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Introduction to Haemophilia

Haemophilia is a genetic disorder that impairs blood coagulation. Due to a lower level of specific clotting factors the blood's ability tofor coagulate is reduced meaning that even small injuries can lead to severe blood loss.  The two most common types of Haemophilia are:

  • Haemophilia A – caused by deficiency of coagulation factor VIII (FVIII)
     
  • Haemophilia B – caused by deficiency of coagulation factor IX (FIX)


Treatment Options for Haemophilia

The treatment differs according to the severity of the haemophilia, classified as mild, moderate or severe, depending on how much clotting factor is still detectable in the patient’s blood. Most patients have severe haemophilia A (residual activity of less than 1% of normal).

Today most haemophilia patients are treated by administering the missing coagulation factor (VIII or IX) via a vein directly into the bloodstream. This is most often performed at home by self-administration and takes no more than a few minutes when the patient or care-giver e.g. parent, is properly trained by the haemophilia centre staff.
 

Types of Treatment

There are two main treatment regimes:

  • Prophylactic treatment: this is an ongoing treatment to prevent bleeding and given with regular doses every 2 to 3 days.  This regime is often used in infants, children and adults with severe haemophilia and provides vital protection against bleeding into joints, thus preventing permanent joint damage.  This type of treatment is now standard in young people until the end of their growing phase.
     
  • On-demand treatment: this is used to instantly treat sudden haemorrhages and is the most common type of treatment in adult patients. 


Natural and Artificially Produced Clotting Factors

Extensive research and development work was necessary before replacement therapy with modern coagulation factors (VIII, IX) could become today’s standard. In the late 1960s, the first factor concentrates found their way into pharmacies and dispensaries. Like the majority   of the preparations used today, they were obtained from human blood. These made effective haemostasis possible for the first time. Since the late 1990s, clotting factors have also been produced by genetic engineering, as so-called “recombinant” preparations.

In modern factor concentrates derived from human blood, attention is paid to particularly high purity and safety. Both are ensured by numerous control steps during as well as after manufacture; the entire production process is subject to strict regulatory guidelines. Thanks to this, for more than 20 years no dangerous pathogens have been transmitted by factor concentrates.

Treatment with clotting factors is still the best therapy of haemophilia available. Research, however, makes further progress to get a better grip on various therapeutic problems (e.g. inhibitor formation, see below).
 

Natural Factor VIII

Genetically engineered coagulation factors are proteins artificially generated in cultured animal cells, while the preparations produced from human blood plasma contain the original natural factor in concentrated form. Natural factor VIII is commonly known as 'wild-type'. Naturally obtained clotting factor is repeatedly purified, concentrated and filtered in multiple steps, and finally freeze-dried. The modern process is more gentle and therefore the factor concentrate maintains its natural composition. Of particular importance here is the content of another protein substance essential for blood clotting, the so-called von Willebrand factor (vWF). vWF is found in the bloodstream and scans the blood vessels for injuries. In addition, it transports and stabilizes factor VIII.

Researchers have found in recent years that factor preparations comprising a specific quantity of the combination of factor VIII and vWF – as present in the blood of healthy persons – have properties advantageous for haemophilia treatment. For example, the clotting factor is naturally stabilized by vWF, so additives such as albumin or sugar are not necessary.


Inhibitor Haemophilia – a Serious Issue in Treatment

As with all foreign proteins, therapy by introducing coagulation factors may lead to the formation of antibodies: the body's attempt to get rid of the substances perceived as “alien”. In haemophilia patients, these antibodies are known as “inhibitors” and cause the injected factor to become ineffective. This usually happens during the first three months of treatment and will affect up to 30% of patients with haemophilia A (it is much rarer in haemophilia B, only about 3%).

This said, inhibitors can arise at any time and are usually noticed by the usual dosage of factor being no longer sufficient to stop bleeding. The Bethesda test allows the determination of the presence and quantity of inhibitors. The more inhibitors in the blood, the more clotting factor can be rendered ineffective.

If in inhibitor haemophilia bleeding cannot be stopped by the usual factor treatment any more, there are other coagulation-inducing substances, which must then be administered for a short term. This is not a good permanent solution, however.

In haemophilia A patients with high levels of inhibitors require a special treatment method to permanently overcome this serious complication which can prevent successful therapy. This is described below.
 

Immune Tolerance Induction – Tricking the Immune System by Applying Large Quantities of Factor

This treatment method is called immune tolerance induction, or ITI. It is intended to induce tolerance in the body’s immune system to therapy with coagulation factors so that no inhibitors are formed.  Once the patient achieves tolerance it should be possible to carry out the treatment with factor VIII quite normally. This treatment can take a very long time to be successful, maybe up to 2 years. There is some evidence that vWF containing products can improve the chance of success even in patients who have previously failed treatment with recombinant product.