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. Extended half-life factor concentrates, introduced in Canada in 2016, allow the factor to circulate in the bloodstream for a longer time. The median half-life of factor VIII is 16-18 hours; factor IX 50-100 hours.
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 12 months.
- They are easy to mix. A small amount of sterile water, about 5 to 10 millilitres, is mixed with the powdered concentrate. A few seconds to 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
- Some of the concentrates have extended half-lives.
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 cells, such as baby hamster kidney (BHK) cells, Chinese hamster ovary (CHO) cells or human embryonic kidney (BHK) 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.
- In some factor concentrates, a molecule is linkeded to the factor VIII or IX molecule to extend half-life. Depending on the 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 over more than 25 years. Plasma-derived blood products go through four separate safety steps.
- Each blood donor is questioned each time he/she gives blood to find out if he/she has a greater than normal risk of carrying a blood-borne virus. If the person has a risk factor, he/she is not allowed to donate.
- Each blood donation is tested for known pathogens, for example: HIV, hepatitis B and hepatitis C. If a blood donation tests positive, it is not used. The donor can no longer donate blood.
- After the plasma is pooled, the plasma is again tested for known pathogens. If the plasma pool contains any trace of contamination, it is discarded.
- After manufacture, the final product undergoes a viral inactivation process. This is to kill any viruses which might be in the blood product. Methods of viral inactivation are: heating the clotting concentrate with vapour heat, treating the clotting concentrate with solvent detergents and nano-filtering. These viral inactivation methods are very effective in killing HIV, hepatitis B and C.
- 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
- hemophiliacs with inhibitors.
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.
- 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 :
- elevation of the limb
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.’
Desmopressin is a synthetic drug which is a copy of a natural hormone. Desmopressin is not made from blood. Desmopressin is useful in treating people with mild or moderate hemophilia A. It is of no value for people with severe hemophilia A or with any type of hemophilia B.
It acts by releasing von Willebrand factor stored in the lining of the blood vessels. Von Willebrand factor is another protein which is important in blood clotting. One of its roles is to transport factor VIII in the bloodstream. Doctors think that by increasing von Willebrand factor levels, more factor VIII is brought to the site of damaged blood vessels.
Desmopressin can be taken in three different ways.
- It can be injected into a vein. Most often, the brand name for this kind of desmopressin is DDAVP.
- It can be injected under the skin. The brand name for this kind of desmopressin is often Octostim.
- It can be taken by nasal spray. The brand name of the nasal spray is often Octostim Spray.
Desmopressin is usually effective for mild and moderate hemophiliacs. However, different people respond to desmopressin in different ways. Therefore, a doctor needs to do tests to find out each individual’s response to the drug. Ideally, these tests are done before any urgent need for the drug, such as surgery.
Since desmopressin acts by releasing von Willebrand factor stored in the body, you cannot ‘go to the well’ too often. A sufficient amount of time, usually 24 hours, must elapse between doses of desmopressin to allow the body to rebuild its stores.
In serious bleeds or major surgery, desmopressin alone may not be enough to control bleeding. In such a case, a person should also receive a concentrate of factor VIII.
Desmopressin can sometimes have some mild side effects. These are:
- facial flushing
- mild headache
- nausea and abdominal cramps.
Desmopressin can make the body retain water. Therefore, doctors recommend that after receiving desmopressin people drink only enough fluid to satisfy thirst.
If a person has a very bad headache or has not been able to pass water 24 hours after taking desmopressin, he / she should go to the hemophilia / bleeding disorder clinic or emergency room for help.
Cyklokapron and Amicar
Cyklokapron (tranexamic acid) and Amicar (aminocaproic acid) are useful in treating both hemophilia A and B.
Cyklokapron and Amicar are drugs that help to hold a clot in place once it has formed. They act by stopping the activity of an enzyme, called plasmin, which dissolves blood clots.
They do not help to actually form a clot. This means they can not be used instead of desmopressin or factor VIII or IX concentrate.
They can be used to hold a clot in place in mucous membranes such as:
- the inside of the mouth
- the inside of the nose
- inside the intestines (the gut)
- inside the uterus (the womb).
Cyklokapron and Amicar have proven very useful for people with hemophilia and for carriers who experience bleeding. They are used:
- before dental work
- when a person has mouth, nose and minor intestinal bleeding
- for carriers with heavy, prolonged menstrual bleeding.
These drugs come in tablet form.
Cyklokapron and Amicar can sometimes have some mild side effects. These are:
- feeling sick to the stomach (nausea)
- feeling tired or sleepy
- feeling dizzy
- having loose bowel movements (diarrhea)
- having pain in the stomach.
These mild side effects go away when a person stops taking the drugs or the doctor reduces the dosage.