Queen Victoria's male descendants were cursed with poor health. The 19th century British monarch's son Leopold, Duke of Albany, died from blood loss after he slipped and fell. Her grandson Friedrich bled out at age 2; her grandsons Leopold and Maurice, at ages 32 and 23, respectively. The affliction, commonly known as the "Royal disease," spread as Victoria's heirs married into royal families across Europe, decimating the thrones of Britain, Germany, Russia, and Spain. Based on the symptoms, modern researchers concluded that the royals suffered from hemophilia--a genetic disease that prevents blood from clotting--but there was never any concrete evidence. Now, new DNA analysis on the bones of the last Russian royal family, the Romanovs, indicates the Royal disease was indeed hemophilia, a rare subtype known as hemophilia B.
Hemophilia prevents proteins known as fibrins from forming a scab over a cut or forming clots to stop internal bleeding. Even minor injuries can lead to bleeding, which lasts for days or weeks and can be fatal. The disease is recessive and is carried on the X chromosome, meaning that men are more likely to develop it, whereas women usually act as carriers and don't show symptoms.
Such was the case with Prince Alexei Romanov, son of Tsar Nicholas II, great-grandson of Queen Victoria, and heir to the Russian throne. From an early age, Alexei was prone to prolonged bleeding, and his family feared that he wouldn't make it through his first month of life, says Evgeny Rogaev, a geneticist at the University of Massachusetts Medical School in Worcester. The disease didn't kill Alexei, however: He was murdered at age 13 in 1918 along with the rest of the Russian royal family following the Russian Revolution. Earlier this year, Rogaev and his colleagues reported that, based on DNA analysis, the bodies of two children found near the murder site were indeed those of Alexei and his sister Maria. They further confirmed that the other bodies near the site belonged to the rest of the Romanov family. But Rogaev wanted to solve the final Romanov riddle: Did they really suffer from hemophilia?
He and colleagues analyzed DNA from the royal bone fragments again, this time looking for genetic markers of hemophilia. The most common type of the disease, hemophilia A, accounts for about 80% of hemophilia cases and is caused by a mutation to a gene called F8, which encodes a protein involved in blood clotting. They didn't find the mutation. So Rogaev moved on to looking for a rarer form of the disease, hemophilia B, which involves another gene, F9. This time, the team found a mutation in F9, which would have inhibited clotting, in bones from Alexei, his sister Anastasia, and their mother Alexandra.
The findings, published online today in Science, indicate that Alexei did indeed have hemophilia B and that his mother and Anastasia were carriers for the disease, bearing out the previous speculation. They also confirm that the other instances of "Royal disease" in the family line were hemophilia, Rogaev says, because they all shared a common genetic heritage. The last carrier of the disease in the royal family was Prince Waldemar of Prussia, who died in 1945.
The disease impacted not only the Romanov family but also probably Russian history, Rogaev adds. Alexei's frail condition encouraged his mother Alexandra to keep close company with the Russian mystic Grigori Rasputin, who claimed to wield healing magic. "There was no medication at that time," Rogaev says. "She tried to do everything possible." According to some historians, when Rasputin used his close relationship with the Romanovs to influence bureaucratic affairs in his favor, the public grew increasingly suspicious of the regime, possibly hastening the revolution.
Katherine High, a hematologist who studies blood coagulation at The Children's Hospital of Philadelphia, says that the mutation found in the Romanov bones fits an established genetic pattern known to cause hemophilia B, further supporting Rogaev's findings. Tracing this pattern back to the royal family and its history of disease is "very interesting and very exciting," she says.
People affected by the disease today should be excited to see hemophilia B step out from under the more common A-type's shadow, says pediatric hematologist Paul Monahan of the University of North Carolina, Chapel Hill. "Now it's clear it's had an enormous impact on Western history."
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In the late nineteenth century, hemophilia was an incredibly devastating disease, killing people as high in society as Prince Leopold, son of Great Britain’s Queen Victoria. Leopold’s case of hemophilia — a hereditary disease in which a patient’s blood does not coagulate property — appears to have led to an increase in hemophilia research and understanding in the late 1800s. Discoveries in the late nineteenth and early twentieth centuries laid the foundations for future scientists to develop treatments. Today, hemophilia is an almost completely controlled and less devastating disease.
Research into the hereditary nature of hemophilia may also have increased the understanding of hereditary diseases in general. Ironically, however, the hereditary characteristic of Leopold’s disease shrouded the malady in society, since the Royal Family did not want to have its “tainted” blood known. But because of Leopold’s prominent position in society as a member of the Royal Family, his condition drew greater attention to the disease, resulting in a spike in publications in the 1880s and eventually more research towards a cure. This paper traces Leopold’s struggle with hemophilia and the shame it brought to the Royal Family. This paper also analyzes the breakthroughs that occurred after Leopold’s death and their later implications for hemophilia treatment.
Prince Leopold’s Hemophilia
In the normal body, lesions in blood vessels cause clotting factors in the blood to coagulate. In hemophilic patients, this clotting does not occur properly, resulting in excessive bleeding.
Prince Leopold, Duke of Albany, was the fourth son of Queen Victoria. He was born in London on April 7, 1853. According to Leopold’s biographer Charlotte Zeepvat, he was first diagnosed with hemophilia in 1858 or 1859. From a very young age, Leopold began to exhibit symptoms of the disease. He appeared physically weak and clumsy and he bruised very easily. In addition to hemophilia, Leopold suffered from epileptic seizures during his lifetime.
When Leopold was diagnosed, some doctors blamed his disease on Queen Victoria’s use of chloroform during childbirth. This was a new type of anesthetic, and many believed for religious or moral reasons that women’s bodies were meant to endure the pain of childbirth without anesthetics (1).
It is a well-established fact, as evidenced by the appearance of hemophilia in her descendents, that Queen Victoria was a carrier of hemophilia. The Queen must have either received the gene from one of her parents or experienced a gene mutation causing her to become a carrier of hemophilia. Most historians agree that Victoria acquired the hemophilia gene through a mutation. According to Rosendaal, et al., the mutation rate for normal males producing carrier daughters is two to ten times higher than the mutation rate for normal females producing hemophilic males (2). Out of Victoria’s eight other children, two of her daughters, Princess Alice and Princess Beatrice, inherited the hemophilia gene, which they passed on to the Russian Royal Family and the Spanish Royal Family (3). This evidence indicates that a mutation occurred in Victoria’s DNA, introducing the gene to the British Royal Family (2).
Prince Leopold’s Doctors
While no treatment for hemophilia existed during Leopold’s lifetime to ease his suffering, prominent physicians of this period, such as Sir William Jenner, played a large role in attempting to treat Leopold. Jenner was the personal physician of the Queen, and also attended to her husband, Prince Albert, and other members of the Royal Family. He aided in caring for Leopold’s hemophilia from 1861 until Leopold’s death.
It is very likely that Jenner contributed to the cover-up of Leopold’s disease since he had a close personal relationship with the Queen. According to Victoria’s biographer Stanley Weintraub, “Jenner often described Victoria’s health in language put into his mouth by his employer” (4).
Jenner was also involved in researching the pathology of hemophilia. He was the second doctor ever to study the joints tissues of a hemophiliac under a microscope (5). He reported to the Clinical Society of London in 1876 that hemophilic blood was particularly slow to coagulate, but that this could not completely explain the disease because the bleeding episodes sometimes occur spontaneously in otherwise healthy patients. He believed that hemophiliacs’ bodies produce blood more rapidly and have an abundance of small blood vessels. Furthermore, Jenner’s report shows an uncertainty about the hereditary nature of the disease, because in some cases, it was possible to trace hemophilia back through several generations, whereas for other patients he could find no family history of the disease (6).
It is important to note that in the late nineteenth century, information about medical ideas and discoveries was not well disseminated among doctors, even within London. While some earlier doctors in Germany, the United States, and England had come to the conclusion that hemophilia was a hereditary disease, this information did not necessarily reach Jenner. The restricted spread of information clearly impeded medical progress in this period.
Jenner’s lack of certainty about the hereditary nature of hemophilia in his report tells us either that there is a good chance the Royal Family was not fully aware of this important characteristic of the disease, or that Jenner did not want to implicate the Queen’s family. Those members of the family who did know about Leopold’s hemophilia may have maintained a hope that the disease was isolated within Victoria’s youngest son and would not reappear in later descendents.
John Wickham Legg
John Wickham Legg, who studied under Jenner, served as Leopold’s personal physician from 1866-1867. During his medical training, Legg had witnessed the death of a hemophiliac boy from a nosebleed, and Legg subsequently developed a strong interest in bleeding disorders (7, 8). Legg only served as Leopold’s doctor for a year, but he also maintained a close relationship with Leopold throughout his career: in times of Leopold’s severe illness, Legg’s assistance was requested, and on certain occasions, Leopold called upon Legg to spend time with him as a friend (8).
Legg’s best-known work is A Treatise on Haemophilia, which he published in 1872, just five years after he stopped attending to Leopold. This work became one of the most important sources on information on hemophilia in the nineteenth century (7).
Legg’s 158-page treatise is a comprehensive overview of all the available information on hemophilia during this time period. Besides England, France, Germany, and the United States, Legg wrote that in “the civilized world, the disease seems to be unknown, or to be disregarded” (9).
Legg did not portray hemophilia in an overly positive light. He wrote that while some doctors have asserted that hemophiliacs have special intellectual capabilities, he believed this was a myth. Also, he wrote that hemophiliacs sometimes seemed to take on “womanish characteristics” because of their inability to participate in athletic or other active pursuits (9).
Legg reported that the excessive hemorrhaging of hemophiliacs most likely arose from a problem with the blood vessels, rather than with the blood itself, though he did admit “the pathology of haemophilia is still buried in the deepest obscurity” (9). Still, he reported that German doctors in this period had conducted analyses of the blood of hemophiliacs and normal patients and measured the amount of water, fibrin, albumen, and salts in it. They concluded that the blood composition of hemophiliacs was no different from that of healthy people (9). He was more inclined, therefore, to believe that the disease arose from some sort of variation of the blood vessels (9). However, studies of the organs of hemophiliacs after death, showed no abnormalities, which led to more confusion of the issue of pathology (9).
Legg’s treatise reported that hemophilia is most likely a hereditary disease, but this fact was not absolutely certain in every case (9). The cases in which he found no history of the disease within the patient’s family were most likely cases in which either the disease was not previously correctly diagnosed or cases in which the disease arose from a mutation. Legg also acknowledged the common pattern of asymptomatic daughters of hemophiliacs transmitting the disease to their sons (9).
One politically explosive facet of this work is its mention of marriage for hemophiliacs. Legg wrote, “Should a bleeder, or one of a bleeder family, be allowed to marry? I think that if the person himself be a bleeder, the question of marriage ought not to be entertained. His sons may possibly escape the disease, but it is almost sure to reappear in his daughters’ sons. The prospect of the certainty of so dreadful an entail of disease must repel every right thinking person from such a step, even at so great a sacrifice to himself; and it seems only necessary for the facts to be known to prevent such marriages among the better classes” (9). Given Legg’s extensive knowledge of hemophilia and his firsthand experience with Leopold, there is no doubt that he knew Leopold suffered from hemophilia. Therefore, it is remarkable that Prince Leopold was allowed to marry, given that at least one of his doctors (and probably more) knew that this would perpetuate hemophilia in the British Royal Family.
As for treatment, Legg took a somewhat fatalistic view of hemophilia. He warned against any drawing of blood, major surgeries, amputations, and cold or damp climates. He said that compression of bleeding wounds, application of ice to the wound, and sometimes compression of major arteries might help slow the bleeding, but not much else could be done to make a hemophiliac’s blood coagulate faster. He recommended that hemophiliacs spend as much time as possible in warm climates, a suggestion that Leopold followed as much as possible throughout his life (9). Overall, however, very little could be done to save hemophiliacs from painful experiences and early deaths. Legg wrote, “A sadder heritage of disease could scarcely be entailed” (9). Indeed, Leopold’s painful death would come when he was just thirty years old.
Figure 1: In the 1880s, the decade of Leopold’s death, there was a peak in the number of articles published about hemophilia in Great Britain.
A History of Hemophilia before Prince Leopold
The knowledge of hemophilia that the medical journals summarized in the 1800s was a product of many centuries of reports on the disease. To briefly review the historical understanding of the malady, the earliest mention of hemophilia appeared in the second century A.D. in texts written by Jewish rabbis. There is evidence of two rabbis exempting boys from circumcision because of fear of haemorrhage. In one case, the rabbi decided that a woman’s third son did not need to be circumcised because the first two had died from haemorrhage after circumcision. In the other case, a boy was not circumcised because three of his male first cousins died from the procedure (10).
Scattered records of males bleeding to death from small wounds exist from the tenth and twelfth centuries, as well as a few other mentions of the disease during the Renaissance period, but the definitive recognition of the disease came from the American physician John Otto in 1803. Otto stated that asymptomatic females transmitted the disease to their hemophiliac sons (11). American physician John Hay provided further confirmation of the transmission pattern of hemophilia in 1813 (12). Then, in 1820, German researcher and professor of medicine Christian Friedrich Nasse gave an accurate and detailed account of several aspects of hemophilia. Nasse is best known for confirming the fact that only males get the disease and females transmit it but do not show the clinical symptoms. This pattern of inheritance became known as Nasse’s Law (13).
J. Grandidier, a German physician, published the important Die Hamophilia, oder die Bluterkrankheit (‘Hemophilia, or the sickness of the blood’) in Leipzig in 1855 (8). This substantial work was an overview of all current knowledge of the disease, and stated that hemophilia was the “most heritable of all heritable diseases” (13).
The next major development was Legg’s Treatise on Haemophilia in 1872. By the 1880s, the hereditary nature of hemophilia was relatively well known and documented. In 1881, Legg published an article entitled, “Tissues of a case of haemophilia,” in which he tracked the disease through 200 years of a family’s history and further confirmed that the females acted as carriers, while the males experienced the symptoms of the disease (14).
The fourth edition of John Syer Bristowe’s A Treatise on the Theory and Practice of Medicine, published in 1882, listed hemophilia for the first time. It also stated that bleeders should not be allowed to procreate (15).
Although many articles were published about hemophilia in this period, there was no central source of medical information, so not all doctors knew of the latest breakthroughs in hemophilia research. This led to slower progression because doctors often repeated previous studies or experiments.
Medical Literature Regarding Hemophilia
Medical journals discuss Leopold’s death
Prince Leopold’s sudden death on March 29, 1884 in Cannes, France was reported in every major newspaper throughout the United Kingdom and elsewhere, but the connection to hemophilia was not generally published. Prominent medical journals were also circumspect about Leopold’s hemophilia, but they did draw subtle connections between the Prince and the disease, publishing articles specifically about hemophilia at the time of Leopold’s death.
The Lancet, perhaps the most well known British medical journal, published a standard obituary in the April 5, 1884 issue that was similar to those appearing in the general newspapers. The only medical-related comments in this article concern Leopold’s “oft-recurring pain and weariness of a weakly life worthily lived…” (16). In the same issue of The Lancet, there is an almost full-page article on hemophilia, with no mention of Prince Leopold (17). It is unlikely that doctors were unaware of Leopold’s condition (many of Leopold’s doctors, including Jenner and Legg, were leaders in the field of hemophilia research and would have clearly been able to identify Leopold’s symptoms as those of a hemophiliac over the course of treating him). It is more probable that the editors of The Lancet were respectful of the Royal Family’s privacy.
The British Medical Journal, another leading medical journal, also published two articles in its April 5, 1884 issue relating to Prince Leopold and hemophilia. One is a simple announcement of his death, which states that right before his death, he was “breathing very stertorously” and had a “convulsion, with his face drawn to one side and his hands clenched.” This article contains no other medical information and no direct mention of hemophilia, but does end by stating, “The constitutional malady from which he suffered is the subject of a leader in the present member of the Journal” (18). The article to which this refers is titled “The Haemorrhagic Diathesis.” The terms haemorrhagic diathesis and hemophilia were synonymous in the late nineteenth century and the two terms are used interchangeably throughout the article. This article begins by stating, “The recent bereavement in the Royal Family will naturally turn the attention of the medical public towards the constitutional affection to which the illustrious deceased was subject.” The article goes on to give a final word on Leopold’s death as a result of a fall due to a weakness in his knee that was probably caused by hemophilia and an intracranial complication that arose from this fall (19).
From these articles, it is clear that the medical public knew of Leopold’s hemophilia. The editors of these journals probably assumed that doctors would be particularly curious about a disease that had recently killed such a high-profile member of society.
1880s peak in journal articles on hemophilia
In the 1880s, the decade of Leopold’s death, there was a huge spike in the volume of literature published about hemophilia in the United Kingdom (Figure 1). Of the articles published in the 1880s, the vast majority were case studies rather than reviews of the current literature (20, 21). Nineteen of the articles published in the 1880s mentioned the hereditary nature of hemophilia and sixteen did not. This indicates a widespread knowledge of hemophilia, but as previously mentioned, during this period medical information was not well disseminated, so many physicians may not have known about the hereditary nature of the disease.
During the 1880s, doctors started to speculate on the causes of hemophilia on a more scientific level. In the British Medical Journal in 1882, C. Francis theorized that the excessive hemorrhaging could arise due to a lack of fibrin in the blood, which would inhibit the blood’s ability to clot. In The Lancet in 1886, T. Oliver put forth a hypothesis about the mechanism that led to hemophilia. He wrote, “So far as the pathology of the disease is concerned, I believe the state of the blood and blood vessels and a defective control-action on the part of the vaso-motor centres are the important factors in its causation.” Similarly, Legg theorized that the disease arose from poorly developed blood vessels (8). Although twentieth-century doctors discovered that the latter two ideas were far from true, the fact that doctors were attempting to come up with scientific explanations marked progress in the field of hemophilia. Still, they were far from having a complete understanding of hemophilia.
Breakthroughs in hemophilia research after Leopold’s death
In the decade following Leopold’s death, significant breakthroughs in the treatment of hemophilia occurred. Sir Almoth Wright, an English medical scientist, made a great contribution to hemophilia treatment through his research on the coagulation of blood. Wright demonstrated in 1891 that the blood of hemophiliacs had a longer coagulation time than normal blood because of a deficiency of calcium in the blood. He recommended calcium salts as a possible treatment. Later research showed that calcium in fact had nothing to do with blood clotting; instead a deficiency of certain blood proteins causes hemophiliac blood to coagulate more slowly, but Wright can still be noted for his experiments in measuring coagulation times (22).
Following Wright’s work, in 1910, Scottish physician and scientist Thomas Addis reported that hemophilia arose because of an “abnormality in the nature of the coagulation [that] arises as the direct result of the great prolongation of the time required for coagulation to complete itself” (23). Over the course of the next year, Addis demonstrated that a blood enzyme called prothrombin, derived from normal blood, could be used to more rapidly coagulate hemophiliac blood (10).
In 1911, William Bulloch and Paul Fildes produced parts V and VI of volume one of the Treasury of Human Inheritance, comprising a bibliography of 949 pieces of hemophilia literature in several different languages, as well as 235 pedigrees of families of hemophiliacs (24). Bulloch and Fildes defined the symptoms of hemophilia in simple and straightforward terms: “an inherited tendency in males to bleed.” The small amount of commentary that Bulloch and Fildes provided about this disease was not optimistic. The authors still considered hemophilia to be completely devastating, just as it had been a few decades earlier when Leopold was alive. In summarizing the effects of hemophilia, they wrote, “The disease runs in families, and in the course of time an attitude of fatalism is developed towards the resources of medicine…The barbarous treatment to which may bleeders have been subjected in the well-meant efforts of the physician or surgeon to stanch the haemorrhages must have a terrifying effect and leave an ineffaceable memory” (13).
In the 1930s, doctors began using plasma from healthy patients to treat hemophiliacs and in 1944, an American biochemist named Edwin Cohn invented plasma fractionation to separate plasma into its individual components. Soon after, hemophiliacs began being treated with only factor VIII, which researchers had identified as the specific clotting factor that was lacking in the blood of most hemophiliacs. It was not until the 1960s that plasma fractionation became commercialized and was available on a broad scale. By the 1970s, hemophiliacs could inject themselves with these proteins whenever they started bleeding. Now, proteins are given to hemophiliacs prophylactically (before they have any type of accident that starts bleeding) so they can generally have normal and active lifestyles (25, 26, 27).
Hemophilia devastated Leopold and the Royal Family and lead to the Prince’s premature death. Yet his death was not in vain. It accelerated research on hemophilia, and by the second half of the twentieth century, this previously fatal disease was completely controlled by injectable blood proteins. But research on hemophilia is not finished. According to a recent review, in the near future, “Haemophilia is likely to be the first common severe genetic condition to be cured by gene therapy” (28). The appearance of hemophilia in the British Royal Family increased the attention given to the disease by the medical community of Britain in the late 1800s, and it is unlikely that subsequent research would have progressed as quickly as it did if Prince Leopold had not had the disease.
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