What is Haemophilia?
Haemophilia is an inherited condition that causes bleeding for a long time after injury or surgery and painful swelling of the joints either after injury or even without injury. ("Inherited” means that the disease is passed from parents to children through their genes).

What is the cause?
Haemophilia is due to a deficiency of clotting factor, this results in increased bleeding.  There are two types of Haemophilia A (clotting factor VIII deficiency), which is more common and occurs in about 1 in 5,000 births. Haemophilia B (factor IX deficiency) is less common and occurs in around 1 in about 20,000 births.

How is it inherited?
The disease of Haemophilia is X linked and inherited from the mother, though the disease is present in males. A family history of maternal uncles or other male affected relatives on the mother’s side are often present. Though many cases are due to a new acquired mutation in the genes, and in these families, no family history is present.
In the X-linked variety of haemophilia the inheritance is due to a defective gene on the X chromosome. All humans have X chromosomes, in females there are two X chromosomes, while males have one X and one Y chromosome. Only the X chromosome carries the genes related to haemophilia. A male who inherits haemophilia gene on his X chromosome will suffer from haemophilia. If a female has the defective gene on one of her X chromosomes, she is a "haemophilia carrier.” The carrier does not suffer from haemophilia, but they can pass on the disease to their sons. Their daughters do not have the disease, but they may also be carriers. As said before, this can also occur as a new mutation in families without a history of haemophilia.

What happens in haemophilia?
Patients of haemophilia, bleed for a longer time than others after any injury, injections, operations or tooth extractions. They may bleed inside (internally), and in the joints - knees, ankles, and elbows. This bleeding can damage the joints and internal bleeding (head, abdomen) may be life threatening.
Haemophilia patients bleed for a very long time after injury, and often have delayed bleeding e.g. after a few days after tooth extraction or trauma. Patients with severe haemophilia they can bleed even without injury-spontaneously, this usually occurs in severe haemophilia patients.

Are there different types of haemophilia?
There are two main types of Haemophilia A and Haemophilia B.
Haemophilia A patients have low levels of factor VIII (8), and Haemophilia B patients have low levels of factor IX (9). This is important because patients can be treated with factor VIII or IX injections. So it is important to know which factor is low, so that the right injection is given.

Are there different degrees of severity?
Yes, the severity is graded by measuring the baseline level of factor (without treatment) in a patient. This level is fixed for each patient; their family members may have different levels of factor if they too suffer from the disease. Patients are graded according to the level of factor in their blood, lower levels of factor means more severe disease, as the deficiency from normal is much more. Patients with severe haemophilia that is less than 1% of factor in their blood can bleed spontaneously, without any injury, while mild haemophilia patients with factor level more than 5% will bleed only after injury or surgery.

Severity of haemophilia A or B is based on the amount of factor present in the blood.

Some important sites of bleeding

The Ilio-psoas (a muscle in the hip), is an important site of bleeding. If the patient has a bleed in this site, usually there is pain in the abdomen, because the muscle is deep inside no swelling is seen. The diagnosis is made by the doctor. Other sites of bleeding are the main joints e.g. knee, ankle, elbow joint are commonly affected. If injury any part of the body can be affected. Some patients may have bleeding in the brain, even after a very minor injury. Occasionally patients may have blood in the urine.

How Is Haemophilia Diagnosed?
To diagnose haemophilia the doctor will ask the patient about history of bleeding and any family history related to bleeding problems. This will reveal whether you or your family members, have bleeding problems. However, some families may have haemophilia have a family history of the disease. The doctor will perform a physical exam to see the status of the joints. Then special blood tests to diagnose haemophilia are performed, these blood tests may not be available everywhere. These include a baseline screening tests, which measure the coagulation time of blood called PT, APTT. Then if the APTT is prolonged , as is seen in Haemophilia a more specialized test is performed to see the deficiency of factor VIII (8) or IX(9) and the level of factor present. These test results will reveal if haemophilia is present, what type of haemophilia (A or B), and its severity. Once the doctors have all this information they will be able to advise you on the treatment and precautions.
Severe haemophilia can result in serious bleeding problems even in babies. Children who have severe haemophilia usually are diagnosed during the first year of life. People who have milder forms of haemophilia may not be diagnosed until they are older or have a major injury or surgery. The bleeding problems of haemophilia A and haemophilia B are the same. Only the special blood tests can tell the type of haemophilia, knowing which type is important because the treatments (injections) are different.

How Is Haemophilia Treated? Factor replacement
The main treatment for haemophilia is called factor replacement therapy, the deficient factor is replaced by concentrates of clotting factor VIII (for haemophilia A) or clotting factor IX (for haemophilia B). These factors can be collected from blood plasma donors and purified (plasma derived) or they can be produced artificially in a laboratory (recombinant). They are given to the patient by an injection through a vein (intra venous) directly into the blood.
The purified plasma derived clotting factor concentrates are made from human blood. The blood is treated to prevent the spread of diseases, such as hepatitis, HIV etc. With the current methods of screening and treating donated blood, the risk of getting an infectious disease from human clotting factors is very small. The latest products are called recombinant clotting factors; they are not made from human blood, but produced in a laboratory and have no risk of hepatitis or HIV.
The clotting factors are supplied in vials which need reconstitution, after mixing they are given by intra venous injection over 15 minutes. For very small children a semi permanent venous access device may be needed to give the injections, in older children it is given directly into a vein. The dose of factor depends on the weight of the child, so as children get bigger they will need more factor and it also depends on the severity of bleeding. A mild injury may need only a small dose of factor (e.g. 20%) for 1 or 2 days, but a severe injury e.g. brain hemorrhage or major surgery may need 100% correction for 7 days.

Calculation of factor VIII dose
Desired level of correction X weight in kilograms/2= i.u. (units) of factor for injection

Calculation of factor IX dose
Desired level of correction X weight in kilograms= i.u. (units) of factor for injection

Types of replacement therapy-on demand and prophylaxis
The older method of giving factor replacement was called ‘On demand.’ This means when a patient suffers from a swelling of the joint or has an injury, after the problem occurs injections of the factor are given. The type of replacement decided by the type of haemophilia, A or B and the dose by how severe the injury and the weight of the child. This is calculated by a formula by the doctor. These patients were given many precautions – for children limitation on playing e.g. no contact sports, injury prevention, avoiding intra muscular injections, massages etc.
However many times there was a delay in starting the injections and repeated bleeding into the joints resulted in damage to the joints, this happened even in careful patients. This damage usually led to permanent deformity and disability. Later in life many haemophilia patients may even need joint replacement surgery for the damaged joints or become handicapped.
A better way of treatment is called prophylaxis (PRO-fi-lac-is). In this regular small doses of factor are given to the patient before a joint bleed. When done in a small child before major joint bleeds or target joints it is called primary prophylaxis, and when done in older patients after a severe problem to prevent further problems it is secondary prophylaxis. The amount of factor needed is more that when on demand therapy is practiced, so this is expensive. However the end result of treatment is much better when the joints are evaluated by doctors and by the perception of the patients themselves. Also the child can lead a more active life without too many restrictions and fear. Though severe injury, is still to be avoided.

Complications of Replacement Therapy
Though factor replacement therapy is the treatment of haemophilia there may be complications. Earlier the risk was viral infection- like hepatitis B and C or HIV. However with better purification and safety measures this has reduced in plasma derived factor and is not present in recombinant factor. Now all plasma derived factor production is regulated with careful screening of blood donors, better testing of donated blood products. After collection of the plasma it is treated with detergent and heat to destroy viruses.
Bleeding into the joints, if this occurs it may result in damage to the joint, leading to deformity and disability. The more number of times a joint is affected, the more chances of permanent damage. Commonly affected joints are the knee, ankle or elbow joints. Delay in stating treatment also results in poor results. Once damage to a joint occurs, movement becomes decreased due to pain and difficulty in movement, this causes the muscles to become weak and even wasted. This further can lead to injury due to a fall as the muscles are weakened.
The other risk is the development of inhibitors. These are antibodies that may occasionally occur in patient with severe deficiency of clotting factors, when exposed to factor replacement. These antibodies can be measured in the blood by an inhibitor assay, they are usually suspected when the patient develops bleeding even with injections of clotting factor replacement therapy, as the inhibitor destroys the clotting factor before it has a chance to work. This can develop in about 20–30 percent of patients who have severe haemophilia A and 2–5 percent of haemophilia B.

Therapy of inhibitors
This depends on the level (titer) of inhibitors and whether they are causing bleeding or not. The doctor’s may use larger doses of clotting factor or try different clotting factor sources. If they are high titers and there is severe bleeding the doctor may use bypassing agents to control bleeding –FEIBA and recombinant factor VII (7). Occasionally other medicines may also be tried to reduce the antibodies. Consult your doctor for the best course of therapy for you or your patient.

Precautions
Avoid injury as much as possible, children should be watched for falls, avoid intramuscular injections. Most children’s vaccines can be given in the skin with a thin needle. Avoid strong massage or rough exercise, particularly in a painful joint. If a joint becomes painful or swollen, immediately contact the doctor. Avoid movement-apply ice, raise the joint and rest. Use medicines as prescribed by the doctor for the length of time recommended by the doctor.

Home therapy
Many families are able to give the factor replacement therapy at home, particularly in older children, this will mean fewer visits to the hospital and prompt treatment of each swollen joint. Ask your doctor if this is possible for you.

Free factor replacement
Some states are providing free factor replacement, talk to the government doctor in your state and the haemophilia federation. A few states are also providing free factor for emergencies only. See what is available; and talk to your community government representative to get more access to factor for all patients. Your voice is important, you can help your family and others.

Antifibrinolytic Medicines
Antifibrinolytic medicines (such as tranexamic acid and epsilon aminocaproic acid) may be used along with replacement therapy. They can be used alone for minor bleeds especially mouth bleeds.

Role of physical therapy
Strong muscles may help to protect the joint, so physical therapy is part of treatment for haemophilia. Avoid physical therapy or a new exercise plan if the joint is painful. An increase in factor may be needed if starting physical therapy after a gap or rest period. All physical therapy must be done under supervision of a trained physical therapist and under guidance of your doctor. If pain or swelling occurs, please go back to your doctor for a check-up. The benefit of physical therapy may not be immediate, it is important for long term mobility.

Gene Therapy
Researchers are trying to find ways to correct the defect in the genes that cause haemophilia. Gene therapy has not yet developed to the point that it's an accepted treatment for haemophilia. However, researchers continue to test gene therapy in clinical trials for haemophilia B.

References:

www.haemophilia.org
www.haemophilia.in
www.haemophilia.org

Validated By: Dr. Tulika Seth, AIIMS New Delhi
Dated : 16th October 2014