Haemophilia is a disorder in which the blood does not clot properly. There are two main forms: haemophilia A, and the rarer haemophilia B. The two types of haemophilia have different precise causes but the same symptoms.1 Haemophilia affects males much more commonly, and usually more severely, than females.2,3 The condition is characterised by slow and inefficient formation of blood clots resulting in prolonged bleeding and spontaneous internal bleeds.
What is haemophilia?
When a healthy individual sustains an injury – internal or external – which causes bleeding, the injury (trauma) triggers a process known as the coagulation cascade, also sometimes called the clotting cascade. This cascade is a series of reactions in the bloodstream whose end result is haemostasis – the stopping of a bleed.
In fact, the cascade starts as two series of steps which originate separately. These are known as the intrinsic pathway and the extrinsic pathway. These two pathways converge into a third pathway, called the common pathway. The mechanism by which blood coagulates involves a series of clotting factors circulating in the bloodstream, each activating the next in a specific order.4 If any part of this intricate process fails, there is a possibility that the blood will not clot properly and the individual will bleed excessively.
In haemophilia, one of the clotting factor proteins is partly or completely missing. People with haemophilia take longer than normal for bleeding to stop after an injury. They may also have bleeding into joints and muscles without having had an injury.5
• Haemophilia A is a deficiency of factor VIII (8).
• Haemophilia B (also known as Christmas Disease) is a deficiency of factor IX (9).6
Are there any other conditions similar to haemophilia A or B?
Other rare bleeding disorders exist:
- Haemophilia C, also known as plasma thromboplastin antecedent (PTA) deficiency or Rosenthal syndrome. This is a mild form of haemophilia affecting both sexes and is caused by factor XI deficiency.7 It affects about 1 person per million,8 far fewer people than haemophilia A or B.
- Von Willebrand Disease, a genetic bleeding disorder where patients have a deficient or defective von Willebrand factor (VWF), a protein in the blood that is important for clot formation.9
- Very rarely, individuals may be born with, or develop: Factor I Deficiency, Factor II Deficiency, Factor V Deficiency, Factor VII Deficiency, Factor X Deficiency, Factor XII Deficiency, or Factor XIII Deficiency.10
- Immune thrombocytopenia (ITP), a rare autoimmune disease affecting platelet production. ITP is different from haemophilia, although some of the symptoms are similar. People with ITP have reduced platelets but the rest of their clotting mechanism works normally.11,12
How common is haemophilia?13
Haemophilia A affects about 1 in 5,000 of the male population. Haemophilia B is rarer, affecting around 1 in 30,000 of the male population. Severe forms of haemophilia are very rare in women. Around 30 to 50 per cent of females who are carriers may have milder forms of haemophilia. Haemophilia affects people of all ethnic origins and from all parts of the world.14
What are the symptoms of haemophilia?15
The symptoms of haemophilia A and B are the same:
- Bruises
- Bleeding into muscles and joints, which may cause:
o Aching
o Swelling
o Pain and stiffness
o Difficulty using a joint or muscle - Spontaneous bleeding (sudden internal bleeding for no apparent reason, including life-threatening bleeds i.e. intracranial)
- Prolonged bleeding after surgery or having a tooth extracted
- Prolonged bleeding after an accident, especially after an injury to the head16
How is haemophilia diagnosed?
If an individual is showing some or all of the symptoms of haemophilia, a formal diagnosis may be recommended, especially if there is a family history of haemophilia.17,18 Initially the patient may be invited to take a general blood test, or screening, for blood clotting. If haemophilia is suspected, the next step might be referral for specific tests at a haemophilia treatment centre for factor VIII and factor IX.
Severity
Haemophilia is classed as mild, moderate or severe depending based on the baseline level of clotting factor a person has, as measured in a laboratory test. The same measures are used for haemophilia A and B.
Haemophilia severity levels and what they mean19,20
Without haemophilia
Percentage of normal factor activity in blood
50-150%
Number of international units (IU) per millilitre of blood
0.5-1.5 IU/mL
Mild haemophilia
Percentage of normal factor activity in blood
5-40%
Number of international units (IU) per millilitre of blood
0.05-0.4 IU/mL
When bleeds typically occur
Bleeding following injury or surgery
Moderate haemophilia
Percentage of normal factor activity in blood
1-5%
Number of international units (IU) per millilitre of blood
1.01-0.05 IU/mL
When bleeds typically occur
Bleeding as a result of minor injury
Severe haemophilia
Percentage of normal factor activity in blood
< 1%
Number of international units (IU) per millilitre of blood
< 0.01 IU/mL
When bleeds typically occur
Spontaneous bleeding into joints and muscles
What causes haemophilia?21
Haemophilia occurs in response to an alteration, or mutation, in the gene responsible for producing clotting factor VIII or IX, resulting in the factor not being adequately produced.
- In haemophilia A, the gene responsible for producing factor VIII, known as the F8 gene, is altered.
- In haemophilia B, the gene responsible for producing factor IX, known as the F9 gene, is altered.
Haemophilia is usually an inherited condition, passed on from parents to offspring. However, in about a third of cases of haemophilia A and B there is no family history of the condition. This is because inherited haemophilia can arise as a spontaneous germline mutation – that is, when there is an alteration in DNA in offspring which is not present in the parental DNA but which can then be passed on to the next generation.22,23 This type of gene alteration is also known as a de novo mutation.24,25
Victoria, Queen of the United Kingdom from 1837 to 1901, was a carrier of haemophilia B. The mutation is believed to have arisen spontaneously. Victoria's youngest son, Leopold, was affected by the disease and at least two of her five daughters, Alice and Beatrice, were carriers.
Acquired haemophilia
In rare cases, a person can develop haemophilia at some stage in life even when there is no family history and no spontaneous mutation. This is known as acquired haemophilia (AH). AH is an autoimmune condition – where the body mistakenly attacks healthy cells or tissue. In AH, the body produces antibodies (known as inhibitors) that attack clotting factors, most commonly factor VIII. It affects mainly older people and is believed to affect approximately one person in a million.26
How is haemophilia passed on?
Haemophilia A and B are recessive sex-linked, or X-linked, mutations. To understand what this means, a basic understanding of genetics is needed.
In the human body, every cell normally contains 23 pairs of chromosomes. These chromosome pairs carry all of our genetic material. Each chromosome contains hundreds to thousands of genes. Genes are what carry the instructions for making proteins. Twenty-two of our chromosome pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosome pair, is different in males and females. Females have two copies of the X chromosome (XX), while males have one X and one Y chromosome (XY).27,28
The F8 gene and the F9 gene (responsible for producing factors VIII and IX respectively) happen to be located on the X chromosome, which means that they affect males and females in different ways.
If a female has a recessive mutation for haemophilia (A or B) on only one of her X chromosomes, she will be a carrier. This means that she will herself be unaffected by the disease, or may have it in a mild form, but she can pass the mutation on to her progeny. On average half of her sons will be affected and half of her daughters will be carriers.
If a male has the same mutation on his X chromosome, he will be affected by the disease because he doesn’t have another X chromosome that is free from the mutation. He will pass the altered gene on to any daughters via the X chromosome that he contributes. He cannot pass it on to his sons, because he contributes only the Y chromosome to them.
What treatments are available?
Many years ago, hospital-based blood transfusions were among the few treatments available for people with haemophilia and the life expectancy of a person with severe haemophilia was low. A good deal of progress has been made in recent decades and years.
Contemporary treatments have revolutionised the landscape for individuals with haemophilia, empowering them to surpass conventional expectations and engage more extensively in life. Modern therapies not only enable more active participation in physical pursuits, including sports, but also can enable people with haemophilia to carry out routine activities free from the constant concern of potential bleeding episodes. For children, this progress translates into the opportunity to join their peers in different activities and fosters a more inclusive life experience.
Types of haemophilia treatments
- Plasma Derived
Plasma-derived factor concentrates are derived from human plasma. These products are purified from donated blood plasma, providing a natural source of clotting factors. Rigorous screening and purification processes are employed to minimise the risk of transmitting infections. Plasma derived treatments factors have a standard half-life.29
- Recombinant
Recombinant factor concentrates are produced through genetic engineering techniques, creating clotting factor proteins in a laboratory setting. This method helps ensure a consistent and pure product, reducing the risk of contamination and adverse reactions. Recombinant concentrates can include standard, extended or high-sustained half-life factors.30
- Standard Half-Life Factor (SHL)
Standard half-life factor concentrates involve injections of clotting factor with a traditional half-life, requiring regular administrations to maintain adequate levels in the bloodstream.31 This form of treatment can be used in on-demand therapy and prophylaxis.32
- Extended Half-Life Factor (EHL)
Extended half-life factor concentrates are designed to remain active in the bloodstream for a longer duration, allowing for higher factor levels with less frequent injections. This approach aims to improve bleed control and reduce the frequency of treatment, especially in prophylactic regimens33,34,35, 36.
- Non-Factor Therapy
Non-factor therapies in represent treatment approaches that target the underlying haemostatic defect without directly replacing clotting factors like factor VIII or IX. They aim to enhance haemostasis by either mimicking factor function or rebalancing the coagulation system, offering alternatives to traditional factor replacement therapy. All non-factor therapies to date are administered subcutaneously.35
- Gene Therapy
Gene therapy involves introducing a functional copy of the clotting factor gene into the patient's cells, enabling the body to produce the deficient clotting factor. This approach aims to provide a long-term correction of the underlying genetic cause of haemophilia.36
Theoretical activity level and dosing scenario of a clotting factor
Development of antibodies
For most people, treatment works extremely well. However, for some, their bodies react as if the clotting factor were a foreign substance. Their immune system then develops antibodies known as inhibitors, which means that the injected clotting factor may not work as well or work at all. The antibodies may disappear spontaneously after a period of regular treatment, or a higher dose of the injection may be needed for a period of time. In some people, the antibodies remain and their bleeding must be controlled using a different treatment.37
Liberate Life
Liberate Life is Sobi’s vision for haemophilia and our way of supporting and empowering people living with the condition. Liberate Life is based on the fundamental criteria that treatment should always allow people living with haemophilia to feel safe, be protected from bleeds, have long-term joint health protection, and not feel burdened by haemophilia. The Liberate Life website aims to give people with haemophilia support and information that may help to identify personal goals, limit the impact of the condition, and get the most out of care and treatment.
World Federation of Hemophilia (WFH) Humanitarian Aid Program
More than 75 per cent of people with haemophilia around the world have limited or no access to diagnosis and treatment, particularly in the developing world.
Together with Sanofi, we intend to donate up to 1 billion international units (IUs) of factor replacement for use in developing countries.
Learn more about our commitment to the WFH Humanitarian Aid Program here: Humanitarian aid
References:
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https://haemophilia.org.uk/wp-content/uploads/2017/04/Understanding_haemophilia_WEB.pdf
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132474/
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https://www.ncbi.nlm.nih.gov/books/NBK482253/
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153668/
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Apr, 2024