Factor Levels in Hemophilia B Carriers

By Dr. David Clark

Factor Levels in Hemophilia B Carriers 
from the Summer 2024 Newsletter

Ignoring women with hemophilia has probably kept us from learning more about the mechanism of hemophilia and clotting in everyone.  Our general understanding of hemophilia seems to break down when applied to women.  That suggests that there are things about bleeding and clotting that are still to be discovered. 

The first important clue is that in women, bleeding does not seem to be determined by factor levels [Johnsen J, CDC webinar: Understanding Factor Levels and Bleeding in Hemophilia Genotype-Positive Females, May 16, 2024].  Our general understanding (in men) is that the lower the levels of clotting factors VIII and IX, the higher the chances for bleeding.  We know that is not strictly true.  Within each of the categories of severity, mild, moderate and severe, we know that about 15% of patients don’t fit the bleeding behavior expected for their factor level.  For instance, in severe hemophilia, defined as a factor level below 1% of normal, about 15% of patients bleed more mildly than expected. 

Similarly, some people with mild hemophilia bleed much more severely than would be expected.  This is known as the difference between genotype (genetics) and phenotype (actual experience).  We don’t know why there is a difference, but similar unknown things may be going on in female bleeders to cause them to bleed more than their factor levels would suggest. 

Our history of conclusions about female bleeders demonstrates our hubris about our knowledge of genetics.  First, we thought that women couldn’t have hemophilia because they have two X-chromosomes, so even if one chromosome had a defective factor gene, the other would provide enough clotting factor.  After all, men only have one X-chromosome and that provides enough clotting factor in men without hemophilia. 

Then we discovered that in female cells, one of the X-chromosomes is inactivated.  It turns out that it is dangerous for a cell to have two active copies of the same chromosome.  The inactivation appears to be random, so on average, about 50% of a woman’s cells would have an active X-chromosome from their father and about 50% would have an active X-chromosome from their mother.  If one of her inherited X-chromosomes had a mutated factor gene, the woman should still be able to produce about a 50% level of “good” clotting factor.  Based on our current understanding 50% is the lower limit of normal, so she shouldn’t really bleed. 

Then we discovered that the X-chromosome inactivation could be “skewed.”  Instead of a 50:50 ratio of active X-chromosomes, the ratios in some women could actually be 70:30 or 80:20 or even worse.  If the 70 or 80% of cells were producing the defective clotting factor, that could be the reason why those women bleed.  So, we said, “Aha, that must be the answer!”  That’s about where we are today, but surprisingly, recent research has failed to confirm our suspicion. 

6/23/24  At ISTH a group of Japanese researchers presented a study that suggests that skewing of X-chromosome inactivation is not associated with factor levels in women.  They admit that their study was small and further research is needed, but over the last few years several other similar studies have come to the same conclusion.  Thus, skewing might not be the answer, or may only be part of the answer.  (My main concern with these studies is that they have usually looked at whole-body genomes.  I wonder whether they would find something different if they looked just at the liver cells that actually produce the clotting factors.  Is the skewing different there?)  [ISTH abstract PB0264] 

Fortunately, researchers are now starting to include women in more studies.  This will hopefully give us more information about the bleeding/clotting process in all humans.  We’re already finding things that we didn’t expect, and that’s exciting.  Science always learns more from unexpected results.