What is haemophilia?
Haemophilia is a rare inherited blood disorder that mostly affects men. People with haemophilia are missing a protein in the blood called a ‘clotting factor’; an abnormal gene causes this.  Without this protein, the blood cannot clot normally. There are two types of haemophilia (called ‘A’ and ‘B’), depending on which clotting factor is the problem:
‘Haemophilia A’ is far more common than ‘haemophilia B’, and affects around 1 in 5,000 live male births. 
When a person has a cut, their body quickly turns on blood ‘clotting factors’. These clotting factors help to make a specific protein called ‘fibrin’, which forms a sticky mesh across the injured blood vessels. Other cells in the bloodstream will stick to this mesh and form a clot (essentially a plug) that stops the bleeding. There are many different factors that work together in a complicated chain to form a clot. If any part of the chain is missing or does not work properly, the chain will break and no clot will form. This is what happens if a person has haemophilia. 
If a person has haemophilia A, ‘factor VIII’ (also written as ‘factor 8’) is either missing or ineffective. If they have haemophilia B, ‘factor IX’ (also written as ‘factor 9’) is missing or ineffective. 
The amount of factor produced in the body affects how severe a patient’s bleeding will be. Factor is measured as a percentage of how much is needed to form a clot. People without the haemophilia mutation have factor VIII levels from 50–150%. Anyone with factor VIII levels less than this has haemophilia A. 
How is haemophilia inherited?
Genes are the instructions for how to build a human. Every person inherits their genes from their parents and they contain all the information needed to make each person – from the colour of their eyes to their blood type. Genes are grouped into a long chain of DNA folded up tightly to fit in a cell, called a ‘chromosome’. There are 23 pairs of chromosomes in each cell of the body. In every person, one-half of the pair came from their mother, the other half from their father. 
One of these pairs is called the ‘sex chromosomes’. This pair is made up of the X and Y chromosomes, and determines whether a person is male or female. If a person inherits two X chromosomes, one from each parent, they are female. If a person inherits an X chromosome from their mother and a Y chromosome from their father, they are male. 
These chromosomes not only determine a person’s sex – they also carry many other genes, including the gene for clotting factor VIII, which is carried on the X chromosome. This means that mothers can pass on the mutated gene to their sons. 
Although the mutated haemophilia gene may also be passed on to any daughters from either their mother or their father, females have two copies of the X chromosome. This means that the healthy copy of the gene can compensate for the mutated gene copy. Women who have one copy of the mutated gene are called ‘carriers’ – they can pass on the disease to their children, but will usually show few or no signs of having the disease themselves. [6, 7]
About 30% of people with haemophilia did not inherit the disease from their mother. While they still have a mutation in the factor VIII gene, the mutation happened as a random event in the early stages of development. 
What are the symptoms of haemophilia?
Symptoms of haemophilia are usually noticed very soon after birth, especially in someone with severe haemophilia. However, if a patient has mild haemophilia, they may make it to adulthood without showing any obvious symptoms. 
The most noticeable symptom of haemophilia is the prolonged bleeding time when suffering an injury. [10, 11] Other symptoms include: 
How is the severity of haemophilia classified?
What are the different types of bleed?
Someone with haemophilia can bleed anywhere at any time, even in the absence of an injury.
Bleeding into joints such as the ankle, knee or elbow is common in people with haemophilia. Over time, this can cause damage to the joint and result in arthritis, chronic pain and limited movement. Patients may develop one or more ‘target’ joints – joints that have had multiple bleeds over a short period of time. These joints are most likely to develop long-term damage. 
The doctor may talk about the risks of ‘intracranial haemorrhage’. An intracranial haemorrhage is a bleed inside the skull. Symptoms of an intracranial bleed include severe headache, vomiting, confusion and slurred speech. This type of bleed can be life threatening – if a person thinks that they have an intracranial bleed, they should get medical help straight away. 
If a bleed occurs after an injury, it is called a traumatic bleed. However, people with haemophilia might bleed for no reason at all – this is called a ‘spontaneous bleed’. Whatever the type of bleed, patients should seek treatment as soon as possible to prevent long-term damage to their health. 
What treatment options are available for haemophilia?
Traditionally, haemophilia was treated by replacing the missing clotting factor VIII with concentrated factor made from donated blood. This is typically referred to as
‘plasma-derived factor’. Whole blood from donors was filtered to leave only the clotting factors. These clotting factors were then injected into the haemophilia patient to treat bleeding events. The use of plasma-derived factors quickly reduced in the late 1980s and 1990s following the discovery of contaminated blood products. These products resulted in high levels of the viral infections, human immunodeficiency virus (or HIV) and hepatitis C, in the haemophilia community. [13, 14]
Since then, discoveries in medicine mean that clotting factor proteins can be artificially made. Scientists found a way to clone the gene for factor VIII and make an artificial form in a laboratory without using purified blood. This avoids the risk of contamination with viruses carried in the human blood. These artificial proteins called ‘recombinant clotting factor concentrates’ are much safer than their natural alternatives. ‘Recombinant factor VIII’ (also written as rFVIII) is now the usual treatment for most haemophilia patients. 
When somebody comes into contact with a foreign object (e.g. bacteria), their body produces a type of protein called an ‘antibody’. Antibodies stick to the foreign object and help to destroy it, protecting the body against infection. Sometimes, the replacement factors used to treat haemophilia are recognised as foreign by mistake. When this happens, the body makes antibodies against the replacement factors, destroying them and stopping the treatment from working. These antibodies are called ‘inhibitors’ and can make treating haemophilia very difficult, almost 1 in 3 people with severe haemophilia A will develop inhibitors to factor VIII. [16–18]
A possible first step in treating a person with haemophilia who has developed inhibitors is to try to remove those inhibitors by increasing the ‘tolerance’ of the person’s immune system. Large doses of factor are mixed with other agents, including those that reduce the immune response, in a complicated regimen called ‘immune tolerance induction’ or ITI. If ITI is unsuccessful, bypassing agents are the only remaining treatment option. Bypassing agents boost levels of other clotting factors that work alongside factor VIII to help the body produce a clot. Because these treatments include little or no factor VIII, the inhibitors will not destroy them.  A new treatment option for treating haemophilia A is by using a type of monoclonal antibody, which is a type of antibody made in the laboratory instead of in the body. This has been designed to do the work that factor VIII normally does but, because it has a different structure to factor VIII, it is not affected by factor VIII inhibitors.
Some people without haemophilia can also have an immune response and make antibodies to their own factor VIII – these people will have the same symptoms as a person with the mutated FVIII gene even though they have the healthy version of the gene. This is called ‘acquired haemophilia’ and is more common in older people. 
Haemophilia treatment can be used in two ways: ‘on-demand’ or as ‘prophylaxis’: