Bones and Joints and Pain, Oh My!

By Dr. David Clark

Not that long ago, the main research topic in hemophilia was product safety. Without treatment, many people with hemophilia did not live beyond their teens. That was overcome when clotting factor concentrates purified from human plasma were developed. They opened up a real future for patients, for awhile...

Then in the 1980s people with hemophilia started coming down with unusual diseases. That turned out to be AIDS, caused by the HIV virus, which contaminated many plasma donation pools.

Over ten thousand hemophilia patients and family members died of AIDS. That tragedy sparked a push to develop safer plasma–derived products and then recombinant products not made from plasma. Finally, we have safe life–giving products, and hemophilia patients live normal lifespans.

So, what’s left to do? A lot! When you get to my age, you realize that living a long life is not necessarily the main goal – you want quality of life (QoL), too. QoL has become the focus of much of today’s research. Just getting you to old age is not enough. We aren’t really successful just because we can keep you alive even though you’re curled up in a wheelchair unable to walk. We want you running and jumping and enjoying yourself.

One of the most important aspects of QoL is being mobile. Bone and joint health are crucial. We thought that once everyone was on prophylaxis with safe easier–to–use factor products, all the joint problems would go away. Unfortunately, that hasn’t been the case.

Three recent papers presented at the annual meeting of the European Association for Haemophilia and Allied Disorders (EAHAD), Feb. 2 – 4, 2022, showed that joint damage is still occurring: 1) in about one–third of patients on prophylaxis, 2) even in the absence of apparent joint bleeds and 3) even in mild and moderate patients despite a low frequency of bleeds. [EAHAD abstracts PO083, PO084 and PO085]

What researchers think is happening is called subclinical bleeding, or microbleeds. “Subclinical” means that the bleeding is not apparent tothe patient or physician. The bleeds are so small that there is no pain and no feeling of having a bleed. However, there is still enough blood getting into the joint to cause trouble. A paper at the World Federation of Hemophilia (WFH) annual meeting, May 8–12, 2022, describes an MRI study of hemophilic joints that suggests that about 20% of joints have damage due to microbleeds, without any outward signs of ever having had a joint bleed. [WFH abstract PP–14 (1157875)]

Joints are lubricated with synovial fluid. Earlier on, the thought was that maybe the blood leaking into a joint just diluted the synovial fluid so much that it lost its slipperiness. That could cause physical damage by wearing away the cartilage in the joint, similarly to what would happen if you put water in your car instead of oil. Today, after much more research, we don’t think joint damage has a physical cause like that; it’s more due to changes in the biochemistry going on inside the joint because of molecules coming in with the blood.

Joint health is also important for women who are carriers or who have hemophilia. They are often developing joint damage without knowing it. Women with severe hemophilia usually know they are bleeding, but carriers and those with mild/moderate disease rarely have noticeable bleeds, yet often develop joint damage, apparently from microbleeds. This is one major reason women should try to get treated. Although you might be living a seemingly normal life, you may be piling up joint damage that will affect you in later. [Citla–Sridhar D et al., Haemophilia, online ahead of print 4/13/22]

Joints are not the only issue. In fact, recent research has shown that joint problems tend to go along with low bone density. People with hemophilia tend to develop low bone mass or bone density, known as osteoporosis, which can lead to fractures. This has historically been thought to be caused by prolonged immobility, repeated joint bleeds and lower physical activity levels.

More recently, we have seen that prophylactic, but noton–demand, treatment with clotting factors improves bone density. Therefore, deficiencies of either factor VIII or IX may be involved, not just low physical activity. Factor VIII, which is deficient in people with hemophilia A, has definitely been shown to be involved, but the situation for factor IX and hemophilia B is less clear and needs more research.

Women who are either carriers or have hemophilia may be even more at risk, since women tend to lose bone density with age anyway. Again, more reason for them to try to get treated. Even if they don’t have significant bleeding problems, they may benefit from prophylactic factor to preserve their bones. The same is true of men with mild or moderate disease who aren’t on prophylaxis.

This brings up the question of the new non–factor therapies being developed to treat hemophilia. They seem to do a good job restoring the ability of the blood to clot, but will their lack of factor VIII or IX lead to other problems? We tend to think that the main job of clotting factors is to form clots, but most proteins in the body actually have more than one function.

Factor IX, for instance, is thought to be involved in wound healing. Will the use of a rebalancing agent to restore clotting have a negative effect on healing or some other body process because of a lack of factor IX? We don’t know yet, but we may find out in the near future as these products come onto the market.

Finally, what would joint damage be without pain? Current thinking is that pain is a signal to us that there is a problem in our body. But what about the chronic pain that afflicts so many people? “We know we have a problem – you don’t need to keep reminding us.” As I wrote in the last issue, we are learning more and more about pain and finding that some of our concepts may not be correct. Chronic pain may be a malfunction in the nervous system. It might get stuck in the “ON” condition, even though the pain is no longer needed.

This was demonstrated by a recent study from Belgium and Germany. The researchers looked at 30 adult patients with hemophilia who had ankle damage. They assessed the structure of the 60 ankles by both MRI and ultrasound, while also assessing pain by several methods. What they found is that there was no correlation between ankle structural changes and pain. That is, in the subjects with ankle pain, the pain was not actually coming from the ankle. They propose that the pain is actually due to a dysfunction in the nervous system, but this needs further study. [Roussel NA et al., Haemophilia, online ahead of print 3/16/22]

People with hemophilia need to pay attention to this. Osteoporosis is a silent disease. Many people don’t know they have it until something breaks. Talk to your doctor or HTC. There is a simple X–ray test called a DEXA scan that can measure your bone density. If you do have a problem, there are a number of lifestyle changes and medical treatments that can help.

Now that some of the major issues in hemophilia have been resolved, researchers can focus on some of the other aspects that affect quality of life. These include the crippling joint damage, bone density loss and pain that many patients suffer. We are making progress that hopefully will result in hemophilia patients not only living long but living well.