With new haemophilia therapeutics on the horizon, greater attention must be paid to accurate and timely diagnosis of the disease. To help clinical lab professionals better understand haemophilia and support emerging innovations that can improve patient outcomes, this article provides a brief introduction to its clinical presentation, diagnosis and treatment.

What is haemophilia and how does it present?

Haemophilia is a bleeding disorder in which the blood is unable to clot properly. This can lead to excessive bleeding after injuries or surgery, as well as spontaneous uncontrolled bleeding, which can cause various medical problems and possibly death.

Haemophilia is caused by deficiencies of clotting factors, or proteins in blood that can help to stop bleeding. People with haemophilia typically have low levels of either Factor VIII or Factor IX. The severity of haemophilia is determined by the amount of factor in the blood. The lower the amount, the more likely a patient will face uncontrolled and dangerous bleeding episodes.

While often considered a rare disease, haemophilia is a major health problem worldwide, impacting over 200,000 people (von Willebrand disease or vWD, another inherited clotting disorder, affects another 84,000 people globally). Haemophilia A, which results from Factor VIII deficiency, affects 1 in 5,000 male births; haemophilia B, which results from Factor IX deficiency affects 1 in 25,000-30,000 male births [1].

Even though haemophilia is almost always inherited, some families have no prior history of the disease. Roughly one-third of the time, haemophilia can occur spontaneously. Although haemophilia predominantly affects males, female carriers are common and in rare instances, can also get haemophilia too [2].

In rare cases, a person can develop haemophilia later in life. The majority of these cases of ‘acquired haemophilia’ involve middle-aged or elderly people, or young women who have recently given birth or are in the later stages of pregnancy.  This condition often resolves with appropriate treatment.

How is haemophilia diagnosed?

For most cases of haemophilia, the diagnostic process begins after a person shows clinical signs of the disorder, such as excessive bleeding or bruising with minor trauma.  In children with severe haemophilia, the diagnosis is usually made in infancy. Mild forms of haemophilia, on the other hand, might not become apparent until adulthood (some people learn they have the disease after they bleed excessively during a surgical procedure).

In most cases, the first step in the diagnostic odyssey will involve screening tests that show if the blood is clotting properly and reveal clotting-factor deficiencies. The main types of screening tests are as follows:

• Complete Blood Count (CBC) – measures the amount of haemoglobin, the number of red & white blood cells, and platelets in the blood
• Fibrinogen – assesses the ability to form a blood clot
• Activated Partial Thromboplastin Time (APTT) – measures the clotting ability of Factor VIII, IX, X and XI
• Prothrombin Time (PT) – measures the clotting ability of Factor I, II, V, VII and X

The full diagnostic workup can be viewed in the chart below:

Additional blood tests may then be performed to determine how much Factor VIII or Factor IX is present. These tests will determine the type of haemophilia and whether it is mild, moderate or severe, depending on the level of clotting factor in the blood. The cut-off points are as follows:

• Mild haemophilia: 5-30% of the normal amount of clotting factors
• Moderate haemophilia: 1-5% of the normal amount of clotting factors
• Severe haemophilia: <1% of the normal amount of clotting factors

For people with a family history of haemophilia, genetic testing might also be used to identify carriers and to make informed decisions about becoming pregnant. It is also possible to determine haemophilia status of the foetus through prenatal testing, but the testing process poses some risks to the foetus.

What therapies are currently available for haemophilia?

Treatment for haemophilia today focuses on replacement therapy, a process that involves using clotting factor concentrates to replenish a patient’s blood. Treatment regimes for haemophilia differ depending on the severity of the condition, with severe cases requiring continuous prophylactic treatment while mild to moderate cases require episodic or on-demand treatment in response to acute bleeding episodes.

Clotting factor replacement therapies are plasma-derived or recombinant.  Standard or extended half-life therapies are used to treat haemophilia A and B and some types of vWD.  As the name suggests, extended half-life products are administered less frequently than standard half-life factor.  Alloantibodies to Factor VIII occur in approximately 30% of patients, which necessitates the need for bypass agents such as activated prothrombin complex concentrate, recombinant FVIIa or emicizumab (the first bispecific antibody developed for the management of haemophilia A).

Although replacement therapy remains the mainstay for haemophilia prophylaxis and treatment, other adjunct therapies like desmopressin, antifibrinolytic agents and pain medicines can also be used. Haemophilia treatment methods depend on the severity of the disease, daily activities of the patient, and the probability of any future surgeries or procedures.

What is next in haemophilia therapeutics?

For all their benefits, as described above, current treatments can also cause complications, including the development of neutralising antibodies (inhibitors) that attack the clotting factor in blood, or—although rare today—viral infections from pooled-plasma products clotting factor concentrates. Another challenge is that treatments may sometimes be delayed, causing haemophilia patients to suffer damage to  joints, muscles, or other parts of the body.

To address these issues and others, researchers are exploring a variety of new approaches to haemophilia therapy, including non-factor replacement therapies, and even gene therapies that hold promise to functionally cure the condition. Early results from clinical trials are promising and have generated optimism in the haemophilia community.  These new approaches will require changes to the diagnostic landscape, such as the use of chromogenic assays, and new considerations around therapeutic monitoring.

As excitement grows over emerging haemophilia therapies, early and accurate diagnosis of haemophilia remains essential for accurate identification and management of the disease.  Without quality diagnostics and lab professionals who understand when and how to use them, patients remain unaware of their situation, putting them at risk of unnecessary or excessive bleeding episodes that can lead to negative, long-term health impacts.

References:
[1] World Federation of Haemophilia Report on Annual Global Survey, 2020.

[2] “Giving a voice to women with haemophilia” by Dr Danielle Nance. Access at <https://www.youtube.com/watch?v=D596TyLDY3A>

Further Resources

• Mayo Clinic, Haemophilia
• Centres for Disease Control and Prevention, Haemophilia Homepage
• World Federation of Haemophilia (WFH) Guidelines for the Management of Haemophilia
• National Heart, Lung, and Blood Institute. NHLBI website.