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  • While anticoagulants are important for preventing dangerous blood clots, they increase the risk of excessive bleeding.
  • Future blood thinners may no longer increase the risk of bleeding if further studies confirm the potential of a new compound.
  • Rather than target all clotting pathways to prevent thrombosis, the new compound strategically targets just one, so clotting continues but without a bleeding risk or toxicity.

Anticoagulants, or blood thinners, break down and prevent blood clots, semi-solid clumps of blood cells, and other substances that can block blood flow. However, anticoagulants can do their job too well, preventing clotting altogether and resulting in excessive external or internal bleeding.

A new study from researchers at the University of British Columbia (UBC) and the University of Michigan introduces a new compound, MPI 8, that may one day make anticoagulants much safer.

MPI 8 precisely targets and inhibits just one of the molecules involved in blood clotting, allowing the break-up and prevention of clots without the risk of unwanted bleeding.

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Normally, blood clots form at the site of an internal or external injury, stop bleeding and allow the body to begin to heal. When internal clots break free, they can plug the bloodstream or block blood flow in critical areas of the body such as the brain, heart, and lungs. The result can be a stroke, pulmonary embolism, or heart attack.

The study is published in Nature Communications.

Physicians prescribe anticoagulants to people with atrial fibrillation or who have clotting conditions to avoid thrombosis. They may also be given prophylactically for surgeries that are frequently accompanied by unwanted clottings, such as heart valve, knee, or hip surgery replacement.

“Current anticoagulants generally inhibit all the pathways of forming blood clots and ultimately can cause bleeding,” said Dr. Adi Iyer, who was not involved in the study.

The problem is, he explained, “That could include things like bleeding ulcers, bleeding in the stomach, bleeding in the bone and joints, or even after minor traumas or injuries, accelerated bruising anywhere from the skin and soft tissue to even within the brain.”

“When you’re on blood thinners, even minor cuts and injuries can have much more devastating effects, which can be difficult to control, said Dr. Iyer.

Dr. Iyer said the risk of bleeding in first-generation blood thinners was so high that patients’ blood levels had to be monitored nearly weekly.

Only in the past 20 years have novel direct anticoagulants, or NDCs, been available. Because they inhibit blood clotting at a steady pace, the risk of sudden extreme blood loss is less of a concern.

“The real advance of the [new] study is they’ve identified potential molecules that work on what’s called the ‘contact pathway.’ And this is a pathway that prevents the formation of blood clots, yet the inhibition of which will not increase the risk of bleeding.”
— Dr. Iyer

“This is very, very interesting and exciting work,” said the study’s senior author Dr. Jay Kizhakkedathu.

“You know, for many years we have been doing this, but we finally were able to find a molecule which is a blood thinner, but which could help a lot of people,” Dr. Kizhakkedathu said.

The researchers focused on polyphosphate, one of a collection of molecules that are involved in blood clotting. It had been previously identified as a promising therapeutic target by one of the study’s co-authors, Dr. James Morrissey.

In a press release, Dr. Morrissey said the research team chose polyphosphate because it may be “a safer target to go after with an antithrombotic drug because it would just slow these clotting reactions down — even if we take out 100% of the action of the polyphosphate.”

Nonetheless, targeting a single molecule in the bloodstream is tricky. Dr. Kizhakkedathu explained that electrically speaking, polyphosphate is a negatively charged molecule. It is polyanionic, meaning it contains multiple areas of negative charge. A molecule with a single negative charge, on the other hand, is anionic.

MPI 8 is an abbreviation for “Macromolecular Polyanion Inhibitor 8.”

“Ionic charges are everywhere in our body. Proteins are ionic, cell surfaces are ionic, and almost all surfaces in our body are polyanionic,” said Dr. Kizhakkedathu. “We need to have very selective agents that can bind to a very specific polyanion, polyphosphate.”

In the past, researchers attempted to target polyphosphate with cations, positively charged compounds, but there are so many negatively charged anions in the blood that they bound indiscriminately with many of them and were thus toxic.

The researchers were able to identify a group of molecules, the MPIs, with “very special properties,” recalled Dr. Kizhakkedathu.

“Because [MPI 8] molecules have got a very low cationic density, or cationic charge, they circulate in the body with a very low charge,” passing harmlessly by other molecules, he explained.

“But when it finds its target, it increases the charge density. It binds very strongly [and selectively],” he added.

The researchers describe this property as “tunability.”

So far, the authors of the study have tested MPI 8 on mice and found it effective at preventing blood clots without toxicity or an increase in the risk of bleeding.

UBC and the University of Michigan have applied for a patent for MPI 8, and hope to move next to trials with larger animals, and eventually humans.

“If it gets into the clinical trials and approved, this will a help a lot of people,” said Dr. Kizhakkedathu of the team’s breakthrough.