The History of Hemophilia B

Hemophilia has an ancient history. The earliest written reference to hemophilia may be that found in the Mishneh Torah, a second century compilation of Jewish law. There it states that if a mother has had two sons circumcised who both died as a result, then a third son must not be circumcised. Although it does not specifically state that the deaths were due to bleeding, other sections of these writings do refer to “loose” blood.

Another early reference is the legend of the Curse of Tenna. In 1769 a judge in the small Swiss village of Tenna condemned an innocent man to death. The legend states that this act led to the inflicting of a curse upon the judge and his family. This curse was believed by the citizens of Tenna to be the cause of a serious bleeding disorder, sometimes leading to bleeding to death, which afflicted the family for generations. This was, in fact, a family with hereditary hemophilia, the oldest and largest such family ever described comprising 3072 members, 55 who had hemophilia. It turns out that the family disease is hemophilia B rather than the more common hemophilia A.

An early medical account published in 1803 correctly described the disease as one which affects males but is transmitted by females. In fact, the early passage from the Jewish Torah goes on to say that “…additionally, the sons of the woman’s sister should not be circumcised, but the sons of her brother can be circumcised. Remarkably, it was not until 1865 that Mendel reported the laws of genetic inheritance and not until the early 1900s that such diseases were discovered to be carried by the X chromosome, and thus affect only males.

Queen Victoria of England (1837-1901) was a carrier of the disease who passed it on to her son Prince Leopold. Two of her daughters were also carriers who passed the disease on to a number of their descendants in the royal families of Russia, Spain and Germany.

However, it was not until the early 1950s that hemophilia A and hemophilia B were recognized as separate diseases. Both diseases have identical symptoms, so it was very difficult to distinguish between them.

Since that time, the history of hemophilia B has followed the development of the factor IX products used to treat the disease. Until the late 1950s serum, and later plasma, were the only treatments available. Then in 1959 the first purified factor IX concentrate derived from plasma was developed in France. This was followed by the development of similar concentrates in Britain and the U.S. The first factor IX product in the U.S. was licensed in 1969.

The early products became known as Factor IX Complex concentrates. The word “complex” in the name refers to the fact that in addition to factor IX, these products also contain several related clotting factors such as factor II, factor X, and in some cases factor VII. Because of the similar properties of these factors, it is difficult to purify factor IX away from the others.

The availability of Factor IX Complex and its effectiveness in treating bleeding episodes significantly improved the health and well-being of hemophilia B patients. The use of Factor IX Complex, however, soon became associated with thromboembolic complications — that is, unwanted, and potentially life-threatening internal clotting. This happened most often when the product was used in large amounts for extended periods of time, for instance in hemophilia B patients undergoing surgery. To eliminate this problem, more highly purified products containing only factor IX were developed with the first one being licensed in the U.S. in 1990.

Another serious complication of the use of factor IX products purified from human plasma is the potential for transmission of infectious diseases. Until the mid-1980s, people receiving factor IX products routinely became infected with hepatitis and other diseases. At the time, it was thought that this was an unfortunate but unavoidable consequence of this valuable therapy. However, then AIDS came along in the early 1980s, and one of the groups most affected was people with hemophilia and their families. This led to the rapid development of a number of methods for inactivating viruses in plasma products. Viral inactivation or removal methods have improved significantly since then to the point that now plasma products have an extremely low risk of disease transmission. Finally, in 1997, the first recombinant factor IX product was licensed in the U.S. Since recombinant products are not made from plasma, they do not carry the risk of transmission of human diseases.

Today, hemophilia B patients are treated with high-purity plasma-derived or recombinant factor IX concentrates. Advances in treatment methods, such as prophylaxis, have led to essentially normal longevity and a much higher quality of life. Newer recombinant products, new delivery methods, and FDA-approved clinical trials of gene therapy for hemophilia B are under way that may further alter treatment options and improve quality of life.