Aug 04 2020

Blood Thinning Without Bleeding

There are many “holy grails” in medicine (as in every field) – a treatment or drug that has optimal properties. These are often elusive for a couple of reasons. First, often technology requires a suite of simultaneous traits in order to be useful. Lacking any one is a potential deal-killer. Second, desired traits may be inherently mutually exclusive, or at least very difficult to reconcile. One such holy grail in medicine we have taken a big step towards is a treatment that thins the blood to reduce the risk of abnormal blood clotting (thrombosis) without impairing normal clotting and increasing the risk of bleeding.

A recent article in Nature Communications details a preliminary study of just such a treatment, although it is not yet quite ready for prime-time.

Blood-thinning is a useful treatment for several reasons. Blood clots cause many strokes and heart attacks, which are among the highest killers. They also can form on artificial implants, such as mechanical heart valves and artificial lungs (temporary bridging treatment for patients awaiting lung transplant). Essentially any artificial surface that comes in contact with blood in the body can serve as a trigger for thrombosis.

But, of course, we need our blood to clot, or otherwise we would bleed. Therefore treatments to inhibit blood clotting to reduce the risk of stroke or heart attack have always been a delicate balancing act – thinning the blood just enough to reduce risk while minimizing the increased risk of bleeding. You always get one with the other, however, and optimal treatment is a matter of finding the optimal trade-off. If we could, however, reduce thrombosis without increasing bleeding risk, that would be ideal. But it seems that the two things go hand-in-hand, so how is this possible even in theory?

Fortunately, the clotting system is extremely complex. This makes it challenging to study and understand, but basic researchers have fleshed out much of the system in vertebrates over the decades. The complexity means it may be theoretically possible to inhibit one aspect of the system to prevent clots from forming where they are not wanted, while retaining the ability to inhibit bleeding. Researchers believe they have found just this thing – called clotting factor XII (FXII – or Hageman Factor). This was actually discovered in 1955, when the routine preoperative workup of a man named Hageman was found to have increased clotting time, although he did not have any bleeding symptoms or disorder. Again I like to point out the often very long time between basic science discovery and medical application – in this case 65 years (and we’re not quite there yet).

More recent research found the gene for FXII and then confirmed this property by making knock-out animals where FXII was inactivated. Again, they has increased clotting time but no increased bleeding risk. This then triggered the race to find a drug that could inhibit FXII as a potential safer blood thinner. That brings us to the current study. The researcher present their findings of a synthetic FXII inhibitor they are calling FXII900. They found:

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.

Essentially they looked at the activity of the drug in three species under two conditions, drug-induced clotting and while hooked up to the artificial lung (extracorporeal membrane oxygenation). The inhibitor worked as hoped – it reduced thrombosis without apparently increasing the risk of bleeding. Finding this peptide was no easy task, as the researchers explain:

“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 year and two generations of PhD students and post-docs to complete.”

You may remember phage display from the 2018 Nobel Prize in chemistry. This is a technique of genetically engineering bacteriophage viruses to display an antibody or protein on their surface, which can then be studied. Using this technique the researchers tested over a billion peptides. That is just amazing.

So – if this FXII900 works so well, why aren’t we there yet? Remember I said that for many technologies are also need to have a suite of properties at the same time, and drugs are a classic example of this. Drugs need to get into the body and go where needed (bioavailability), they need to be stable, and they need to not cause harm to the body at therapeutic doses. It’s also nice if they don’t interfere too much with other drugs. FXII900 has many of the properties (at least so far) but has one critical deal-breaker – it is a small peptide that is rapidly cleared by the kidneys. In the test animals the drug was cleared in as few as 12 minutes and as long as about 30 minutes.

The authors report (and this can be confusing in the press release) that the plasma half-life is 120 hours, which is good. But this is referring to the drug just sitting in plasma in vitro. This does not refer to pharmacokinetics – what the body does to the drug. In a living organism, the kidneys efficiently filter out the drug. This is a potential deal-killer for many applications. The drug will not be useful in most contexts if it is so quickly cleared. At best it can be used as a continuous IV infusion over short periods of time. There are uses for this in the acute hospital setting – someone just had a stroke and has a thrombus that is potentially still a risk, but we don’t want to cause the stroke itself to bleed.

But other than the acute hospital setting (not to minimize this – this could be extremely beneficial), such a short half-life will keep the drug from being useful. The researchers feel (as they always do) that this one problem can be fixed. The next step, therefore, is to make variations on the molecule to find one that works as well but is not so easily cleared by the kidneys. This is what pharmaceutical companies are good at – tweaking drugs to get that combination of traits necessary to have a marketable product.

We are still years away from seeing FXII900 in use, and probably it will be a derivative. The clinical trials alone to prove safety and efficacy in humans will take years. If it takes another 10 years to have a product (a reasonable estimate) then it would have been 75 years from that fortuitous observation in 1955 to a drug treating patients. There were many steps and many discoveries along the way, building on advances in other fields like genetics and microbiology. There is a lot of the history of modern medicine in this one development. And if the end result is a blood thinner that does not increase the risk of bleeding, those 75 years of research would have, of course, been worth every hour in the lab.

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