Hemophilia Research News

By Dr. David Clark

Results from 11,341 Subjects Enrolled in My Life, Our Future

6/29/22

Many of you signed up to have your factor IX gene sequenced under the My Life, Our Future (MLOF) program. In fact, out of the 11,341 subjects, 2361 have hemophilia B, including three with both A and B. This is about one-fifth (20.8%) of the total number of subjects, which is consistent with the overall prevalence of hemophilia A and B. For hemophilia B, there were 1616 males (68.4%), 742 females (31.4%) and two transgender people who had transitioned from male to female. Ages ranged from less than two years (5.0%) to 65 and over (3.9%), with the largest segment in the 20 - 44 age range (35.5%).

In 2012, only about 20% of hemophilia patients had been genotyped, that is, had the sequences of their factor VIII or IX genes determined. MLOF, which ran from 2013 to 2017, significantly increased that proportion. In 2016, the program was opened to carriers, so a fairly large group of women was also included. Subjects enrolled through their HTCs, giving permission to MLOF to access their medical records and providing a sample for genotyping.

The subjects were also given the opportunity to give a blood sample to the Research Repository for future studies, which about 80% of subjects did. The medical data were connected to the patient’s gene sequence, but all of the data were de-identified to protect patient privacy. All participants had both their factor VIII and factor IX genes sequenced.

The study found 431 unique factor IX gene mutations, 134 of which were novel, that is, they hadn’t been seen before. They found that about 1.9% of Bs did not appear to have any mutation. All of those with no mutation were milds and moderates. Mutations were found in all subjects with severe disease.

The lack of an identifiable mutation suggests that these people’s hemophilia is not caused by an issue with their factor IX. It could be caused by problems in the vitamin K-dependent processing of the factor IX protein, which is essential for clotting activity, or it could be a result of problems with other proteins with which factor IX interacts. For instance, see the article in this issue on Ehlers-Danlos syndrome, where factor IX can’t bind to collagen because of a problem with the collagen, not the factor IX.

More than one mutation was identified in 95 patients, including 36 female patients. Because they sequenced both the factor VIII and IX genes of each subject, they were able to identify a number of benign mutations, mutations that don’t cause disease. For instance, all the Bs had their factor VIII gene sequenced and a number of variants were found in those genes that did not appear to be harmful. Vice versa for the As who had their factor IX genes sequenced.

The study focused a lot on inhibitors, which are a big problem in hemophilia A. Fewer hemophilia B patients develop inhibitors, but when they do, the issues can be more severe. In hemophilia B, about 12% of severes had a history of inhibitors but only 1.9% of milds and moderates. Overall for all severities about 5.7% of Bs developed inhibitors. This is much higher than the UDC study from 1998 to 2011, which found an inhibitor rate of only 1.3% for Bs. The MLOF result is probably more accurate since it came from a much larger sample size.

They also looked at inhibitor development according to ethnicity and race. For hemophilia B, they found that Blacks have the highest incidence with 13.1% developing an inhibitor, while whites have an incidence of 4.9%. They also looked at Asians, American or Alaskan natives, Hawaiians and other Pacific Islanders and mixed races, but the numbers of patients were too small to show significant differences. For ethnicity, they looked at Hispanic (9.9% incidence) versus non-Hispanic (5.1%). The reasons for these differences are unknown.

The complete study article can be downloaded for free by Googling “DOI:10.1111/jth.15805”, which will take you to the article referenced below. If you want to play around with the results yourself, scroll down to the bottom of the web page where you can download a supplementary Excel file containing all the data. [Johnsen JM, et al., J. Thromb. Haemost., 20:2022-2034 (2022)]

Study on the Use of Pain, Depression and Anxiety Drugs in Hemophilia

1/31/23

A recent study looked at pain, depression and anxiety in hemophilia in Nordic countries by analyzing their use of medication. Pain has been widely studied in hemophilia, but anxiety and depression much less so. The government healthcare systems in those countries make this much easier because all of the patient data is centralized in registries, unlike the U.S. They divided 3246 hemophilia patients (596 Bs, with or without inhibitors) into groups by factor consumption. For hemophilia B, the three groups were moderate-to-high (MTH) factor consumption (≥10 IU/kg/week), low factor consumption (LFC) and women.

The study found that overall, hemophilia patients used more pain, depression and anxiety medications than the controls (the general population without hemophilia). This was most accentuated in the MTH group, but also in males in the LFC group and in women. Opioid use in the MTH group was 4 - 6 times greater than in the controls, and 2 - 4 times greater in the LFC group, across all age groups. The researchers conclude that this “suggests a need for improved bleed protection and hemophilia care for all severities, including mild hemophilia.” [Carlsson KS, et al., Res. Pract. Thromb. Haemost., 7(2):100061 (2023)]

Thrombin Generation as an Indication of Hemophilia Severity

2/1/23

We often divide hemophilia patients into categories of severe, moderate and mild based on their level of clotting factor. However, in about 15% of patients, their bleeding behavior doesn’t fit their category. We need a better system.

A group of researchers in The Netherlands have proposed that a thrombin generation assay (TGA), rather than a factor assay would be a better way to characterize patient’s disorders. Thrombin (factor IIa) is the final enzyme produced by the clotting system. It converts fibrinogen (factor I) to fibrin, a protein that sticks to itself to form the clot. Everything that happens in the clotting system upstream of thrombin formation just determines how much thrombin will be made, and thus, how much of a clot will be formed.

The study looked at 446 patients with hemophilia (35 Bs), measuring their levels of thrombin generation compared to their factor levels and bleeding characteristics. They found that thrombin generation did indeed appear to be a better predictor of bleeding than did factor level.

Measuring thrombin generation is not a new idea. The problem is that TGAs are very difficult assays to run. The results vary from lab to lab and are not very reproducible. However, one of the researchers in the study is also the Chief Science Officer of Enzyre, a Dutch company that, in collaboration with Takeda, is developing a small device that could allow people with hemophilia to test their clotting status at home from a drop of blood. They have developed proprietary compounds that react with thrombin and emit light in proportion to the thrombin level. The device could help patients more precisely determine the amount of factor they need at any given time. [Verhagen MJA, et al., Res. Pract. Thromb. Haemost., 7(2):100062 (2023)]

No Difference in Quality of Life between Hemophilia A and B

2/15/23

Periodically, we see reports comparing hemophilia A and B. For scientists, that could be important for figuring out the basics of the two diseases. For the community, however, these differences sometimes seem to lead to “bragging rights.” I’ve overheard As saying to Bs things like “we have it much worse than you Bs…”. That always makes me laugh. Does having a more severe disease make you the winner?

Anyway, the results of these studies are often mixed. As have it worse in some areas and Bs have it worse in others. In other cases, there does not seem to be a difference. That seems to be the case with quality of life, based on a study from The Netherlands. Using several different measures, they found that there is no statistically significant difference between the two groups. In both cases they found that joint health was a major factor. The worse your joints, the worse your quality of life.

The issue then became, not a difference between As and Bs, but the fact that both groups, even with prophylaxis, had diminished quality of life. We’ve seen this kind of finding as a byproduct from a number of recent studies. We still have a way to go before all people with hemophilia can lead normal lives. [Kihlberg K, et al., Haemophilia, online ahead of print 2/15/23]