History of hemophilia
The earliest written references to what may have been human hemophilia are attributed to Jewish writings of the 2nd century AD. A ruling of Rabbi Judah the Patriarch exempts a woman's third son from being circumcised if his two elder brothers had died of bleeding after circumcision. And Rabbi Simon ben Gamaliel forbade a boy to be circumcised because the sons of his mother's three sisters had died after circumcision. There are subsequent similar historical references. These features of fatal bleeding after minor surgery in brothers or in maternally related boy cousins are characteristic of what we nowadays call hemophilia.
The first descriptions which we may say probably do refer to hemophilia are from the end of the 18th century. Authors of that period described families in which males suffered abnormally prolonged post-traumatic bleeding. For example, there is a story of a family in which six brothers bled to death after minor injuries. However, their half-siblings (by a different mother) were unaffected. It was noticed that, although only males showed the symptoms, the disorder was transmitted by apparently unaffected females to a proportion of their sons.
These accounts began to define a clinical syndrome on which the 19th century developed an extensive literature. Various long names were use: haemorrhoea, idiosyncrasia, haemorrhagica, haematophilia, hereditary haemorrhagic diathesis, until a rather strange name occurred, hemophilia, which means love of blood. It appeared in a famous treatise of 1828. The involvement of joints, to us the most characteristic symptom of hemophilia, was described in detail later, in 1890. This had earlier been confused with tuberculous, rheumatic, and other types of arthritis.
Queen Victoria and Alexis, her great-grandson
Queen Victoria cannot be left out of the history of hemophilia. She became queen of England at the age of 18, but there was a part of her heritage which she could not know until after the birth of her eighth child, 16 years later, Leopold, Duke of Albany, who had hemophilia.
Alexis was born in 1904, son of Alexandra (grand-daughter of Queen Victoria) and Tsar Nicholas II of Russia. He is presumably the world's most famous child with hemophilia. Romanovs’ anguish and despair forced Alexis’ parents to call for innumerable doctors with diverse treatments until they met Rasputin, a legendary character that could control the child’s pain and whose influence on both private and public affairs increased inordinately and contributed to the fall of the Romanovs.
In the laboratory
At the beginning of the 19th century, some scientists were convinced that the essential defect in the person with hemophilia was a “toughness” of the platelets, preventing their breakdown and the liberation of thromboplastin, a substance that in the right conditions can aid the conversion of prothrombin to thrombin, key element in the clotting process. Later, other researchers showed that normal platelets added to plasma from people with hemophilia did not shorten the clotting time, and that platelets from people with hemophilia worked normally in normal plasma. Apparently that was not the root of the problem.
Meanwhile another line of study had developed. In Edinburgh, it had been shown that the addition of a small proportion of a prothrombin preparation made from normal blood would markedly correct the prolonged clotting time of blood from a person with hemophilia.
Twenty years later, in Belgium, it was proved it was not really the prothrombin. And five years later, at Harvard, researchers re-examined the fraction precipitated from normal plasma and called that “globulin”. They confirmed that a small proportion would markedly correct the clotting time of blood from a person with hemophilia. Later, this fraction was called “anti-hemophilic globulin”.
To avoid confusion with other names, we now call it factor VIII, the Roman numeral by which this clotting factor has been designated by international agreement. We could therefore think of hemophilia simply as a sex-linked, recessive coagulation disorder due to a deficiency of factor VIII. However, there has been yet another twist in the course of events.
There is another important distinction to be made from hemophilia, which illustrates an alternative approach to the definition. Suppose two blood samples show a long clotting time, and when they are mixed together the clotting time shortens; then it may be inferred that they have different defects, because each has supplied something which the other lacked. If, on the other hand, they do not correct each other like this, but are nevertheless each corrected by blood from a person without hemophilia, then they have the same defect.
In 1944, Alfredo Pavlovsky, a world-renowned Argentinian hematologist described mutual correction on mixing the blood of two people with hemophilia. It has revealed then a condition that is clinically and genetically similar to hemophilia A, but caused by a different defect: now we know that factor IX is what was missing. In the British literature it was known as Christmas disease, named after the first diagnosed patient in Europe, Stephen Christmas. Nowadays we call it hemophilia B.
The treatment of hemophilia
One of the first treatments to be based on sound experimental work was the topical application of coagulant snake venom. In 1973 an essay proved that the venom of Russell's viper clotted a person with hemophilia’s blood rapidly when diluted in the blood up to 1 in 1,000,000 and so was eminently suitable as a local application, for which it has been much used.
The key to modem treatment was of course the development of blood transfusion. By 1938, researchers had appreciated that only blood transfusion offered effective treatment for a bleeding episode, no doubt by replacing temporarily a missing essential component.
Preparations of human factor VIII were developed in the 1950s in Britain, France and Sweden. During that time, concentrates from animal blood were also prepared. Experience was gradually accumulated on the use of blood products in dental extraction and in progressively more daring surgery.
This simple 'cryoprecipitate' procedure (1965) has been widely adopted by transfusion services to provide a supply of antihemophilic material for routine treatment.
The supply of freeze-dried concentrates is now steadily improving, and now patients treat themselves by intravenous injection of factor VIII and factor IX preparations which they keep at home.
Fortunately we have reached the point where we can effectively treat episodes of spontaneous bleeding and we can prevent abnormal bleeding after trauma or surgery and also prevent joint bleeding, which significantly decreases prevalence of hemophilic arthropathy.
References:
Ingram, G.I.C., Evans, D.I.K. “The History of Haemophilia”, Haemophilia, Vol. 3, Suppl. 1, 1997.
Kelley, L.A. Alexis. The prince who had haemophilia, 1992.
Evans, D.I.K. “Twenty one years of haemophilia”, Haemophilia, Vol. 3 Suppl. 1, 1997.
Miller, F.A. Nicolas II, Emperor of Russia, 1992.
