History of Hemophilia

 Although effective treatment has only become available in recent decades, hemophilia was known to the ancient world. The earliest written references to what appears to be hemophilia are encountered in Jewish texts of the second century AD. Rabbinical rulings exempted male boys from circumcision if two previous brothers had died of bleeding after the procedure.

The Jewish physician Moses Maimonides (1135-1204) applied this ruling to the sons of a woman who had married twice, thus apparently appreciating the hereditary nature of the condition. The Arabic physician Albucasis (1013-1106) also described a family where males died after trivial injury.

The first modern description of hemophilia is attributed to Dr. John Conrad Otto, a physician in Philadelphia, who in 1803 published a treatise entitled “An account of an hemorrhagic disposition existing in certain families.” He clearly appreciated the three cardinal features of hemophilia:an inherited tendency of males to bleed.

Otto traced back the pedigree of the family he studied to a woman who had settled near Plymouth, New Hampshire, in about 1720. However, the first use of the word “hemophilia” appears in an account of the condition written in 1828 by Hopff (“Über die haemophilie oder die erbliche Anlage zu todlichen Blutungen”), a pupil of Schönlein at the University of Zurich. Hemophilia B was only distinguished from the more common type in 1952, and is often referred to as “Christmas disease” after the surname of the first child reported with this condition.
Hemophilia is sometimes referred to as “the royal disease” because several members of noble families in Europe were affected by it. Queen Victoria had no ancestors with the condition but soon after the birth of her eighth child, Leopold, in 1853, it became evident that he had hemophilia. Queen Victoria was thus an example of how the condition can arise as a spontaneous mutation. Leopold died at the age of 31 from an intracerebral hemorrhage after a fall. Two of Queen Victoria”s own daughters, Alice and Beatrice, were also carriers of hemophilia. The condition was transmitted through them to several royal families in Europe, including Spain and Russia. Perhaps the most famous affected individual was the son of Tsar Nicholas II of Russia, Tsarevich Alexis, who was born in 1904. There has been speculation that the illness led to severe strain within the royal family, and enabled Rasputin to gain influence over the family, ultimately leading to the downfall of this once powerful dynasty.

Many reputable scientists claimed early success in treating with unusual substances. A report in The Lancet in 1936 extolled the virtues of a bromide extract of egg white. As recently as 1966, a report in the esteemed scientific journal Nature claimed that peanut flour was also effective for the treatment of hemophilia. The first hint of success came with the report from R.G. Macfarlane in 1934 that snake venoms could accelerate the clotting of haemophilic blood, and he reported success in controlling superficial bleeds in people with hemophilia after topical application.
Blood transfusion
However, the major advances came from developments in the field of blood transfusion. A report from a surgeon, Samuel Lane, in The Lancet in 1840 described the control of post-operative bleeding with fresh blood in a boy with severe hemophilia. However, a lack of understanding of blood groups and basic transfusion methods hindered further development at the time. The identification of factor VIII and the development of specific assays then permitted the subsequent development of therapeutic materials.

In the early 1950s, plasma from animals was used for treatment. While often effective, allergic reactions to these porcine and bovine materials were frequent and often severe. The work of Dr. Edwin Cohn in developing fractionation of plasma with variation of temperature and concentrations of saline and alcohol led to the development of fairly crude plasma concentrates of human factor VIII in a number of centres (“AHG” or “antihemophilic globulin”).
A truly major advance was the discovery by Dr. Judith Pool in 1965 that slow thawing of plasma to around 4°C led to the appearance of a brown sediment which was rich in factor VIII, which she called cryoprecipitate. Within a decade, lyophilized coagulation factor concentrates made an appearance. These offered considerable advantages: they could be stored in a domestic refrigerator at 4 oC, and permitted the administration of a large and assayed quantity of coagulation factor rapidly and in a small volume. The availability of such products facilitated home treatment, allowing patients for the first time to treat themselves at home, work, school, or even whilst on holiday abroad — freeing them from the physical and psychological Shackles of hemophilia.
However, we now recognise that this introduced the potential for the transmission of viruses. The impact of HIV was particularly devastating, with large numbers of patients around the world being infected in the period 1979-1985. The hepatitis C virus (HCV) was first identified in 1989, and it soon became clear that an even higher proportion of people with hemophilia had been exposed to this virus which results in chronic liver disease. Fortunately, the introduction of physical treatments of concentrates such as exposure to heat or the addition of a solvent-detergent mixture has effectively eliminated the risk of the transmission of these viruses. Another landmark was the recognition by Prof. Pier Mannucci in 1977 that desmopressin (DDAVP) could boost levels of both factor VIII and von Willebrand factor, and this remains a useful option in mild forms of these conditions.

The structure of the factor VIII gene was characterised and cloned in 1984. This led to the availability of recombinant (genetically engineered) factor VIII a decade later. The availability of safe products has stimulated the growth of prophylactic treatment, although it must be emphasized that the concept is certainly not new and was developed by Prof. Inga Marie Nilsson in Sweden in the 1950s.The rate of progress continues apace, and gene therapy is a realistic goal. However, we do not forget that many people with hemophilia around the world still receive absolutely no treatment. Perhaps the current position can best be expressed in words paraphrased from Sir Winston Churchill: this is not the end of our struggle to conquer hemophilia, and not even the beginning of the end. However, we can at least say that this is the end of the beginning of our campaign.