By Dr. David Clark

Years ago, Kim Phelan asked me whether there was a connection between Ehlers-Danlos syndrome (EDS) and hemophilia B. She asked because we seem to have an unusually large number of members who have both. I looked into the medical literature to see what I could find and found little. There might be a connection, but no one could explain it. However, new ideas about how factor IX actually works have shown that there might, in fact, be a direct connection.

EDS is a connective tissue disease. Connective tissue is “tissue that supports, protects, and gives structure to other tissues and organs in the body,” according to the National Cancer Institute, part of NIH. Connective tissue is the material that makes up a lot of the physical structure of the body. Much of it is made of collagen, the main structural protein in our body. Collagen is in everything from our skin and bones to the walls of our blood vessels. It’s what holds our bodies together.

Patients with EDS have mutations in their collagen genes. In the same way that hemophilia B patients have mutations in their gene for factor IX that keep the factor from working properly, EDS patients can have mutations that keep their collagen from performing correctly. Since there are several different types of collagens and it has so many uses, the mutations can cause a number of different disorders.

One possible symptom is being “double-jointed.” Back in the dark ages when I was a kid, we had a girl in our class who could bend her thumb completely backward against the back of her hand. We all thought that was pretty cool, but in fact she might have had EDS. Many collagen mutations make the protein stretchier. Our classmate might have been doublejointed because the collagen in the ligaments and tendons in her hand stretched too much.

That might have seemed cool to us kids, but EDS can cause a number of not-so-cool symptoms. Easy bruising is a common result. This was thought to be a result of collagen mutations causing weak blood vessels that break easily. However, as we’ll see below, some of this bruising might arise from poor clotting. More serious outcomes of EDS include delayed wound healing, rupture of arteries causing severe internal bleeding or death, and rupture of hollow organs like the intestines or uterus.

The association of EDS with hemophilia is not new. A publication from 1960 is titled “Plasma Thromboplastin Component Deficiency in the Ehlers-Danlos Syndrome.” Plasma thromboplastin component is now called factor IX, and its deficiency is now called hemophilia B. What is new is that we can now see what the connection might be between EDS and hemophilia.

Let’s go back to the hemophilia side before we connect the two. Research over the past couple of decades has shown that factor IX binds inside the walls of blood vessels. More specifically, it binds to the type IV collagen that gives the vessel wall its strength. So what? We’ve thought all along that the factor IX in the blood vessel walls was only there as an extra supply in case we used up too much in the bloodstream. We were apparently wrong.

I got into clotting research in the early 1980s, right at the time of a revolution in how we thought clotting happened. Before that, everyone assumed that clotting happened in solution, since the clotting factors are dissolved in the blood. However, people had noticed that clotting required phospholipids.

Phospholipids are the molecules that make up the walls of cells. Researchers figured that the phospholipids came from the broken cell walls at the injury site. They floated out into the bloodstream where they could interact with the clotting factors to cause the clotting reactions.

Not so fast! Some very smart people did some extensive experiments that showed that the clotting reactions were actually taking place on the phospholipid surfaces, not out in the bloodstream. They were actually happening on the broken cell walls at the injury site, as well as on the walls of platelets and other cells. That makes sense since you need to keep the clotting reactions at the site of injury. If the reactions were happening out in the bloodstream, the clots could just float away.

We’ve got another revolution going on today. We’re realizing that the factor IX that is bound inside the walls of the bloodstream is not just extra; it’s essential. (See the article “Where Is the Factor IX and What Does It Do There?” in the Winter 2021 issue.)

A recent study along these lines shows that if you give hemophilia B mice a recombinant factor IX that is less able to bind to collagen, the mice don’t clot as well as if you gave them normal factor IX. However, if you give them a factor IX that binds more strongly to collagen, they clot even better than with normal factor IX.

This is further evidence that the factor IX that binds to collagen in the walls of the blood vessels is not just extra material, it is important for clotting. [Machado SF et al., Thromb. Haemost., online ahead of print May 10, 2023]

Now let’s tie these together. Note that this hasn’t been completely proven yet, so some of it is just speculation. We’re joining the scientists working on this at the edge of our current knowledge.

If you have EDS and make a mutated form of collagen, type IV that factor IX doesn’t bind to, you won’t have much factor IX inside your blood vessel walls. Because of the lack of factor IX in the vessel walls, you won’t clot as well. You’ll look as though you have hemophilia B, even if your factor IX is completely normal.

Your factor IX won’t be able to do its job, not because it is faulty but because the collagen that it’s supposed to bind to, won’t accept it. Note that von Willebrand factor and platelets also bind to collagen, so collagen mutations could also affect them, causing other bleeding disorders.

What we’re apparently seeing with EDS is that you could have perfectly fine factor IX, but have hemophilia B because your collagen isn’t working right – it doesn’t bind to your factor IX. You’ve also seen some of the scientific process. We often only learn things by baby steps. First, we had to discover factor IX. Then we had to figure out how it works. Now we’re figuring out where it works and why.

Along the way, we have to make assumptions and then do experiments to show whether or not those assumptions are correct. It’s a long slow process, and that’s frustrating for many people. However, if we’re patient, it can have a big payoff.

When I first started, hemophilia B patients were treated with Factor IX Complex, a mixture of clotting factors; we didn’t even have a method for purifying factor IX. However, factor IX complex had lots of limitations. It couldn’t be used for prophylaxis or surgery. Now, four decades later, we have gene therapy, a possible cure.

Where has the time gone?