Factor replacement therapy

The basic treatment to stop or prevent bleeding in people with hemophilia A and B is factor replacement therapy. This is the infusion (injection into the bloodstream) of factor VIII and IX concentrates to prevent or control bleeding.

These concentrates come from two sources:

• human plasma (a component of blood) or
• a genetically engineered cell line made by DNA technology, called recombinant.

In both cases, the factor VIII or IX protein is nearly identical to the protein which is lacking in the blood of hemophiliacs. After an infusion of the concentrate, all the proteins needed for clotting are in place. A hemophiliac's blood becomes 'normal', at least for a few hours. This allows the time for a clot to form at the site of the damaged blood vessel. (See The clotting problem in hemophilia.)

Unfortunately, the replacement of the missing clotting factors is not permanent. Half of the clotting factor activity which was infused is removed by the body every 12 to 24 hours. This means that within 2 or 3 days almost none is left. The hemophiliac's blood is again unable to clot normally.

The clotting factors available in Canada today have many advantages over products available in the 1950s, 1960s, 1970s and 1980s. (See The history of hemophilia.) These are the advantages.

• They are very concentrated. This means that a small amount contains enough factor VIII or IX activity to control bleeding, even in major surgery. Thus, they are very effective.
• They are convenient. The concentrates can be stored in a home refrigerator for up to a year or kept at room temperature for 3 to 6 months.
• They are easy to mix. A small amount of sterile water, about 5 to 10 millilitres, is mixed with the powdered concentrate. One minute later the preparation is ready to be infused.
• They are quick to infuse. From beginning to end, the infusion takes no more than 15 to 20 minutes.
• They are very safe. None of the factor VIII or IX concentrates, whether plasma-derived or recombinant, used in Canada since 1988 have ever transmitted HIV or hepatitis.

Factor VIII and IX concentrates can be divided into two categories:

• recombinant, genetically engineered factor VIII and IX
• plasma-derived factor VIII and IX.

Recombinant, genetically engineered factor VIII and IX

Recombinant, genetically engineered factor VIII and IX are not made from human plasma. They are made like this.

• The human factor VIII (or IX) gene is isolated through genetic engineering. The gene contains the code which has instructions for the cell on how to make human factor VIII (or IX).
• The gene is inserted into non-human cells, such as baby hamster kidney cells or Chinese hamster ovary cells.
• These cells are grown in a cell culture. They produce factor VIII (or IX).
• The factor VIII (or IX) is separated from the cell culture and purified.
• Sucrose is then added to stabilize the final factor VIII (or IX) product.

Plasma-derived factor VIII and IX

Plasma-derived factor VIII and IX are made from human plasma. Plasma donations are pooled together in a pharmaceutical plant. Then, the plasma is separated into different products. This is called fractionation. The main products are:

• albumin (to treat burns)
• immune globulins (to treat problems of the immune system)
• factor VIII (to treat hemophilia A)
• factor IX (to treat hemophilia B).

The plasma-derived clotting factor concentrates available in Canada have an excellent safety record - no cases of transmitting HIV, hepatitis B or C. Plasma-derived blood products go through four separate safety steps.

Genetically engineered (recombinant) factor VIII is the clotting factor concentrate used by Canadians with hemophilia A. It has been the product of choice since being introduced in 1993. The brand names used in Canada are Kogenate^®FS, Advate^®, Helixate^®FS and Xyntha^®.

Plasma-derived factor VIII is no longer used by many Canadians with hemophilia A.

Recombinant factor IX, which goes under the brand name of Benefix^® is the blood product used by most Canadians with hemophilia B. It was introduced in Canada on a regular basis in 1998.

Plasma-derived factor IX is also used by Canadians with hemophilia B. The brand names used in Canada are ImmunineVH^® and Mononine^®.

Depending on the person, factor concentrates are given:

• every day
• several times a week
• several times a month
• only in cases of an accident or surgery or
• almost never.

The hemophiliacs who receive factor concentrates the most often are:

• severe hemophiliacs
• children who are very active
• hemophiliacs on prophylaxis therapy.

In prophylaxis therapy, hemophiliacs receive factor concentrates one or more times a week to prevent bleeding. The goal is to keep the levels of factor VIII or IX in the blood high enough that bleeding does not happen. This therapy is common with children with severe hemophilia.

On-demand therapy is the infusion of factor concentrates immediately after the beginning of a bleed. The goal is to stop the bleeding quickly, before any damage is done to the joint or muscle.

Research has shown that prophylaxis therapy gives children the best chance to reach adulthood without damage to their joints.

Yes, for most hemophiliacs, factor concentrates are very effective in stopping bleeding. Hemophiliacs can even have major operations without bleeding more than a person whose blood is normal.

However, some hemophiliacs' bodies reject the infusions of factor concentrates. They develop inhibitors. Inhibitors are the body's way of fighting off what it sees as a foreign agent. This means that as soon as the coagulation factor is injected, it is eliminated. This often happens before the factor concentrate is able to do its work and stop the bleeding.

Fortunately, there are ways to help most hemophiliacs who have inhibitors. (See The complications of hemophilia.)

No. Minor bleeding episodes associated with hemophilia sometimes do not require medical treatment. For example:

• small bruises usually disappear on their own
• bleeding from minor cuts can be stopped by applying pressure
• very minor bleeding into tissues can sometimes be treated by :
  • rest
  • elevation of the limb
  • applying ice to the site of the bleed.

Bleeding into a joint or a muscle (especially around the hip, calf or forearm) is never minor. Treatment with factor concentrates is essential.

Doctors say, 'When in doubt, infuse. Ask questions later.'