Bleeding Disorders

Hemophilia

Hemophilia is an inherited blood clotting disorder, occurring primarily in males, in which one or more of the 15 vital clotting proteins, called clotting factors, are either deficient or inactive. If you will, imagine a set of dominos lined up on end, in a row, placed a little less than one domino length apart. Normally, if you pushed the first domino, you would have a cascade effect. However, if a domino is missing the sequence will be interrupted and some of the dominos will be left standing. The same is true of the clotting process. If one of the elements in the clotting process is missing or inactive, the next clotting factor in the sequence will not be triggered and the clotting process will stop. Many believe that an individual with hemophilia will bleed harder or faster than normal, or that they can bleed to death from a small cut. THIS IS NOT TRUE! However, individuals with hemophilia, because of their inability to form a blood clot, will bleed longer. Small surface cuts and bruises are usually not a problem and normally clot on their own. Internal bleeding into a muscle, joint, organ, or head is more serious and typically requires treatment. Head injuries resulting in brain hemorrhage can also be life threatening.

Types of Hemophilia

Inheritance

More than 95% of all of the individuals with Hemophilia are males. In fact, about one out of every 5,000 males is born with Hemophilia. In about one-third of these cases, there is no known family history of the disoder

Hemophilia A and B are both inherited sex-linked disorders that are generally passed on from mother to son: A woman who has the gene for hemophilia, is called a carrier, and has a 50% chance of passing the gene on to each child she has. If she bares a child with the gene for hemophilia and the child is a female, she will also be a carrier. However, if her child is a male and inherits the gene, he will have Hemophilia. Various tests are available to determine if a woman is a carrier. Prenatal tests are also available to determine the Hemophilia status of the baby.

All female children of a man who has Hemophilia will be carriers. If he fathers a child with a carrier of the same disorder, there is a possibility that their female children will be born with the condition. In order for a male with hemophilia to father a male child with hemophilia, the gene would have to come from the mother as well. Some bleeding disorders, like von Willebrand’s, are not sex-linked; occurring with equal frequency in men and women.

Severity

Hemophilia is divided into three classes: severe, moderate and mild. The severity, and thus seriousness of the symptoms, is based on the amount of active clotting factor in the blood. The normal amount of clotting factor an individual maintains generally varies between 50% and 150%. Whereas, individuals diagnosed with Hemophilia have less than 50%.

Individuals with Mild Hemophilia have active clotting factors vary from 6% to 50%. These individuals rarely experience a bleeding problem and may bleed only after severe injury.

Individuals with Moderate Hemophilia have between 1% and 5% active clotting factor. These individuals have fewer bleeds than individuals with Severe Hemophilia, usually bleeding only as a result of injury.

Individuals with Severe Hemophilia have less than 1% active clotting factor. As a result, they are subject to the greatest number of bleeds, often several per month, and may bleed spontaneously.

All individuals with hemophilia must take appropriate precautions when having dental work or surgery performed. Factor level and severity do not change over the life of an individual. Moreover, the severity of factor deficiency tends to be familial; relatives will often show similar factor levels and severity.

Treatment

The treatment of hemophilia is very expensive, costing the average individual with hemophilia upwards of $140,000 per year, and usually consists of injecting a concentrated form of the missing clotting factor into the bloodstream.

A single infusion of factor, when administered early, is often effective in controlling most minor bleeding episodes. More serious bleeds may require several infusions over several days. Individuals with mild hemophilia A can often be treated with a synthetic hormone called desmopressin acetate (DDAVP) which may boost factor VIII levels high enough to make treatment with clotting factor unnecessary.

Treatment is more complicated for some individuals whose immune systems produce antibodies, or inhibitors, which attack the factor molecule and render it ineffective. The development of inhibitors occurs in approximately 20 to 30% of individuals with hemophilia A and 2-3% of the individuals with hemophilia B. The development of inhibitors is a serious complication, which requires an individual treatment plan and close monitoring.

Treatment Evolution

The first effective means of treating hemophilia involved infusing cryoprecipitate, a cold-insoluble solid that forms when frozen blood plasma is thawed. Cryoprecipitate was first used to treat hemophilia in 1964 when it was recognized that it could be separated from the plasma by centrifugation and stored frozen, then dissolved by warming and infused. A major advance in the treatment of hemophilia occurred in 1966 with the development of lyophilized (freeze-dried) concentrates of factor VIII from large pools of cryoprecipitate. Compared to cryoprecipitate, the concentrates were much easier to use and store and had a much higher concentration of active factor VIII. Concentrates also enabled people with hemophilia to infuse themselves at home, resulting in faster, more convenient treatment and significantly increased autonomy.

The purity of factor VIII concentrates improved dramatically in 1988 with the introduction of monoclonal antibody affinity purification. Monoclonal antibodies are substances capable of binding with the factor VIII molecule and removing it from plasma or cryoprecipitate, after which the factor VIII is separated from the monoclonal antibodies. This purification procedure results in ultra pure factor VIII with almost no extraneous proteins, which may cause infusion reactions and adversely affect platelet and immune function.

The latest milestone in factor replacement therapy occurred late in 1992 when the FDA approved synthetically produced factor VIII, known as recombinant factor VIII. Synthetic factor VIII uses recombinant DNA technology to alter a group of culture cells genetically to allow them to produce factor VIII. The factor VIII is then purified in a manner similar to monoclonal factor VIII. Both of these types of products have been shown to be very pure.

What does the future hold? Current research is aimed at finding a temporary or permanent cure for hemophilia by utilizing gene therapy. Gene therapy involves inserting the gene for the missing factor into the cells of a person with hemophilia. These altered cells may produce normally active factor for several months or possibly years. There are still many obstacles to be overcome before the procedure can become a reality, however most researchers are confident that solutions to these problems will be found within the near future.

Treatment Complications

Ironically, the advent of concentrates in the mid 60’s that allowed individuals with hemophilia more autonomy to live normal lives, also infected many of them with several blood-borne viruses.

During this time, manufacturers made factor VIII and IX economically feasible by making the concentrates from pools of 2,000 to 30,000 units of plasma. Unfortunately, these concentrates were not treated to inactivate viruses. Because of this, users of concentrate ran a high risk of being infected by blood-borne viruses.

In the mid to late 60’s, hepatitis B and hepatitis C were the first viruses to appear in the blood supply, inadvertently infecting many individuals with hemophilia. By the late 1970’s the Human Immunodeficiency Virus (HIV), the virus that causes Acquired Immune Deficiency Syndrome (AIDS), appeared in the blood supply, adding a whole new element to contend with. Unfortunately, HIV tests were not readily available until early 1985. As a result, the a large number of individuals with severe hemophilia who infused factor concentrate between 1978 and 1985 were infected with HIV.

Fortunately, today’s monoclonal factor concentrates are highly purified and treated to inactivate viruses and recombinant is available. For young people with hemophilia born since 1986, treatment with monoclonal purified concentrates and recombinant products has all but eliminated many of the common complications associated with preceding versions of concentrates. Although no blood product is guaranteed to be 100% safe, there have been no cases of HIV infection since viral inactivation procedures were instituted in 1985.