In Rare Disease Advisor, we cover a wide range of diseases that are scattered across the scale of severity. Some diseases allow patients to live with a broad sense of normality; others place a profound disease burden on patients.
Many of our articles here discuss emerging therapies and breakthroughs that have the potential to make a tremendously positive impact on the lives of our patients. However, sometimes it is also worth looking back at the progress we have made on certain diseases that were once without a single disease-modifying therapy.
Pier Mannuccio Mannucci from the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy wrote a paper titled “Hemophilia therapy: the future has begun” that was published in Haematologica. His paper was a celebration of the astonishing progress we have made in the field of hemophilia therapies in the last few decades alone. Viewed through the wide lens of history, it is indeed remarkable that a once life-threatening disease that was without a cure for centuries could make so much progress in such a short time.
Read more about hemophilia epidemiology
Many of us doctors are unfamiliar with the history of medicine as it relates to certain diseases. This should not come as a surprise since it is rarely emphasized in medical education. However, sometimes a brief review of the therapeutic advancements of a disease can inspire hope on just how much can change in a matter of decades. In this article, we will look at the history of therapeutic progress in hemophilia, which only began in earnest in the 1960s.
Hemophilia Treatment Over Time
Hemophilia, in the absence of treatment, is a devastating disease. It causes spontaneous bleeding in the joints and muscles that can cause severe damage in the long run. In cases of trauma, patients can expect to have prolonged, uncontrollable bleeding that is incredibly painful and potentially life-threatening. In addition, bleeding can occur without the patient being aware of it, thus resulting in situations where prolonged bleeding has taken place before the patient realizes anything is wrong.
A century ago, there was no treatment available for hemophilia. Life expectancy was between 10 and 15 years at best. The patients that survived beyond that tended to suffer from musculoskeletal injuries that severely limited mobility. Analgesia and splinting were the only therapy options to alleviate pain and symptoms associated with bleeding. In other words, it was a rare and deadly disease.
World War II triggered the improved preparation of plasma (containing all clotting factors), which was a significant step in developing more targeted therapies for hemophilia. This was much better than whole blood, which was the only treatment approach available at the time but was known for its poor clinical efficacy. Well into the 1960s, the life expectancy of hemophilia patients ticked upwards only slightly to no more than 20 to 30 years.
In 1964, it was discovered that the cryoprecipitation of fresh frozen plasma could be used to concentrate factor VIII (FVIII) and other coagulation factors in the pellet. This was a significant breakthrough, although it was not until freeze-dried plasma concentrates of FVIII for hemophilia A and other coagulation factors were commercially produced on an industrial scale that the tide began to turn. The main advantage to these commercially available products was that they came in small amounts of fluid that could be easily stored in a refrigerator, unlike whole blood. This meant that patients could administer self-care and home treatment.
In the 1980s, blood-borne viral infections like HIV/AIDS and hepatitis began to come under the spotlight, which triggered additional research into blood-related disorders, including hemophilia. In the 1990s, the therapeutic development of coagulation factors VIII and IX began, which coincided with an emphasis on virucidal or virus-removing precautions in the manufacturing process of blood products, making plasma-derived coagulation products safer.
Read more about hemophilia etiology
As hemophilia treatment became safer and more widely available, researchers began to turn their attention to the bane of hemophilia therapeutics: the development of alloantibodies that make patients refractory to replacement therapy, which results in the coagulant activity contained in FVIII replacement products being neutralized by specific inhibitors. In the late 1990s, plasma concentrates of activated factors of the prothrombin complex and the production of activated factor VII by recombinant DNA technology became available. Importantly, researchers discovered that inhibitory alloantibodies could be mostly eradicated by inducing immune tolerance through the long-lasting administration of large doses of plasma-derived or recombinant FVIII products.
It was in the late 1990s that hemophilia treatment as we understand it today began to take shape. The purity of recombinant factor products was constantly being improved. Life expectancy increased dramatically, reaching figures very close to that of men in the general population without hemophilia.
The medical advancements made in hemophilia are all the more astonishing when compared to its progress against other monogenic diseases, such as thalassemia, cystic fibrosis, and muscular dystrophy, and the progress in hemophilia treatment has not stopped. Today, hemophilia care has moved into the prophylactic space. Nonfactor therapies are being developed to fill the gaps in hemophilia treatment. Gene therapy is being explored as an option to permanently cure hemophilia at its very roots.
Slowly, Then Suddenly
The history of hemophilia shows how a disease once regarded with hopelessness and gloom can turn into one in which routine treatment is available and life expectancy is close to normal—all in a matter of decades.
Attention now turns towards poorer countries that still do not have access to the latest advancements in hemophilia care. Mannucci ended his study with an appeal to action, writing that “despite great progress in medium-income countries, the great majority of low-income countries are still in the same situation they were in 100 years ago: ice, splinting, bed rest, and blood transfusions.”
It is our moral obligation to ensure that people everywhere can gain access to life-saving hemophilia therapies. By doing so, we will finally be able to consign the intolerable pain and agony of untreated hemophilia to the dustbin of history.
Mannucci PM. Hemophilia therapy: the future has begun. Haematologica. 2020;105(3):545-553. doi:10.3324/haematol.2019.232132
Saxena K. Barriers and perceived limitations to early treatment of hemophilia. J Blood Med. 2013;4:49-56. doi:10.2147/JBM.S43734