Brief overview
- Description: Hemophilia is a congenital disorder of blood clotting. There are two main forms: Hemophilia A and B.
- Progression and prognosis: Hemophilia cannot be cured. However, bleeding and complications can be prevented with the right treatment.
- Symptoms: Increased tendency to bleed, resulting in easy bleeding and bruising.
- Treatment: Mainly replacement of the missing coagulation factor; in certain cases antibody therapy or gene therapy; in mild cases desmopressin if necessary.
- Cause and risk factors: Genetic deficiency or defect in certain proteins that are necessary for blood clotting (clotting factors).
- Diagnosis: Medical history, measurement of various blood parameters (aPTT, Quick value, plasma thrombin time, bleeding time, platelet count), determination of the activity of relevant coagulation factors.
- Prevention: Not possible due to genetic cause; however, correct treatment prevents excessive and potentially life-threatening bleeding.
What is hemophilia?
If these clotting factors are not produced in sufficient quantities or in sufficient quality, blood clotting is impaired. This is why haemophilia patients tend to bleed excessively long or heavily.
Incidentally, hemophilia is not a malignant blood disorder (such as blood cancer = leukemia)!
The medical term for a blood clotting disorder with an increased tendency to bleed is “haemorrhagic diathesis”. The general term for a coagulation disorder is “coagulopathy”.
Haemophilia: forms
There are different coagulation factors. Depending on which coagulation factor is affected in haemophilia, doctors distinguish between different forms of the disease. The most important are haemophilia A and haemophilia B:
- Haemophilia A: This involves coagulation factor VIII (antihaemophilic globulin A). Either the body does not produce it in sufficient quantities or it is defective. Around 85 percent of all hemophiliacs suffer from hemophilia A. Almost all of them are men.
- Haemophilia B: Those affected lack coagulation factor IX (antihaemophilic globulin B or Christmas factor). Here, too, they are mostly male.
Another bleeding disorder that is usually inherited is von Willebrand-Jürgens syndrome, also known as von Willebrand syndrome (vWS). Here, the transport protein of coagulation factor VIII – the von Willebrand factor – is present in insufficient quantities or is defective. As with haemophilia A and B, this leads to an increased tendency to bleed. You can read more about this in the article “von Willebrand syndrome”.
How does haemophilia A and B progress?
Most people with hemophilia are affected by hemophilia A. The disease is present from birth and is chronic.
Hemophilia A – like other forms – is not yet curable. However, there are therapies that compensate for the effects of haemophilia or the lack of clotting factors. As a result, people with haemophilia now generally have the same life expectancy as healthy people.
Without treatment, “haemophiliacs” can bleed conspicuously heavily or for a long time, even with minor injuries. It is very rare for people with haemophilia to bleed to death as a result of an injury. But the excessive bleeding damages various organs in the long term.
How hemophilia progresses in individual cases depends not only on the therapy but also on how severe the disease is in the person affected.
What are the symptoms?
The symptoms of haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency) are the same – although a different coagulation factor is affected in each case.
Most of those affected often develop “bruises” (hematomas) as early as childhood. In addition, internal bleeding in any organ area is possible in haemophilia.
Bleeding into joints is typical. These often occur spontaneously (i.e. without prior trauma such as a fall injury), especially in severe haemophilia. The bleeding causes the “synovial fluid” (joint fluid, synovia) to become inflamed. Doctors then speak of acute synovitis. It manifests itself as a swollen, overheated joint. The skin over it is reddish in color. The joint is sensitive to touch and its mobility is painfully restricted. This is why those affected often adopt a relieving posture.
Chronic synovitis in haemophilia can result in permanent joint changes. Doctors refer to this as haemophilic arthropathy.
In principle, synovitis in haemophilia can occur in all joints. However, the knee, elbow and ankle joints are most frequently affected.
Other possible haemophilia symptoms can result from bleeding into the muscles: The bleeding damages the muscle tissue and, in severe cases, leads to muscle weakness.
Severe bleeding in the mouth and throat affects the airways. Bleeding in the brain is rare, but also dangerous: it impairs thinking and concentration, for example. Severe bleeding in the brain can even be fatal!
Bleeding in the abdomen can also be life-threatening in extreme cases.
Haemophilia: degrees of severity
The severity of the bleeding disorder determines how clearly symptoms manifest themselves. As a general rule, the fewer functional clotting factors are present, the more pronounced the clinical picture.
The classification of haemophilia A and B into three degrees of severity is based on how much the activity of the clotting factors is reduced compared to their function in healthy people:
Mild haemophilia
Moderately severe haemophilia
The activity of the coagulation factors (factor activity) is one to five percent of normal activity. The symptoms usually become apparent in the first few years of life with unusually prolonged bleeding and frequent bruising. As with mild hemophilia, bleeding is usually the result of injuries or operations. Spontaneous bleeding is rare.
Severe haemophilia
Factor activity is less than one percent of normal activity. The smallest injuries or bumps cause severe bleeding under the skin (bruising) in those affected. Internal bleeding also occurs more frequently, for example painful bleeding into large joints such as the knee or elbow. Typically, many bleedings have no recognizable cause. Doctors then speak of spontaneous bleeding.
How is hemophilia treated?
Haemophilia therapy depends on the type and severity of the haemophilia. The attending physician will draw up a suitable treatment plan for each patient.
Factor concentrates
Factor concentrates must be injected into a vein. Many sufferers learn to inject them themselves. This gives them a great deal of independence despite the disease.
In the case of mild haemophilia, the administration of factor concentrate is only necessary when needed (on-demand treatment): The anticoagulant is administered, for example, in the event of severe bleeding or before a planned operation. Minor injuries such as abrasions, on the other hand, do not require treatment with factor concentrate. Bleeding can usually be stopped by applying light pressure to the bleeding area.
People with moderate to severe haemophilia, on the other hand, need regular injections of preparations containing the missing clotting factor (long-term treatment). How often this is necessary depends, among other things, on the particular preparation, the patient’s activity and their individual bleeding tendency.
A possible complication of treatment with factor concentrates is so-called inhibitor hemophilia: some people form antibodies (inhibitors) against the coagulation factors in the factor concentrate. These inactivate the added coagulation factor. The therapy is then not as effective as desired. This complication occurs significantly more frequently in people with haemophilia A than in people with haemophilia B.
Desmopressin
In mild cases of haemophilia A, it is often sufficient to administer desmopressin (DDAVP) as required (e.g. for minor bleeding), for example as an infusion. This is an artificially produced protein that is derived from the body’s own hormone vasopressin (adiuretin, ADH).
Desmopressin causes the inner vessel wall (endothelium) to release stored factors for blood clotting: coagulation factor VIII and its carrier protein, von Willebrand factor (vWF). However, because these storage quantities in the endothelium are limited, the active substance can only be administered for a few days.
Desmopressin retains water in the body, thus reducing the amount of urine. A side effect of DDAVP therapy can therefore be water intoxication, which throws the blood salts (electrolytes) out of balance. This can lead to seizures, for example.
Antibody therapy
There is another treatment option for haemophilia A: the regular administration of an artificially produced antibody (emicizumab). This binds simultaneously to the coagulation factors IXa and X, as the coagulation factor VIII normally does. Emicizumab therefore takes over the role of the factor missing in haemophilia A in the coagulation cascade. This helps to prevent bleeding.
Gene therapy
The first gene therapy for adults with severe haemophilia A (Valoctocogene Roxaparvovec) has been approved in the European Union since 2022. It can prevent or reduce bleeding. The gene therapy works as follows:
The genetic blueprint for the missing coagulation factor (VIII) is introduced into the body of the affected person via an infusion. A modified virus (adeno-associated virus, AAV), which cannot reproduce in the human body, acts as a transport vehicle. It transports the gene for factor VIII into some liver cells, where it can be read.
What causes hemophilia?
Hemophilia is a congenital genetic disease that is usually inherited. Less frequently, it occurs as a result of a spontaneous genetic mutation (spontaneous mutation).
In haemophiliacs, the genetic information for the production of a functional coagulation factor is defective. The incorrect blueprint means that the clotting factor in question – factor VIII in haemophilia A and factor IX in haemophilia B – is not produced sufficiently in a functional form. This disrupts blood clotting: wounds do not close as quickly, meaning that bleeding lasts for an unusually long time. In severe cases, spontaneous bleeding is also possible.
Haemophilia A and B: Inheritance
The genes for the coagulation factors are located on the X chromosome. If one of the two X chromosomes in women contains a defective blueprint for a coagulation factor, the other X chromosome can usually compensate for this. The women are therefore largely asymptomatic throughout their lives. However, they can act as carriers (conductors) for the genetic defect: If they father children with a man who is healthy for clotting, they have a 50% probability of passing the genetic defect on to them:
- Daughters who have received the defective X chromosome from their mother are then also potential conductors of hemophilia.
- Sons who have inherited the defective X chromosome from their mother cannot compensate for this because they do not have a second X chromosome. They are therefore born as hemophiliacs.
When men with haemophilia have children with a healthy woman (not a conductor),
- then all daughters are conductors,
- and all sons are born without the genetic defect.
If a female conductor has children with a male hemophiliac, the probability of both sexes having the disease is 50 percent. The decisive factor is which of her X chromosomes the mother passes on to a child:
- If the mother passes on her defective X chromosome, this means that both daughters and sons will be born with haemophilia.
Experts describe the inheritance of hemophilia as autosomal recessive (sex-linked recessive).
How is hemophilia diagnosed?
If someone frequently bleeds spontaneously or bruises very easily, this is a possible indication of haemophilia. This suspicion is particularly likely if there are known cases of hemophilia in the family tree. To clarify the suspicion of haemophilia, the GP is the first point of contact. They can then refer those affected to a specialist in haematology or a specialized medical center (haemophilia center).
The doctor will first take the patient’s medical history (anamnesis): He or she will ask the patient to describe the symptoms in detail, ask about any underlying illnesses and whether there are any known cases of haemophilia in the family.
Laboratory tests are particularly important for clarifying a possible hemophilia. The doctor takes a blood sample from the patient to have it tested in the laboratory for various parameters:
- In haemophilia, the so-called aPTT is prolonged compared to healthy people. This is the “activated partial thromboplastin time” (you can read more about this in the article PTT).
- At the same time, the so-called Quick value (see INR value) and the plasma thrombin time (PTZ) are generally unremarkable; they are only prolonged in severe haemophilia.
To determine whether someone has haemophilia A or haemophilia B, the activity of the relevant coagulation factors (VIII, IX) must be analyzed.
Depending on requirements, further examinations may be necessary, for example ultrasound examinations if bleeding into joints is suspected as a result of haemophilia.
Haemophilia: test for newborns and unborn babies
If haemophilia has already occurred in a family, the coagulation of male newborns is usually tested immediately after birth. This allows hemophilia to be detected at an early stage. A test can also be carried out during pregnancy to determine whether the unborn baby has haemophilia.
If a woman suspects that she has a genetic predisposition to haemophilia and is therefore a potential carrier (conductor), a genetic test will provide clarity.
How can hemophilia be prevented?
In the vast majority of cases, haemophilia is genetic. It is therefore not possible to prevent it. Factor preparations and antibody therapy keep excessive bleeding in check. In many cases, this helps to prevent the consequences of bleeding, such as joint damage. Doctors also recommend that people with haemophilia avoid activities or sports with an increased risk of injury as far as possible.
