Ehlers-Danlos, Factor IX and Vitamin C

By Dr. David Clark 

9/23/24 

A few years ago, Kim Phelan pointed out to me that we seem to have a higher-than-expected number of members who have both Ehlers-Danlos Syndrome (EDS) and hemophilia B.  I couldn’t tell her why at the time, but recent research may be pointing to a cause.  EDS is a connective-tissue disorder that is thought to be caused by mutations in the genes for collagen.  Collagen is the main structural protein of the body.  Our skin, bones and ligaments are made of collagen.  The structural framework of our organs is made of collagen.  Our blood vessels have a collagen framework that makes them strong.  A common feature of EDS is being “double-jointed.”  Because of a mutated collagen gene, the ligaments (connective tissue) that hold the joints together ends up being stretchier, so the joint can bend further than normal. 

We’ve also been learning that factor IX accumulates inside the walls of blood vessels where it binds to a type of collagen called collagen IV.  That “extravascular” factor IX, factor IX residing outside the bloodstream, seems to be important for good clotting.  Studies have shown that even if you have <1% of normal factor IX activity in your blood, you can still have fairly good clotting if there is enough factor IX inside the walls of the blood vessels.  We don’t know why this extravascular factor IX is important for clotting or how it does whatever it does, so this is a subject of much research interest. 

EDS patients can have bleeding problems.  One reason seems to be that the collagen mutations make the blood vessels weaker so they break more easily.  However, that doesn’t account for all their bleeding issues.  Another idea is that a mutated collagen IV might lose its ability to bind factor IX, and thus the ability to let factor IX do whatever it does inside the blood vessel walls to promote clotting. 

So, can any of this help us understand the “bleeding disorder of unknown cause” (BDUC) that predominantly affects women.  These are people who don’t clot properly but whose bleeding disorder isn’t hemophilia A or B or any other known clotting factor deficiency, von Willebrand disease, a platelet disorder or anything else that we know.  With the above background, a group of Danish researchers looked at BDUC and found that it is frequently associated with EDS and related connective tissue disorders. 

Secondly, they also looked at vitamin C levels in people with BDUC.  Vitamin C is something of an enigma.  It was popularized years ago by Nobel prize winner Linus Pauling as kind of a cure-all.  It probably isn’t that, but one thing we know is that it is involved in the production of collagen.  The researchers found that vitamin C levels were, in fact, lower in the BDUC/EDS patients.  They propose a study of vitamin C supplementation in BDUC patients. 

This is an exciting area of research.  In addition to helping BDUC patients, findings could also help us understand hemophilia better.  We know that about 15% of hemophilia patients don’t fit into our current model of how clotting works, and this could shed some light on that.  There is obviously a gap, probably several gaps, in our understanding of clotting that need to be filled in order to help BDUC patients and other patients with problematic bleeding disorders.  Science often proceeds slowly, but at least we’re on the way.  [Leinøe E et al., Haemophilia, online ahead of print 9/23/24]