Etiology
Haemophilia B is caused by mutations in the F9 gene (Xq27) encoding coagulation factor IX.

Diagnostic methods
Diagnosis is suspected based on coagulation tests revealing prolonged blood coagulation times (activated partial thromboplastin time – aPTT) and can be confirmed by specific measurements of factor IX activity.

Differential diagnosis
The differential diagnosis should include haemophilia A, von Willebrand Disease (VWD), and other coagulation anomalies leading to prolonged blood coagulation times.

Antenatal diagnosis
Prenatal diagnosis performed on chorionic villi or amniocytes is rapid and informative when the familial, causative F9 mutation is known. Knowing the familial F9 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. Female carriers may express mild to moderate symptoms. 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
Treatment is provided by multidisciplinary comprehensive haemophilia care centres. Replacement therapy consisting of the administration of the missing factor IX (recombinant or plasma-derived factor IX concentrates) is the usual treatment approach. Among recombinant FIX concentrates EHL products are those allowing for more protective and user-friendly prophylactic regimens. Other treatment options include anti-tissue factor pathway inhibitors (anti-TFPI), fitusiran (not yet available in Europe) and gene therapy.

Treatment may be administered after a haemorrhage (treatment on demand) or to prevent bleeding (prophylactic treatment). The most serious complications are the production of inhibitory antibodies against the administered coagulation factor complicated by allergic/anaphylactic reactions. 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 haemophilia B, which is generally fatal. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas 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 the prognosis is favourable. Haemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death in patients with haemophilia.

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 technique 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 anti-tissue factor pathway inhibitors (anti-TFPI) 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 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; due to the risk of allergic reactions in case of inhibitor development people with HB must receive their first treatment under medical supervision in a treatment centre where the right medical facilities and expertise are available in case of inhibitor development or other allergic reactions. In fact, allergic reactions may amplify when treatment is given over time. 

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.