Etiology
Haemophilia A is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII.

Diagnostic methods
Diagnosis is suspected based on prolonged coagulation times (activated partial thromboplastin time, aPTT) and can be confirmed by measuring factor VIII activity.

Differential diagnosis
Differential diagnosis includes von Willebrand Disease (VWD), including type 2N VWD and other coagulation anomalies leading to prolonged coagulation times, in particular combined factor V and factor VIII deficiency.

Antenatal diagnosis
Prenatal diagnosis on chorionic villi or amniocytes is rapid and informative when the familial, causative mutation is known. Knowing the familial mutation status in the foetus allows for preparation for delivery and early newborn medical management.

Genetic counselling
Inheritance is X-linked recessive, and genetic counselling is recommended for affected families. For a female carrier, there is a 50% risk that male offspring will be affected and a 50% risk that each female offspring will be a carrier. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with haemophilia and a 25% risk that the baby will be a heterozygous female offspring.

Management and treatment
Management is provided by multidisciplinary, comprehensive haemophilia care centres. Replacement therapy consisting of the administration of the missing factor VIII is the most straightforward treatment approach, using recombinant or plasma-derived factor VIII concentrates. Treatment may be administered after a haemorrhage or prophylactically, to prevent bleeding. The most frequent complication is the production of inhibitory antibodies against the administered coagulation factor. Among recombinant FVIII concentrates, the new generation includes FVIII molecules with enhanced PK properties allowing for higher protective levels and fewer injections during prophylaxis. Other treatment options include FVIII mimetics, anti-tissue factor pathway inhibitors (anti-TFPI) and fitusiran. To date, fitusiran is not available yet in Europe. One gene therapy product was recently licensed for haemophilia A in 2 European countries but was already withdrawn from the market and is no longer available. 

Surgical interventions, most notably orthopaedic surgery, may be carried out but should be conducted in specialised centres.

Prognosis
Left untreated, the disease course is severe in severe haemophilia A. Insufficient or incorrect treatment of recurrent haemarthroses and haematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications, and prognosis is favourable. Haemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death.

Inhibitors
People with bleeding disorders are primarily treated with what is called replacement therapy. This means that the missing clotting factor is infused into their body on a regular basis so that the clotting process can occur normally. Unfortunately, some people develop antibodies, called inhibitors, that neutralise the replacement clotting factor.

This means that the body induces an immune response to the treatment and therefore prevents the infused clotting factor from functioning normally. In this case, bleeds become very hard to control and can lead to permanent joint or muscle damage, making people with inhibitors disabled.

Treatment of inhibitors is the biggest challenge in haemophilia care today. It is possible to get rid of inhibitors using a treatment strategy called Immune Tolerance Induction (ITI). However, this type of treatment requires specialised medical expertise, is expensive, and takes a long time. Drugs called bypassing agents and FVIII mimetics can be used to work around inhibitors and help blood clot.

In haemophilia, inhibitors occur more often in individuals with the severe form than in those with moderate or mild haemophilia. It is estimated that approximately 30% of patients with haemophilia A and 1.5% to 10% of patients with haemophilia B develop inhibitors to factor VIII and factor IX concentrates, respectively. For rare bleeding disorders, figures are unclear due to the limited patient population and the lack of treatment.

Inhibitors typically occur in the first 75 exposures to the treatment. People with HA can also receive their injections in the home setting and come to the centre regularly to check for inhibitor status (every 3-5 EDs for the first 20EDs, then every 10 EDs up to 50 EDs). 

Ideally, children and adults who are newly diagnosed with haemophilia should be tested regularly for inhibitors between the first and the 50th day of treatment. Even after the 50th day of treatment, they should be checked at least twice a year until they have received 150-200 doses and at least once a year after that. Testing for inhibitors should also be done before any major surgery.

Some studies have shown that people who receive regular treatments with factor concentrates to prevent bleeds (prophylaxis or prophylactic treatment) have a lower chance of developing inhibitors in their lifetimes.