Haemophilia: Blood Love
Haemophilia: Haem = Blood, Philia = Love
by Kenneth Lyen
“Haemophilia does not define who I am”
Nicholas Lim can probably be the poster boy of haemophilia in Singapore. He was first diagnosed with the disease when he was 3 years old. He was covered with bruises, and the parents consulted a doctor, thinking that he was being abused by his nanny. Subsequent tests diagnosed haemophilia A. He was started on Factor VIII and currently he gives himself injections every 2 or 3 days, which cost nearly $3,000 per month. The condition was more severe when he was younger. His classmates were envious that he was exempted from physical education, and bullied him, throwing pencils at him and even biting him. On one occasion he fractured his hip, and luckily the injury was attended to promptly at the accident and emergency department. Doctors advised him to avoid contact sports like rugby and soccer, and he now swims and goes to the gym regularly. Determined not to be handicapped by his illness, he developed a positive mindset and was determined to live his life to the fullest. This spurred him to enter Manhunt Singapore 2018, where he went all the way to the finals. “Haemophilia does not define who I am” he declared.
Blood Love
“Blood Love” is the ironic meaning of “haemophilia” derived from the Greek “haima” meaning "blood, bloodshed, or streams of blood", and “philia” meaning "to love". It is a sex-linked inherited condition, meaning that it is genetically passed on by the mother who has no symptoms, and it only affects boys. The commonest clotting protein or factor deficiency is that of factor VIII, and the less common deficiency is that of factor IX.
Classification of Bleeding Disorders
Bleeding disorders can be divided into four main categories:
1. Coagulation Disorders, and this can be subdivided into
a) Hereditary (eg haemophilia)
b) Acquired (eg liver disease or vitamin K deficiency)
2. Fibrinolytic Disorders when clots formed are dissolved prematurely
3. Vascular Disorders affecting blood vessels(eg scurvy due to vitamin C deficiency)
4. Platelet disorders
Inherited Coagulation Disorders
Let us focus on the inherited bleeding disorders caused by a deficiency of clotting factors. These include the haemophilias, and deficiencies of other clotting factors, and von Willebrand Disease. The latter is a deficiency of clotting factor VIII plus impaired platelet adhesion, and is inherited either as an autosomal dominant or autosomal recessive. There are several other clotting factor disorders but they are rarer.
What is Haemophilia?
Haemophilia is a group of genetic disorders where there is a deficiency of clotting factors, resulting in easy bleeding. It is classically divided into two major categories: Haemophilia A which is due to a deficiency of Factor VIII and is inherited as a sex-linked recessive, and Haemophilia B which is due to a lack of Factor IX and is also inherited as a sex-linked recessive. Some researchers have proposed further classification of patients into Haemophilia C, where there is a deficiency of factor XI and is inherited as an autosomal recessive, and Haemophilia D which is due to a deficiency of Factor XII. I will focus on the classical Haemophilia A and B..
Genetics
Haemophilia A and B are inherited as a sex-linked recessive disorders, meaning that the vast majority of individuals affected are boys, and females carry the gene for the condition. The abnormal gene is located on the X-chromosome, and as boys only have one X-chromosome, when that X-chromosome is affected, it will readily express the abnormality. In contrast, females have two X-chromosomes, and this will compensate or cover-up the abnormality if only one X-chromosome is abnormal. Hence females with only one abnormal chromosome, also known as carriers, will not exhibit any signs of haemophilia.
A female child inherits two X-chromosomes (XX), one from her mother and one from her father. A male child will inherit an X-chromosome from his mother and a Y-chromosome from his father (XY). This means that fathers cannot pass haemophilia onto their sons but mothers can. The chances of carrier mothers passing haemophilia to their sons is 50%, and their daughters will have a 50% chance of being a carrier.
When a carrier female has a daughter with a haemophiliac father, there is a 50% chance of that female developing haemophilia, and a 50% chance of the son having haemophilia as well.
Above is a picture of a brother and sister, both with haemophilia.
In about 30% of haemophilia cases, there is no history of haemophilia in the family because it is due to a new or spontaneous mutation.
The Royal Disease
The most famous royal family with haemophilia is that of Queen Victoria, and as a result, haemophilia is also called “The Royal Disease”.
Queen Victoria
Queen Victoria was a carrier for haemophilia B, and one of her sons, Prince Leopold, died bleeding from an accident at the age of 30. Queen Victoria had two daughters who carried the haemophilia gene, Princess Beatrice who married Prince Henry of Battenberg and their two sons and two grandsons all had haemophilia. The other daughter, Princess Alice, married Louis Grand Duke of Hesse and their son had haemophilia, while two of their daughters, Irene and Alexandra, carried the haemophilia gene. Of particular interest is Alexandra,who married Tzar Nicholas II Romanov of Russia.
Tzar Nicholas II with his wife Alexandra and their five children
Alexandra had four daughters before they bore a son, Alexei, who suffered from haemophilia. His saga may have altered the course of world history. Unfortunately the entire Russian royal family were killed during the communist revolution ending the genetic transmission of the disease.
Tsarevitch Alexei Nikolaevich (1904-1918)
Alexei was the youngest child and only son of Tzar Nicholas II and Princess Alexandra. He was the heir to the throne of the Russian Empire. He was born with Haemophilia B and from an early age suffered many bleeding and bruising episodes.
On 2 October 1912, at the age of 8, Alexei was sitting in a carriage traveling through the woods. The intense jolting over bumpy roads caused an earlier haematoma in the upper thigh to bleed again. By the time they reached their destination, he had to be carried out semi-conscious. There was a fever and his pulse was feeble. A week later he had continued to deteriorate and he was administered the last sacrament. His mother’s lady-in-waiting suggested calling for the monk Grigori Rasputin who was a well-known faith healer. A telegram was sent to the monk, and there was a prompt short reply that stated: “The little one will not die. Do not allow the doctors to bother him too much.” A few days later Rasputin arrived, but by then Alexei had already started to improve, and was given physiotherapy to straighten his left leg. Rasputin must have taken credit for the miraculous improvement, and so gained the confidence of Princess Alexandra.
Grigori Rasputin (1869-1916)
Upon capturing the trust of Princess Alexandra, Rasputin became increasingly powerful in his ability to advise her to change her husband Tzar Nicholas’ handling of the peasants who were becoming more rebellious during that period.
In 1914 Russia battled Germany in the first world war. Disruption of the supply chain led to food scarcity especially in the cities. The cost of living rose dramatically, and there was uncontrolled monetary inflation. Strike action spread all over the country, and gained momentum from 1915 to 1917. There was growing unemployment, famine, and widespread looting. The military responded by shooting the looters.
Rasputin, through Princess Alexandra, advised the Tzar to be very firm with the populace that was now demanding for a greater say in public affairs and policies. His influence was so great that Rasputin could even dictate to the Tsar the appointment or dismissal of officials of all ranks. His negative influence on society engendered social tensions. Rumours abounded of the role of Rasputin in influencing government actions, and his prominent presence led to the public’s loss of respect for the royal family. Only his murder in December 1916 reduced social tensions.
Vladimir Lenin (1870-1924)
In February 1917, revolution erupted in St. Petersburg because of food shortages leading to industrial strikes and rampant inflation. The unrest spread throughout Russia, and fearing that he would be violently overthrown, Tsar Nicholas II abdicated. The federal assembly assumed control of the country, establishing a provisional government and converting the Empire into a new Russian Republic. On hearing the news, Vladimir Lenin, who was in Switzerland at the time, returned to Russia to take a leadership role. This eventually resulted in establishing a communist regime. Lenin quickly signed a peace treaty with Germany in March 1918 to extricate Russia from the First World War. On 17 July 1918, the entire Romanov family were executed and their bodies were buried in an unmarked grave that was not discovered until July 1991.
Nicholas and Alexandra: the movie (1971)
The movie Nicholas and Alexandra depicts in greater detail how Alexei’s haemophilia allowed Rasputin to enter the royal household, and exert a deleterious influence on Princess Alexandra and Tzar Nicholas. The resulting political unrest enabled Lenin and the Russian revolution to gain ascendency and eventually to overthrow the Russian royalty.
I would like to take this thesis one step further and to postulate that if Russia did not become communist, then China would probably not have followed suit, and neither North Korea nor North Vietnam would have done so either. Hence haemophilia profoundly altered the entire course of world history!
What about Singapore?
In 2015, the Singapore population was nearly 4 million, and there were about 200 males with Haemophilia A , making a prevalence of 10 per 100,000, and 40 males with Haemophilia B, which gives a prevalence of 2 per 100,000
Inhibitor antibodies developed in 18% of Haemophilia A persons, compared to only one individual with Haemophilia B. The absence of family history for Haemophilia A was 30%, and for Haemophilia B it was 20%. Unfortunately, 35 out of 108 haemophiliacs were Hepatitis C carriers due to administration of blood products, and 8 patients were treated with interferon and ribavirin. None of the subjects had the Human Immunodeficiency (HIV) virus.
One fifth of cases with moderate to severe haemophilia were uemployed.
Haemophilia Society of Singapore
My personal interest in haemophilia began when two former classmates of mine invited me to join them to help set up the Haemophilia Society of Singapore and we successfully registered it as a charity in 1985. The main focus of the society is to help families cope with their children who have haemophilia and other bleeding disorders. My role was to recruit families of haemophilia patients to join the association as well as to treat some patients with bleeding disorders.
The Haemophilia Society of Singapore has noted that a haemophilia individual spends on average, $3,000 to $4,000 a month on regular infusions of clotting factor to prevent spontaneous bleeding.
Patients typically receive a 50 to 65 per cent government subsidy and HSS members get an extra 20 to 25 per cent subsidy. With the subsidies, the treatment costs about half the usual price.
The nonprofit society, established in 1985, spends about $130,000 to $150,000 a year, mainly on medication subsidies for its members.
Symptoms and Signs
Haemophiliacs can bleed from may places. Commonly they present with multiple bruises. This can sometimes pose a diagnostic problem. Boys often display bruises along their shins, and this is attributable to the relative roughness of their play. However, it is important to exclude non-accidental injuries, such as when the child is being bullied by their colleagues, or excessively punished by their parents.
Other common sites of bleeding are minor cuts, nosebleeds, bleeding from the gums detected by noticing blood on the toothbrush, and bleeding into the muscles or joints. The latter can be extremely painful. More worrying is bleeding into the intestines and brain as they may not be detected quickly; blood loss into the intestines can be quite substantial before it i recognised, and intracranial haemorrhage can cause brain damage.
How early can haemophilia present with bleeding? As early as during birth, if labour is unduly prolonged. If a child undergoes circumcision, there may be excessive bleeding, and others develop bruises during childhood vaccinations. Some children start bleeding around 10-13 months when they start to crawl or walk, and the bleeding is usually into the knee joint. Other haemophiliacs may only develop symptoms during their teens or early 20s, especially when they undergo dental procedures or surgery.
Diagnosis
Haemophilia is diagnosed by several blood tests. It is conventional to do general tests like a haemoglobin level (normal or slightly low), platelet count (normal), prothrombin time (normal), activated partial thromboplastin time (significantly prolonged in haemophilia).
One can assay Factor VIII or Factor IX, and the level gives us an idea of the severity of the haemophilia:
Treatment
When we started the Haemophilia Society of Singapore, there was some difficulty getting hold of enough fresh frozen plasma for treatment. Therefore, we could only give the plasma on demand, meaning that it was only when a child had a bleed that it was administered. However, as Factor VIII or Factor IX could be obtained more readily, injections were given more regularly, ranging from alternate days to once a week. But if there was an acute bleed, the appropriate clotting Factor would still be administered promptly.
How useful is Desmopressin for Haemophilia A? There is still some uncertainty about the efficacy of this form of treatment.
Contraindicated Drugs
Drugs that may worsen bleeding, like aspirin or warfarin, should be strictly avoided.
Advice for Children: Vaccinations and Sports
Some vaccines are given subcutaneously while others are given intramuscularly. Subcutaneously administered vaccines generally do not present much of a problem with haemophiliacs, and bleeding is easily controlled by applying superficial pressure for a slightly longer period of time. However, intramuscular injections may cause bleeding into the muscles which can be more painful. Therefore, if possible, vaccinations should be given subcutaneously. However, there are some vaccines that have to be given intramuscularly, and it is recommended that the vaccinator use a smaller needle, and inject into a larger muscle like the thigh muscle. If there is intramuscular bleeding, applying ice over the bleeding site can ease discomfort and reduce bruising.
We recommend that haemophiliacs should avoid contact sports like soccer or rugby. Instead, they can participate in non-contact sports like swimming, athletics, table tennis, tennis and badminton.
Breakthrough Treatments
Inhibitors
One of the potential problems of injecting clotting Factors on a regular basis is that there is a greater chance of stimulating the body’s immune system to produce antibodies that neutralize the factor. The antibodies usually appear within a few months from the start of treatment. About 25% of people with Factor VIII deficiency develop these inhibitory antibodies, compared to about 3% of people with Factor IX deficiency. The result is that the clotting factors become ineffective, and warrants the administration of increasing doses of Factor VIII or Factor IX.
For haemophilia A patients, the current treatment of these inhibitory antibodies against Factor VIII is emicizumab. This is a recombinant, humanized, bispecific monoclonal antibody that bridges activated factor IX and factor X to restore the function of missing activated factor VIII. This prolongs the half-life of Factor VIII, and hence enables the blood to clot more normally. Emicizumab has a unique structure so that it will not induce the development of antibodies against itself.
Gene Therapy
There has been a major breakthrough in gene therapy for both Haemophilia A as well as Haemophilia B. Patients given gene therapy have increased levels of Factor VIII and Factor IX respectively, and the requirement for clotting factors has decreased significantly. Researchers have used the word “miracle” for this form of therapy.
Evolutionary Advantage?
One would imagine that the inability to clot may have some evolutionary advantage in reducing the risk for heart attacks, stroke, deep vein thrombosis, pulmonary embolism and other diseases associated with excessive clotting. That does not appear to be the case. On the other hand, haemophiliacs tend to have a slightly increased prevalence of hypertension.
What is the Future?
We are overjoyed by the successful use of gene therapy in treating haemophilia. The future hope is that this treatment becomes available for everyone at a more affordable price with fewer side effects. Perhaps other inherited coagulation disorders can also be treated by gene therapy as well. The future is very exciting!
References
What is haemophilia?
Hemophilia video: https://www.youtube.com/watch?v=nkC1vZaUpxs
Hemophilia Emergency Treatment video: https://www.youtube.com/watch?v=dkdmZNo8ozg
Rasputin and the fragmentation of imperial Russia:
https://pdxscholar.library.pdx.edu/cgi/viewcontent.cgi?article=1116&context=younghistorians
From Tzar to Lenin: https://www.thenational.ae/arts-culture/from-the-tsar-to-lenin-revisiting-the-russian-revolution-in-new-reads-1.31759
Royal Disease: https://haemophilianewstoday.com/2017/05/24/haemophilia-royal-disease/
Haemophilia in Singapore: Ng HJ, Lam J, Koh PL, Ho L, Lim CY, Akhbar Ali M, Tien SL (2015) Haemophilia : the official journal of the World Federation of Haemophilia, 21(5):e428-31. doi: 10.1111/hae.12729
Haemophilia Society of Singapore
https://www.tnp.sg/news/others/20000-month-manage-his-blood-disorder
Gene Therapy for Hemophilia A: https://www.nejm.org/doi/full/10.1056/NEJMoa1708483
Gene Therapy for Haemophilia A: https://www.youtube.com/watch?v=NtUG6pv8UJI
Gene Therapy for Hemophilia B http://www.bloodjournal.org/content/131/9/952?sso-checked=true
Gene Therapy for Hemophilia B https://www.youtube.com/watch?v=6TpLoZCaL3c
A cross-sectional analysis of cardiovascular disease in the hemophilia population
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998925/
Kenneth Lyen
14 October 2018, updated 27 April 2019