Hemophilia A
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Mortality. It is a word littered across medical literature; it lurks in clinical reports, epidemiological papers, and case presentations. It is also an indispensable parameter when it comes to evaluating the lethality of a disease, the promise of a new drug, or a patient’s response to a newly introduced medical intervention. 

In other words, mortality is something we have come to both dread and expect in clinical practice. In order to formulate a robust response to an illness, we need to understand how it kills, and how well. Hence, mortality figures are something we must brace ourselves to confront—again and again. 

Hemophilia A is one disease that has had a tortured relationship with mortality. Before blood transfusions were routinely available in medical practice, hemophilia A carried a high mortality rate, as affected boys (most of whom were active and prone to cuts and bruises) did not tend to survive past childhood.


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In the 1960s, a significant breakthrough occurred: scientists were able to isolate factor VIII (FVIII) from blood plasma. However, when the HIV epidemic occurred in the 1980s, blood transfusion safety protocols were still far behind what they are today, causing many patients with hemophilia A to become unintentionally infected through contaminated blood products. In the US, some estimates place the figure around 5000. 

However, if we were to draw a graph of the life expectancy of patients with hemophilia A over the last few decades, it would show a line climbing steadily upwards. So just where are we with regards to mortality rates of patients with hemophilia A? This is the subject of a paper by Hay and colleagues, which we will be reviewing in this article. 

Still a Deadly Disease 

Hay et al set out to study data on patients with hemophilia A, both those with and without FVIII inhibitors. Their research yielded some interesting results. Here are some of their discoveries: 

  • Studies consistently indicate that mortality rates of hemophilia patients have decreased over the last few decades.
  • A Swedish study demonstrated that patients with hemophilia had higher mortality rates compared to the control group, regardless of HIV/hepatitis C/hepatitis B infection. 
  • Among the most common causes of death were the presence of FVIII inhibitors and severe disease. 
  • A study reported that hemophilia A patients who had FVIII inhibitors had an all-cause mortality rate that was 5.6 times higher than among those without FVIII inhibitors. 
  • Severe hemophilia A was correlated with higher mortality rates, compared with milder forms of the disease. 
  • Compared to the general population, a study showed that patients with severe hemophilia (without HIV) had a higher mortality rate by a factor of 2.7.

Hay and colleagues encountered a few notable difficulties when studying mortality rates among patients with hemophilia A. First, many studies reported small sample sizes, and mortality reports from nationwide registries did not necessarily have rigorous quality check protocols in place. Second, many studies were not conducted over a sufficiently long period of time for changes in mortality rates to be observed. Third, the way in which the causes of death among patients with hemophilia A were reported was inconsistent. 

Read more about hemophilia epidemiology 

“In conclusion, although there are a number of historic reports on mortality in patients with congenital hemophilia A, current evidence surrounding the mortality rates and causes of death among patients with congenital hemophilia A is disparate,” the team wrote. 

In the Context of Emicizumab 

Emicizumab is the first non-factor replacement therapy available for patients with hemophilia A. What difference has this medication made in terms of patient mortality? This is the subject of a study conducted by Peyvandi et al in their quest to establish the safety profile of emicizumab. 

To achieve their objective, they applied an algorithm to categorize fatal events contemporaneous to emicizumab using data from the Roche Emicizumab Global Safety Database. Using this methodology (and a cut-off date of May 15, 2020), they found 31 deaths of patients with hemophilia A who were on emicizumab. 

Read more about hemophilia treatment 

Of the 31, 15 were determined to be associated with hemophilia A. The largest related category was hemorrhage (n=11), three were related to HIV/HCV, and one was related to hepatic causes. No death was categorized as being thrombotic in origin. 

The research team concluded that their research “demonstrates an absence of unique mortality risks associated with the administration of emicizumab prophylaxis in patients with hemophilia A.” This means that as far as their data demonstrated, emicizumab has an acceptable safety profile.

Future Considerations

Whenever we track mortality rates for the purpose of generating clinical data, we need to be wary of our own biases and wean ourselves off from relying on anecdotal evidence. Combined, large-scale literature reviews (such as those conducted by Hay et al), as well as clinical studies (such as those conducted by Peyvandi et al), can give us a broad picture of the reality behind the numbers.

Peyvandi and colleagues ended their study with a suggestion on how future research should be conducted: “In rare diseases such as hemophilia A, isolated reports of fatalities are not useful for a broad understanding of safety; rather, a framework must be applied prospectively to consistently track trends over time and enable comparisons across treatments.”

References

Hay CRM, Nissen F, Pipe SW, et al. Mortality in congenital hemophilia A – a systematic literature review. J Thromb Haemost. Published online December 16, 2020. doi:10.1111/jth.15189

Peyvandi F, Mahlangu JN, Pipe SW, et al. Application of a hemophilia mortality framework to the Emicizumab Global Safety DatabaseJ Thromb Haemost. Published online December 16, 2020. doi:10.1111/jth.15187