What is Haemophilia?

Haemophilia is a rare inherited bleeding disorder where the blood doesn’t clot properly. It is caused when blood does not have enough clotting factor.

The deficiency in clotting factor produces a wide range of bleeding episodes, usually into the joints or muscles. Bleeding is most commonly internal.

If internal bleeding is not quickly stopped with treatment, it will result in pain and swelling. Over a period of time bleeding into joints and muscles can cause permanent damage such as arthritis, chronic pain and joint damage requiring surgery.

Cerebral bleeding is one of the leading causes of death in a person with Haemophilia. Currently, there is NO CURE.

The most common type of hemophilia is called hemophilia A. This means the person does not have enough clotting factor VIII (factor eight).

About Hemophilia A

Hemophilia A is a serious genetic disorder in which a person’s blood doesn’t clot properly, leading to uncontrolled and often spontaneous bleeding. These bleeds can present a significant health concern as they often cause pain and can lead to chronic swelling, deformity, reduced mobility and long-term joint damage.

Hemophilia A is caused by missing or defective Factor VIII protein. It is inherited, but in about one-third of known cases it is caused by a spontaneous genetic mutation.

The blood disorder affects all ethnic groups equally. More than half of all people with hemophilia A have a severe form of the disease.

Hemophilia A is carried by the X chromosome. It is inherited in an X-linked recessive manner. As such, two hemophilia-carrying X chromosomes must be inherited for the disease to be active in women, but only in one X chromosome for men.

A female inherits two XX chromosomes, one from her mother and one from her father (XX). A male inherits an X chromosome and a Y chromosome from her father (XY). This means that if a son inherits an X chromosome from his mother who carries hemophilia, he will have hemophilia. But because women receive two X chromosomes, only if both parents carry the defective gene can they develop the disease.

Hemophilia A has three stages: mild, moderate and severe, depending on the ratio of Factor VIII clotting protein in the blood. Mild hemophilia 6-49 percent, moderate hemophilia is 1-5 percent, and severe is less than 1 percent.

People with hemophilia A bleed longer than others, internally or externally. Those with mild hemophilia A generally bleed only after serious injury, trauma or surgery. Often, the disease is diagnosed after one of these situations due to prolonged bleeding, and the first episode may occur only in adulthood. Women often experience heavy menstrual periods and can hemorrhage after giving birth.

Moderate hemophilia patients tend to have more frequent bleeding episodes after less important injuries, or even spontaneously. In severe cases, bleeding may occur spontaneously in the joints and muscles.

Hemophilia A should be diagnosed and treated at a specialized hemophilia center. Tests that evaluate clotting time and a patient’s ability to form a clot may be ordered. A clotting factor test, called an assay, will determine the type of hemophilia and its severity.

The main treatment for hemophilia A is concentrated Factor VIII product, which is administered intravenously.

Patients with severe hemophilia may be given a routine treatment regimen called prophylaxis to maintain enough clotting factor in their bloodstream to prevent bleeds.

About Hemophilia B

Hemophilia B is less common. A person with hemophilia B does not have enough factor IX (factor nine). The result is the same for people with hemophilia A and B; that is, they bleed for a longer time than normal.

Hemophilia B is a genetic disorder caused by missing or defective Factor IX clotting protein. It is also inherited, and just like hemophilia A, it can be caused by a spontaneous genetic mutation in one-third of the cases. This type of hemophilia also affects all ethnic groups equally, but it is about four times as rare as hemophilia A.

Hemophilia B is also carried in the X chromosome and inherited in the same way as people with haemophilia A. Severity levels are also the same as hemophilia A, as well as symptoms.

Like hemophilia A, hemophilia B should be diagnosed at a specialized medical facility. Tests that evaluate clotting time and a patient’s ability to form a clot may be ordered. A clotting factor test, called an assay, will determine the type of hemophilia and its severity.

In hemophilia B, the most common treatment is the administration of concentrated Factor IX, administered intravenously. Severe cases of hemophilia B will also be on prophylaxis treatment, to maintain Factor IX clotting factor.

The signs and symptoms of hemophilia A and B are the same:

• Big bruises
• Bleeding into muscles and joints
• Spontaneous bleeding (sudden bleeding inside the body for no clear reason)
• Prolonged bleeding after getting a cut, removing a tooth, or having surgery.
• Bleeding for a long time after an accident, especially after an injury to the head.

Bleeding into a joint or muscle causes:

• an ache or “funny feeling”
• swelling
• pain and stiffness
• difficulty using a joint or muscle

Inhibitors

A serious complication of treatment is the development of inhibitors to factor replacement therapies. Inhibitors are antibodies developed by the body’s immune system that bind to and block the efficacy of replacement factors, making it difficult, if not impossible, to obtain a level of clotting protein sufficient to control bleeding.

The immune system defends the body from harmful germs and viruses. Sometimes in the case of an inhibitor, a person’s immune system reacts to proteins in factor concentrates as if they were harmful foreign substances because the body has never seen them before. When this happens, inhibitors (also called antibodies) form in the blood to fight against the foreign factor proteins. This stops the factor concentrates from being able to fix the bleeding problem.

Bleeding is very hard to control in someone with hemophilia who develops inhibitors. A person with inhibitors faces more bleeding and pain because treatment with factor concentrates does not work. In patients with persistent inhibitors, if bleeding into the muscles and joints (the most common type of bleeding in hemophilia) is not controlled, permanent joint damage is likely.

A person with hemophilia who develops inhibitors does not get better after standard treatment with factor concentrates. Inhibitors are suspected when the person, family members, or medical staff notice that treatment is less effective than it used to be.

Signs and symptoms of inhibitors include:

• A bleed is not promptly controlled with the usual dose of factor concentrates.
• Normal treatment seems less and less effective.
• Bleeding is more and more difficult to control.

Today, inhibitors are often discovered during a routine laboratory test. A diagnosis based on signs and symptoms of inhibitors should be confirmed by repeated laboratory tests.

For people with sufficient access to care, treatment of inhibitors is one of the biggest challenges in hemophilia today. It is possible to get rid of inhibitors using a technique called immune tolerance induction. However, this type of treatment requires specialized medical expertise, is expensive, and takes a long time.

Drugs called bypassing agents can be used to work around inhibitors and help blood clot.

How does immune tolerance induction work?

With immune tolerance induction (ITI) therapy, factor concentrate is given regularly over a period of time until the body is trained to recognize the treatment product without reacting to it. When immune tolerance induction is successful, the inhibitors disappear and the patient’s response to factor concentrates returns to normal. The majority of people who undergo ITI therapy will see an improvement within 12 months, but more difficult cases can take two years or longer.

Different dosing schedules are currently being used for ITI therapy, and the best one for eliminating inhibitors has not yet been defined. Daily high doses of factor concentrates may induce tolerance faster, but this type of regimen is more expensive and carries different risks than do schedules that involve giving less factor concentrate, less frequently.

What factors influence the outcome of immune tolerance induction therapy?

It is still unclear why ITI works better in some people than in others. Factors that have been associated with successful ITI therapy include:

Beginning ITI in people whose inhibitor levels are below 10 BU/mL and ideally below 5 BU/mL.
Beginning ITI in people whose inhibitor levels have never gone higher than 200 BU/mL and have ideally stayed below 50 BU/mL.
Beginning ITI within five years of a person being diagnosed with the inhibitor.

Stopping treatment early or taking breaks in the treatment schedule (missed doses) may interfere with the success of ITI and/or increase the time it takes for the person with inhibitors to achieve tolerance.

Researchers are also looking at whether the type or brand of factor concentrate (intermediate or high-purity plasma-derived factor concentrates or recombinant products) used in ITI can influence the success of therapy. So far, similar success rates have been obtained with both recombinant and plasma-derived products.

About Hemophilia C

A third, rarer form of haemophilia is called Hemophilia C.

Haemophilia C (also known as plasma thromboplastin antecedent (PTA) deficiency or Rosenthal syndrome) is a mild form of haemophilia affecting both sexes, due to factor XI deficiency.

The disease was first recognized in 1953 in patients who experienced severe bleeding after dental extractions.

The incidence of hemophilia C is estimated at one in every 100,000 people in the general population. This is because a Factor XI deficiency is inherited in an autosomal recessive pattern, meaning both parents must carry the gene to pass it on to their children. Unlike hemophilia A and B, men and women are affected equally.

Factor XI plays an important role in the clotting cascade, which leads to clotting. It helps generate more thrombin, a protein that converts fibrinogen to fibrin, which traps platelets and helps hold a clot in place.

Unlike hemophilia A and B, symptoms don’t correlate with Factor XI levels in the blood. People with lower levels may bleed less than those with higher levels of Factor XI. Many women may not know they’re deficient in Factor XI until they experience menorrhagia (heavy menstrual periods) or postpartum bleeding. In hemophilia C, joint and muscle bleeds are uncommon.

Common symptoms:

• nosebleeds (epistaxis)
• easy bruising
• heavy or prolonged menstrual bleeding (menorrhagia)
• abnormal bleeding during or after surgery, injury, or childbirth

Other reported symptoms:

• bleeding in the gut (gastrointestinal hemorrhage)
• bleeding in the mouth, particularly after dental surgery or tooth extraction
• blood in the urine (hematuria)

To diagnose hemophilia C, doctors will order a bleeding time test, platelet function tests, and prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests.

Treatment:

There are several treatments available to help control bleeding in people with factor XI deficiency.

• Factor XI concentrate
• Antifibrinolytic drugs (used to control nose bleeds or after tooth extraction)
• Fibrin glue (used to maintain clots after mouth bleeds)
• Fresh frozen plasma (FFP) (used to control bleeding after circumcision and hernia repair)

Excessive menstrual bleeding in women with factor XI deficiency may be controlled with

• Hormonal contraceptives (birth control pills)
• Intra-uterine device (IUDs), or
• Antifibrinolytic drugs.

Sources;

• What is Haemophilia https://www.wfh.org/en/page.aspx?pid=646
• What are inhibitors https://www.wfh.org/en/page.aspx?pid=651
• What is factor XI deficiency? https://www.wfh.org/en/page.aspx?pid=660
• Types of Haemophilia https://hemophilianewstoday.com/types-of-hemophilia/