Factor IX Deficiency (Haemophilia B)

A rare haematological disorder characterised by spontaneous or prolonged haemorrhages due to factor IX deficiency.

Epidemiology
Prevalence is estimated at around 1 in 30,000 males. Hemophilia primarily affects males, but a symptomatic form of hemophilia B in female carriers has also been described with a generally milder clinical picture.

Clinical description
In general, onset of the bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of the clinical manifestations depends on the extent of the factor IX deficiency, both in males and in females. If the biological activity of factor IX is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia B). If the biological activity of factor IX is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia B). If the biological activity of factor IX is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia B). Bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.

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

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

Differential diagnosis
The differential diagnosis should include hemophilia A, von Willebrand disease, 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 fetus allows for preparation of delivery and early newborn medical management.

Genetic counseling
Inheritance is X-linked recessive and genetic counseling 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 carriers. 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 hemophilia and a 25% risk that the baby will be a heterozygous female offspring.

Management and treatment
Treatment is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor IX (plasma-derived or recombinant factor IX concentrates) is the usual treatment approach. Recently, bioengineered prolonged half-life factor IX products were approved for the treatment of hemophilia B and significantly improve the quality of life of patients. Treatment may be administered after a hemorrhage (treatment on demand) or to prevent bleeding (prophylactic treatment). The most serious complications are production of inhibitory antibodies against the administered coagulation factor and anaphylactic shock in response to factor IX therapy. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.

Prognosis
Left untreated, the disease course is severe and in, severe hemophilia B, 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 favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death in patients with hemophilia.

Normal
Range

Percentage of normal factor activity in blood

50%-150%

Number of international units (IU) per millilitre (ml) of whole blood

0.50–1.5 IU

Mild
Haemophilia

Percentage of normal factor activity in blood

5%-40%

Number of international units (IU) per millilitre (ml) of whole blood

0.050–0.40 IU

Moderate
Haemophilia

Percentage of normal factor activity in blood

1%-5%

Number of international units (IU) per millilitre (ml) of whole blood

0.01–0.05 IU

Severe
Haemophilia

Percentage of normal factor activity in blood

less than 1%

Number of international units (IU) per millilitre (ml) of whole blood

less than 0.01 IU

Having haemophilia means that an individual’s body cannot naturally stop the bleeding that occurs once a blood vessel is damaged. These bleeds can be caused both by trauma and stress. If the bleed is not stopped and properly managed it can result in damages to the joints (such as ankles, hips and knees), which can cripple an individual (to the extreme an individual is at risk of losing limbs such as legs and arms) and limit his or her range of movements. Furthermore, intracranial bleeds can be both debilitating and fatal. In recent years, we have still seen reports of deaths in Europe due to untreated intracranial bleeds.

It is important to understand that besides being debilitating and life-threatening, bleeds are also extremely painful. This is why people with haemophilia need to have access to proper pain management.

Haemophilia has a greater impact on people affected by its severe form. This patients’ population needs to constantly have access to treatment and to specialised healthcare services. People with moderate and mild haemophilia may need treatment only if they injure themselves or if they undergo a great deal of stress. They may also need specialised services for dental care and other types of surgery, however in general they are not as affected by the disorder as people with severe haemophilia and are able to live a fairly normal life.

Living with severe haemophilia means that individuals with this condition need to infuse their treatment product several times a week when they are on prophylaxis. The missing factor is administered intravenously either by a medical professional or by the patient him- or herself. Although in most European countries home treatment is possible (this means that individuals can infuse their treatment without the supervision of a medical professional), it is still a time-consuming activity that may have an impact on an individual’s ability to travel, work and take part in social activities.

Finally, it is also important to know that at the moment approximately 30 per cent of the haemophilia population will develop an inhibitor to their treatment. This means that the body will reject the treatment, leaving the haemophiliac with no treatment solutions. For further information on this, please consult the inhibitors’ section.

Inhibitors

People with bleeding disorders are treated with what is called replacement therapy. This means that the missing clotting factor is infused in 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 (ITT). However, this type of treatment requires specialised medical expertise, is expensive and takes a long time. Drugs called bypassing agents can be used to work around inhibitors and help blood clot.

In haemophilia, inhibitors occur more often in individuals with the severe form than those with moderate or mild haemophilia. It is estimated that approximately 30% of patients with haemophilia A and 1.5% to 3% 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, this is why it is important that people with bleeding disorders 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 first (1) and fiftieth (50) day of treatment. Even after the 50 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. Little is known about whether the type of factor concentrates (recombinant or plasma-derived) that is used plays a role, but there are ongoing studies to shed light on this matter.

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