Breakthrough in blood clot breakdown treatment

Bleeding disorders are very common: some of them affect as many as one person in every one hundred. And in the case of conditions like haemophilia, where blood fails to clot efficiently, which can lead to painful sustained bleeds into joints, internal organs and even the brain, the emphasis on treating the problem has focused hitherto on replacing the clotting chemical factor that’s missing from the blood in affected people. This often necessitates daily injections. But as Christian Kastrup, at the University of British Columbia has shown this week, we might be able to think about treating this in a different way: rather than making blood clot better, perhaps we can reduce the ability of the blood to break down blood clots, a process driven by an enzyme called plasmin. This is actually activated as soon as a blood clot starts to form. The purpose of this apparently counter-intuitive measures is to prevent the clotting system going out of control and blocking blood vessels. So he’s developed a way, using mRNA a bit like the Covid vaccine technology, to temporarily turn down the production of the precursor chemical used to make plasmin in the liver. The result is a rebalancing of the clotting process…

Christian - During bleeding, what happens in a normal situation, our blood will react and it'll set off a process where proteins accumulate, then that's called a blood clot. But the problem is for some people, they don't have the right proteins in their blood. They might be missing a protein, and so they're not able to form a really good blood clot. And so that can lead to excessive bleeding. And so what we wanted to do in this study was to come up with a way to control the proteins in the blood to help make that blood clot stronger and help prevent it from getting degraded by the enzymes that would normally degrade blood clots in blood.

Chris - Because in the circulation there's a sort of dynamic equilibrium, a seesaw in operation where the body's trying to clot, but at the same time trying to break down a clot. And so you've got the things in balance in the healthy situation. So in someone who has a bleeding disorder like haemophilia, is the seesaw tipped too far one way and you are saying, well, can we try and balance it back up again?

Christian - Yeah, that's exactly right. Someone with a bleeding disorder, and there's many different types that can include haemophilia or von Wands disease or many other types of bleeding disorders. It's hard to form a blood clot in the wound. And sometimes in those cases, the blood clot is not very strong. And so that that balance that you're referring to, the balance can come into play and the blood clot can be degraded before it's able to do its job and stop the bleeding. And so what we're trying to do in this study is to create an agent that can help remove those enzymes that degrade blood clots. And so by doing that, any blood clot that the person's bleeding disorders will form, even though normally it'd be unstable, we can make it more stable.

Chris - It's effectively then taking some weight off one side of the seesaw. So it does tip the balance back a bit more.

Christian - Yep, that's exactly right. So we tip the balance away from having too much degradation of the blood clot back to where it's in balance and the person would be able to form a stable blood clot.

Chris - So what is the element or the chemical that you've gone for to try to balance things up a bit more?

Christian - The chemical we've gone after is an enzyme called plasmin. Plasma's role in the body is to degrade the clot. And in the clot there's another protein called fibrin. And so what plasmin does is it comes in and cleaves fibrin and helps dissolve the blood clot. We wanted to come up with a way to remove some of that plasmin to rebalance the system. Plasma in the enzyme actually comes from this protein plasminogen and plasminogen is circulating in our bodies all the time. But where the blood clots form, that's where plasminogen leads to plasmin. And so we targeted plasminogen and we target it where it's made in the liver from messenger RNA. So develop an agent that would degrade that mRNA, which then removes plasminogen from the blood and then prevents the formation of plasmin and prevents excessive degradation of the blood clot.

Chris - How long does the effect last for? So if you take an individual or an animal that's got a bleeding problem, how long can you control it with this technology?

Christian - The advantage of this technology is that it has a really long acting time. So when we do one injection targeting plasminogen, it actually decreases the amount of plasminogen for several weeks.

Chris - And how effective is it if you do this in the animal equivalent of haemophilia? For example, can you do what you set out to achieve, which is to rebalance the clotting system so that you don't have bleeding problems anymore?

Christian - It's very effective. If plasminogen is normally at a hundred percent, we can take it down to a 5 - 10%. And in animal models of bleeding disorders, it's really effective at decreasing the amount of blood loss. And so with animals that have haemophilia A, they would normally bleed a lot more than normal animals. But with this therapy, the amount of time that they're bleeding for and the amount of blood loss they lose is much less when they're on the agent.

Chris - Is there not danger if you de-power the body's ability to bust its own clots that there's a chance you could end up clogging up blood vessels when you don't want to and you increase the risk of things like a coronary thrombus, a heart attack in other words, or a stroke?

Christian - It's a really good question for that. We looked really closely at people that actually have deficiencies in plasminogen. It's a rare condition, but it does occur, and it was really surprising. These patients, they don't have a risk of thrombosis. They don't have a risk of getting blood clots. And so what that tells us is if you have just a little bit of plasminogen in your blood, it's enough to degrade clots when we have a big clot in your blood vessel that shouldn't be there.