Hemophilia Landscape Updates
Spring 2025
By Dr. David Clark
Real-World Unmet Needs of Hemophilia Patients
5/5/25: The explorer6 study was set up by Novo Nordisk to collect information about the current state of hemophilia patients around the world. Novo used the data as a comparison baseline for their Phase III study of concizumab (now Alhemo), but it also gives the community some reliable information about the experiences of hemophilia A and B patients, with or without inhibitors, in today’s world. A group of the explorer6 researchers recently published the findings.
During the study, the participants maintained whatever treatment regimens they had been on, either prophylaxis or on-demand treatment. They had 72 hemophilia B subjects without inhibitors (19 on-demand; 53 on prophylaxis) who had factor IX levels up to 2% plus 31 B inhibitor patients of any severity (14 on-demand; 17 on prophylaxis). They intentionally increased the number of inhibitor patients in the study because a random selection would have resulted in very few B inhibitor patients. One of Novo’s primary aims in developing Alhemo was to develop better treatments for inhibitor patients.
The average annualized bleeding rates (ABRs) for the non-inhibitor hemophilia B patients was 2.2 for prophylaxis and 10.5 for on-demand treatment. The average ABRs for the hemophilia B patients with inhibitors was 12.4 for prophylaxis and 9.3 for on-demand treatment. These results agree with the idea that prophylaxis is far superior to on-demand treatment for non-inhibitor patients. Interestingly, though, the on-demand inhibitor patients had a lower average ABR than those on prophylaxis. For comparison, the averages for the hemophilia A patients were 4.7 and 21.5, respectively, for non-inhibitor patients for prophylaxis and on-demand treatment. For the A inhibitor patients, the ABRs were 10.3 and 15.2, respectively.
The authors also looked at physical activity and joint health. As expected, physical activity scores were lowest for the hemophilia B patients with inhibitors. About two-thirds of the non-inhibitor patients on prophylaxis reported engaging in sports activities. Joint scores were similar among the various hemophilia types and treatments, but overall scores were lower (better) for those on prophylaxis. The results show that the greatest unmet needs are for patients with inhibitors and those using on-demand treatment. [Wheeler AP et al., Haemophilia, online ahead of print 5/5/25]
Less Bleeding in Hemophilia B Patients on EHL Prophylaxis
2/14/25: Current information on bleeding in patients with severe hemophilia B who are on prophylaxis is scattered and inconsistent. A group of Italian researchers performed a systematic literature review and meta-analysis to better understand their outcomes. Starting from 2440 possible studies, they winnowed the group down to 42 studies that contained good information on bleeding in patients with severe hemophilia B. Meta-analysis is a statistical method to pool results from a number of independent studies to produce a better overall picture of a question than any of the single studies can provide.
They looked at ABRs for patients on prophylaxis with either standard half-life (SHL) factor IX products or extended half-life (EHL) products. EHL products were originally developed with the aim of reducing the burden of infusions, but their most important benefit has been the ability to maintain higher factor IX levels between infusions. The authors found a significantly lower average ABR of 1.29 for patients on EHL products compared to an ABR of 3.12 for those on SHL products. They also found that 53% of patients on EHL products had zero bleeding events compared with 24% of those on SHL products. In a subgroup analysis, they found no significant difference in ABRs according to age. Thus, EHL products appear to offer more bleed protection than SHL products, along with less-frequent dosing. [Franchini M et al., Haemophilia, online ahead of print 2/14/25]
Non-Inhibitor Antibodies May Affect Hemophilia Severity
10/28/24: Some patients develop neutralizing antibodies (NAs) against infused factor VIII or IX. NAs bind to the factor molecules and interfere with (neutralize) their activity, preventing them from working properly. In the hemophilia world, NAs are called “inhibitors.” Patients with inhibitors have an especially difficult time with their hemophilia because typical factor replacement products for their type of hemophilia don’t work for them. We know that the immune system also produces non-neutralizing antibodies (NNAs). NNAs also bind to factor molecules but don’t interfere with their activity – or at least we’ve always thought so.
A group from Scandinavia looked at NNAs in moderate A and B patients in their treatment centers and found some surprising results. In a study of 137 subjects, they found NNAs in 13% of their A patients and also in 13% of their Bs. The NNAs were found regardless of whether the patients were on prophylaxis or on-demand treatment and regardless of their baseline factor level. Most often the NNAs appeared after about 150 exposure-days to their product. All patients were negative for actual inhibitors.
Bleeding rates were similarly low in all patients, but joint health scores were significantly higher (worse) in the patients with NNAs. The NNA-positive patients also had undergone more frequent joint surgeries. This suggests that although NNAs don’t interfere directly with clotting behavior, they may be binding at locations on the factor molecules that are important for maintaining hemostasis in the joints. The authors recommend that these findings be followed up by larger, more in-depth studies. [Maseide RJ et al., Res Pract Thromb Haemost, online ahead of print 10/28/24]
Infants with Hemophilia Lag in Gross Motor Development
1/27/25: Infants with hemophilia have difficulty with full motor development (ability to move the body) compared with non-hemophilic infants. This is thought to be due to overprotection by the parents. A group from Greece looked at infants with hemophilia compared with non-hemophilic infants who had either partial- or full-term births. They used the Alberta Infant Motor Scale (AIMS), which rates 58 motor skills performed by an infant from birth to independent walking (19 months). The results were striking.
The full-term infants (39 weeks; Group A, 1068 babies) had normal scores on average, as expected. The partial-term infants who were born more than 32 weeks after conception (Group B, 150 babies) lagged significantly behind. The partial-term infants who were born 32 weeks or less after conception (Group C, 405 babies) lagged significantly behind group B. Finally, the infants with hemophilia (Group D, 15 full-term babies) lagged significantly behind Group C. The authors conclude: “Differences in AIMS scores could be attributed to the reduction of movement activity, since infants with haemophilia are often deprived of certain positions, being held and carried in the parents’ arms, as well as from free play time on the floor.” [Syrengelas D et al., Haemophilia, online ahead of print 1/27/25]
Spinal Stenosis May Be Part of Aging with Hemophilia
2/5/25: Spinal stenosis is a narrowing of the space in the backbone that the spinal cord runs through. This puts pressure on the nerves of the spinal cord, which can have effects ranging from no symptoms to debilitating pain. It is a common condition of aging affecting about 4% of the general population. At EAHAD, a group of Irish researchers presented what is thought to be the first study of spinal stenosis in hemophilia patients.
In a group of 100 males, 40 years or older, with moderate or severe hemophilia, the authors identified 13 (13%) subjects with spinal stenosis, over three times the rate in the general population. They saw no difference between the moderate and severe patients but did see an increase with age. The 40- to 59-year-old group had a rate of 3.5%; the 60- to 69-year-old group had a rate of 19.2%, and the over-70 age group had a rate of 35.3%. Interestingly, they saw no significant difference between the non-stenosis and stenosis patients according to the Hemophilia Joint Health Score (HJHS), which mainly measures the condition of the large joints, such as the ankle, knee and elbow. Therefore, the HJHS, which many patients receive during their annual exams, doesn’t appear to be useful for diagnosing spinal stenosis.
Although there was no significant difference in orthopedic surgeries between the two groups, the group with stenosis had a significantly older age at first surgery than the non-stenosis group. This might suggest that delaying joint surgeries may promote stenosis because the patient may be putting more stress on the back trying to limp along on bad joints.
One question this brings up is whether this has anything to do with bleeding into the joints between the vertebrae in the back. That hasn’t been studied in hemophilia, but it’s possible that a lifetime of subclinical (micro) bleeds in the spine could cause damage that leads to stenosis. In the general population, arthritis is a known risk factor for spinal stenosis. Hemarthrosis, which is caused by bleeding into the joints in hemophilia, has many similar characteristics to arthritis. It could similarly be a risk factor for stenosis.
This could be one more of the conditions that we’re going to have to deal with as the hemophilia population ages. [European Association for Haemophilia and Allied Disorders (EAHAD) annual meeting, February 4–7, 2025, abstract PO036]
Bone Health in Hemophilia Patients
Several recent studies have looked at bone health in hemophilia patients. Both hemophilia A and B are associated with reduced bone mineral density (BMD). However, the reasons for this are not well studied and neither are the consequences. Until the 1970s, hemophilia patients were discouraged from physical activity due to concerns about increased bleeding risk. However, with today’s plethora of treatment options making it possible, we now know that physical activity is absolutely indispensable both for general health and for minimizing joint bleeding.
3/18/25: One question is whether reduced BMD increases the risk of fractures in hemophilia patients. A group of researchers from Greece did a comprehensive review and meta-analysis of past studies. In 18 studies spanning 2007 to 2022, which included 13,221 subjects, they found that people with hemophilia had a 4.56 times greater risk of fracture than the general population. [Divaris E et al., Haemophilia, online ahead of print 3/18/25]
3/26/25: We know that regular physical activity helps to strengthen the muscles around the joints and minimize joint bleeds. A group from Germany looked at the effects of physical activity on bone and muscle health in terms of handgrip strength and hemophilia severity. Handgrip strength is a good indication of overall muscle strength. Interestingly, they found that physical activity levels do not vary significantly across the three hemophilia severities. That’s actually not good news since patients of all severities only performed low-intensity activity, which is probably not enough to improve BMD. Handgrip strength was positively correlated with improved BMD, bone health and muscle mass. [Ransmann P et al., PLoS ONE, online ahead of print 3/26/25]
3/21/25: Kinesiophobia, literally the fear of movement, refers to an excessive and irrational fear of performing physical movements due to a perceived vulnerability to painful injury or re-injury. As mentioned above, until the 1970s, kinesiophobia was actually encouraged in hemophilia patients. A group from Turkey looked at kinesiophobia in terms of hemophilia management. They found that treatment adherence and physical activity tended to reduce kinesiophobia.
That physical activity reduces kinesiophobia, the fear of physical activity, may seem somewhat circular, but it reflects the opposite situation, which is that avoidance of physical activity can start a downward spiral in which avoidance of something tends to make us more afraid of that something. It has been understood in human psychology for decades that the best way to change a person’s attitude is to change their behavior. [Akan DC et al., Haemophilia, online ahead of print 3/21/25]
3/7/25: Despite the apparent importance of bone health for people with hemophilia, a study by U.S. researchers shows that screening of bone health is not consistently performed at U.S. Hemophilia Treatment Centers (HTCs). With responses from 66 of the 147 current HTCs, they found that only 21 HTCs (31.8%) routinely screened for vitamin D deficiency and only nine (13.6%) regularly performed dual-energy X-ray absorptiometry (DEXA) scans on their patients. Vitamin D is important for bone health and studies have shown that not only hemophilia patients (see below), but also the general population, tend to have low vitamin D levels. A DEXA scan measures bone density by determining how much x-ray energy is blocked by the minerals in the bones. The more blockage, the higher the BMD. The authors emphasize the need for standardized screening guidelines for bone health among all the HTCs. [Citla-Sridhar D et al., Haemophilia, online ahead of print 3/7/25]
3/6/25: Another group from Turkey looked at bone health in 62 hemophilia patients at their center. They looked at DEXA scans as well as various chemical markers like vitamin D levels and calcium levels. The study included 42 (67.7%) patients with severe hemophilia, 13 (21%) moderates, and seven (11.3%) milds. A total of 85.5% were on prophylaxis and 75.4% had a target joint.
They found that 75% of the subjects had a vitamin D deficiency and 62.9% had a lower-than-normal BMD. Among the chemical markers, they found that the ratio of parathyroid hormone (PTH) level to calcium level (PTH/Ca) correlated well with BMD. Thus, the PTH/Ca ratio may be an accessible cost-effective and practical test for BMD in hemophilia patients. [Ersal T et al., Diagnostics, 15, 638 (2025)]
One final comment… There may be an interplay between physical activity and vitamin D. Our bodies make vitamin D in response to sun exposure. The lack of physical activity may mean that hemophilia patients are also not spending as much time outside in the sun. Although nowadays people can take vitamin D supplements and many exercise indoors, a prescription for good bones might be to “go play in the sun” (with sunscreen, of course).
Iron Deficiency in Women with Bleeding Disorders
3/18/25: Iron deficiency is an under-diagnosed, under-appreciated concern for many women and girls with bleeding disorders (WGBD). Physical effects of iron deficiency include reduced exercise capacity and performance, fatigue, alopecia, and restless legs. It has also been linked to anxiety and depression. In school-age children, it is linked to poor school performance and cognitive difficulties. During pregnancy, it is associated with higher rates of miscarriage, postpartum depression, and suboptimal brain development in the fetus. Women with heavy menstrual bleeding (HMB) are at greater risk for iron deficiency. One study found that 87.5% of adolescent females with HMB had low iron levels. In spite of all this, there are no specific recommendations for screening WGBDs for iron deficiency.
A group of U.S. researchers looked in more depth at iron deficiency in WGBD. They found that only 70% of HTCs routinely screened female patients for iron levels. Only 3.6% of the patients in the ATHN data set had been tested for iron deficiency, even though 71.9% of those tested were iron deficient. They also found that Black or African-American women, women with platelet disorders, and women with HMB were most at risk.
Another issue is that many WGBD are only tested using CBC (complete blood count) and/or hemoglobin assays, which may miss an iron deficiency. They found that 41.7% of WGBD who were not anemic, had iron deficiencies that would only have been identified with more extensive testing. Finally, they found that many physicians are not up-to-date on the best methods for iron supplementation, which have been changing. Interestingly, recent studies have shown that every-other-day dosing may improve iron absorption in women compared with daily dosing. [McCormack M et al., Haemophilia, online ahead of print 3/18/25]
Lick Your Wounds!
12/19/24: When you cut yourself, do you feel a compulsion to lick the wound? Do it! Recent research has shown that saliva contains tiny particles that promote clotting. Extracellular vesicles (EVs) are tiny, hollow particles that cells release to communicate with other cells. EVs may contain proteins, nucleic acids (the building blocks for DNA and RNA) and other molecules. A European group has recently shown that some EVs in saliva contain tissue factor and factor VII, which together activate factor X to promote clotting. Factor VII activation of factor X is the first step in the normal clotting cascade, and it is independent of factor VIII or IX. That’s one of the reasons that inhibitor patients are given activated factor VII (tissue factor activates factor VII) to treat bleeds, when they can’t take factor VIII or IX.
An earlier study by some of the same researchers showed that pro-coagulant EVs are also present in human milk, urine, semen, and amniotic fluid. The reasons they are there are currently unknown, but don’t let that stop you. We seem to have an instinctual desire to lick our wounds, and now we know why. [Thaler J et al., Blood, 144(25) 2666-2677, 2024]