Written by: David Clark, PhD, chair of the Coalition for Hemophilia B

Many physicians would say that this title doesn’t make any sense—women don’t get hemophilia. Today we know that women can have hemophilia, and in fact, the number of women with hemophilia is significant. Unfortunately, this “news” hasn’t reached many physicians, especially those who do not specialize in hemophilia treatment. This is in spite of the fact that since the 1950s the medical literature has contained reports of hemophilia carriers with factor VIII or IX deficiency and bleeding problems. 

Because the idea that women don’t get hemophilia has been so ingrained, early researchers tried to imagine all kinds of other explanations for these reports. The genetics seemed so simple that there had to be an alternate reason. Now we know that the genetics are actually much more complex, and it is obvious that women can and do have hemophilia. The rest of this article will focus on hemophilia B, but the situation is very similar for hemophilia A.

The lack of recognition of an obvious condition can make it difficult for women with hemophilia to be taken seriously about their disease. This is not a small issue. It is estimated that there are up to five times as many carriers as there are men with hemophilia. Another estimate is that at least one-third of carriers have factor levels below the normal range. Although not all of them have bleeding problems, a significant number of them do. Today, more and more Hemophilia Treatment Centers (HTCs) are treating carriers. However, there is still a general lack of information on bleeding tendencies and treatment options for women.

THE GENETICS EXPLAINED

Carriers have a defective factor IX gene on one of their X chromosomes, which they can pass on to their offspring. All of the daughters of a man with hemophilia are carriers, sometimes called obligate carriers. On average, half of the daughters of a female carrier will also be carriers and half of her sons will have hemophilia. The carrier daughters might or might not have hemophilia. It depends on other things, most of which are not yet understood.

Chromosomes are structures in the nucleus of a cell that hold the genes. Except for a few specialized types of cells, every cell in the human body has 46 chromosomes that together hold a copy of all of the body’s genes. This collection of all the body’s genes is known as the genome. Two of the chromosomes are the X and Y chromosomes, which determine the sex of a person. The X chromosome is shaped like an X and the Y like a Y. Men have an X and a Y chromosome, and women have two X chromosomes. Men inherit their X chromosome from their mother and their Y chromosome from their father. Women inherit one X from each. The factor IX gene is located on the lower leg of the X that is missing on the Y chromosome. Therefore, men have only one factor IX gene but women have two, one on each X chromosome.

Carriers usually have a second X chromosome that contains a normal factor IX gene. It is only the rare carrier who has defective factor IX genes on both X chromosomes…. These women unquestionably have hemophilia, even by old-school standards.

Because women have two X chromosomes, carriers usually have a second X chromosome that contains a normal factor IX gene. It is only the rare carrier who has defective factor IX genes on both X chromosomes. She would be the child of a carrier mother and a father with hemophilia B; on average, half of their female offspring will have two defective factor IX genes. These women unquestionably have hemophilia, even by old-school standards. (This situation may not actually be as rare as the medical establishment has assumed. They look at the overall population and figure that the chances that a man with hemophilia will meet and marry a carrier is very small. This overlooks the fact that the hemophilia community has bonded together so that many hemophilia families know each other.) 

THE MORE COMMON SITUATION

In the rest of this article, we’ll focus on the more common situation of carriers with one normal and one defective factor IX gene.

The idea that women do not get hemophilia comes from the fact that most carriers still have one normal factor IX gene. Reasoning that males with one normal factor IX gene do not have hemophilia, it was thought that most carriers should also not have hemophilia. However, this reasoning is faulty because it doesn’t take into account a phenomenon that has only more recently become appreciated. It turns out that even though every cell in a carrier’s body contains a normal factor IX gene, those genes are not all active. Because having two copies of every gene on the X chromosome could cause problems, the body has a mechanism to inactivate one of the two X chromosomes in women. Therefore, a carrier’s cells will only contain one active factor IX gene; the other one on the inactivated X chromosome will not produce any factor IX. This process is called X chromosome inactivation or “lyonization,” after Dr. Mary Lyon, the researcher who discovered it.

Lyonization is normally a random process, so each cell has a 50-50 chance of having the active factor IX gene be the normal one. Therefore, in the liver, where factor IX is made, about half of a carrier’s cells will make normal factor IX and half will make defective or no factor IX, depending on the gene mutation. Thus, a carrier will usually have approximately half of the amount of normal factor IX that a non-carrier woman has. Several studies have found that the factor IX level in hemophilia B carriers can range from less than 1% to as high as 150% of normal (<0.01 to 1.50 units/ml of plasma). That encompasses the whole range from severe hemophilia (<1%) through moderate (1–5%) and mild hemophilia (5–40%) and the complete normal range of 50–150%. Thus, just based on factor levels, carriers can have anything from severe hemophilia to no bleeding problems at all.

The idea that women do not get hemophilia comes from the fact that most carriers still have one normal factor IX gene…. However, this reasoning is faulty because it doesn’t take into account a phenomenon that has only more recently become appreciated: X-inactivation.

No one knows why one carrier might have a factor level of 25%, for instance, and another might have a level of 150%. For persons without hemophilia, the actual level appears to depend on parameters such as blood type and body mass index, but those parameters do not seem to affect levels for men or women with hemophilia. One thing that does appear to cause the extremely low factor levels seen in some carriers is a phenomenon called skewed X chromosome inactivation (sometimes called extreme lyonization). Again, for reasons that are not well understood, the lyonization process may preferentially inactivate one of the X chromosomes. If the X chromosome that is inactivated in more cells is the one with the normal factor IX gene, the carrier will primarily produce defective or no factor IX. She will thus have a much lower level of normal factor IX in her blood than would be the case if the inactivation were 50-50.

Carriers with low factor IX levels bleed the same way and have the same kinds of problems as males who have hemophilia and similar factor levels. They are susceptible to easy bruising, joint damage, and bleeding problems after dental and surgical procedures, among other things. They can also develop inhibitors and target joints. In addition, some of these women have excessive menstrual bleeding, a tendency toward miscarriages, and excessive bleeding after giving birth. These are all issues that can be managed once it is accepted that they have a bleeding problem.

In the past, carriers who exhibit bleeding problems have been called “symptomatic” carriers. It is becoming more obvious that these women have hemophilia as shown not only by their bleeding symptoms but also by their genetics and factor levels.

Bleeding in carriers can also be due to other bleeding disorders. Just because a woman is a hemophilia carrier does not keep her from having other bleeding problems. Some carriers, for instance, might have von Willebrand Disease (vWD), which is much more prevalent in the general population than hemophilia. Many of the symptoms are similar between some types of vWD and hemophilia, so proper testing is important to establish the actual cause.

The nomenclature is also an issue. In the past, carriers who exhibit bleeding problems have often been called “symptomatic” carriers, as though they have bleeding symptoms but are somehow different from males with actual hemophilia. It is becoming more obvious that these women are not different. They have hemophilia as shown not only by their bleeding symptoms but also by their genetics and factor levels.

One recent study has shown that carriers tend to develop reduced range of motion (ROM) in their joints, just like males with hemophilia. This indicates that they have suffered joint damage, presumably from bleeding into the joints. The reduced ROM gets worse with age and in general is worse in proportion to the carrier’s factor level—the lower her factor level, the greater the reduction in ROM.

According to the usual criterion, people with factor levels above 40% aren’t considered to have hemophilia and don’t suffer joint damage. However, a couple of the carrier studies have noted that women with factor levels in the 40–60% range sometimes do have bleeding problems and joint damage. The reason for this is also unknown. Note that a similar occurrence can happen in men with hemophilia—the factor IX level does not always predict the severity of bleeding symptoms. For example, some men classified as severe because their factor level is below 1% bleed more like moderates, and some with mild or moderate levels bleed more severely. As above, the reasons are unknown.

With the recognition that carriers can have significant bleeding problems and suffer joint damage, it becomes more important to identify them, assess their bleeding tendency and offer them treatment, if needed. Several studies have shown that women with bleeding problems are usually identified later in life than men. Men with hemophilia are often identified soon after birth, while many women with hemophilia are not identified until their teens or later, depending on the severity of their condition. Also, because of the incorrect perception that their bleeding is not as serious, only 27% of females with severe hemophilia B are on prophylaxis, according to the UDC database.

Many HTCs offer carrier testing, but often not until a woman has reached adolescence. Since it is now known that joint damage can start to develop undetected at an early age, it would be beneficial to identify affected women early enough to help prevent those issues. Other reasons that it is beneficial for carriers to know their status include decisions about participation in sports, taking certain medications like aspirin, getting tattoos or piercings, and most of the other things that men with hemophilia need to consider. Iron deficiency anemia also appears to occur more frequently in carriers.

MORE AND BETTER INFORMATION NEEDED

The situation for women with hemophilia is slowly getting better, but there is still a lot of misinformation in the medical community. The Coalition for Hemophilia B, the Hemophilia Federation of America, and the National Hemophilia Foundation have all recognized that there are significant unmet needs among the women of the hemophilia community. A number of concerned medical professionals have also founded the Foundation for Women and Girls with Blood Disorders (FWGBD), which has a lot of useful information on its website. Hopefully, with their continued advocacy and leadership, women will be able to receive the care they need.