Introduction to Haemophilia

Treatment Options for Haemophilia

The treatment differs according to the severity of the haemophilia, which is 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 factor VIII less than 1%).
In patients with mild haemophilia A (residual activity of factor VIII more than 10%), treatment with desmopressin (abbreviation: DDAVP, trade name: e.g. Minirin®) is an option. This substance leads to release of factor VIII from internal storage, briefly increasing its activity in the blood. All other haemophilia patients are today administered the missing coagulation factor (VIII or IX) via a vein directly into the bloodstream. This is performed almost always at home by self-administration, takes no more than a few minutes and is learned by the parents or the patient in a haemophilia centre under the supervision of experienced caregivers.

Permanent Treatment (Prophylaxis) and Treatment on Demand

Concerning the type of treatment, preventive permanent treatment (regular administration of the coagulation factor up to three times per week = prophylaxis) is distinguished from on-demand treatment (instant administration in case of a sudden haemorrhage). Prophylaxis is often used in infants, children and adolescents with severe haemophilia (residual activity of clotting factor less than 1%). It also provides the very important protection from repeated bleeding into joints, thus preventing permanent joint damage. This type of treatment is now standard in most children and is administered until the end of growth. In adulthood, then often on-demand treatment is applied. But even here there are situations where it is medically expedient to continue the permanent prophylactic treatment or temporarily resume it. The dosage at which the respective coagulation factor must be given depends on the individual patient, the location of the bleeding and its severity. In doubt, always consult the haemophilia centre for advice.

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 it from human blood plasma. 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 plasma, 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 filtrated in multiple steps, and finally freeze-dried. The more modern and gentler this workflow for preparations from blood plasma, the more the factor concentrate maintains its typical natural composition. Of particular importance here is the content of another protein substance essential for blood clotting, the so-called von Willebrand factor (abbreviation: vWF). vWF is located 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 can be dispensed with. It is also protected from premature degradation  in the bloodstream, so it can be effective for a longer time. The body’s defence system is overall positively influenced, including [prevention of] formation of so-called inhibitors, which are dreaded in haemophilia patients.

Inhibitor Haemophilia – a Serious Issue in Treatment

As with all externally supplied proteins, therapy with coagulation factors may lead to formation of defensive substances, the so-called antibodies. The human body attempts to get rid of the substances perceived as “alien” or neutralize them. In haemophilia patients, these antibodies are also called “inhibitors” and cause the injected factor to become ineffective. Usually this happens during the first three months of treatment and affects, over the course of the treatment, a total of up to 30% of patients with haemophilia A (in haemophilia B, only about 3%). Inhibitors can thus arise at any time and are usually noticed by the usual dosage of factor being no longer sufficient to stop bleeding. The so-called Bethesda test permits determination of the presence and quantity of inhibitors. The more inhibitors in the blood, the more clotting factor can be intercepted and rendered ineffective. Here now the natural von Willebrand factor comes into play. As researchers have shown, vWF protects factor VIII from attack by immune cells. In addition, it transports factor VIII into the important area of the spleen, in which tolerance to the therapeutically supplied clotting factor is organized. Thus, it is perceived as less foreign, and few or no inhibitors are formed.

In scientific studies it could be shown that plasma factor preparations with a significant content of von Willebrand factor only rarely trigger formation of inhibitors.

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 blood levels of inhibitors therefore today a special treatment method is used to permanently overcome this serious obstacle to further 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, abbreviated ITI. It is intended to accustom the body’s defence system to therapy with coagulation factors to the degree that no inhibitors are formed any more. Eventually, it should be possible again to carry out the therapy with factor VIII quite normally. Until then, however, up to two years may pass, requiring a lot of patience and willpower, as up to twice a day high doses of factor VIII may have to be administered. In many patients, this method leads to success. Meanwhile, researchers have also found evidence here, too, that factor VIII products with a high content of von Willebrand factor are particularly effective. This applied even to patients in whom ITI had previously been unsuccessful and therefore needed to be carried out a second time.