – Bleeding free anticoagulation

Limitation of the inhibitor

     The inhibitor has a short retention time in the body, i.e., it is too small so that the kidney would filter it out quickly. The above mentioned is the only problem of the inhibitor. In contrast, when it comes to artificial lungs, this would show a constant infusion and suppresses blood clotting for several days, weeks, or months.

     But Heinis is optimistic: He said that they are fixing this and currently engineering multiple variants of the FXII inhibitors with longer retention time. 

Get more information from the article, “Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs.”

     Also, read my previous article, “Motion capture technology delays the progression of arthritis.”

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