Types and Causes of Haemophilia: Genetic vs. Acquired

When we hear the word “haemophilia,” most people picture a condition someone is simply born with – a hereditary disorder passed silently through families. And while that is largely true, haemophilia is not always inherited. The condition exists in two fundamentally different forms: one written into a person’s DNA from birth, and another that develops unexpectedly during a person’s lifetime. Understanding the distinction between genetic (inherited) haemophilia and acquired haemophilia – and the specific clotting factor each type involves – is essential to grasping the full scope of this bleeding disorder.

What is haemophilia?
Genetic haemophilia: the inherited form
How the genetics work
Haemophilia A: the most common type
Haemophilia B: Christmas disease
Haemophilia C: the autosomal form
Acquired haemophilia: the autoimmune disorder
What causes acquired haemophilia?
Who is most affected?
Known triggers and associated conditions
Key differences at a glance

What is haemophilia?

Haemophilia is a rare bleeding disorder in which blood does not clot properly. Normal blood clotting depends on a series of proteins called clotting factors. When any of these factors are absent or deficient, even a minor injury can result in prolonged bleeding. In severe cases, internal bleeding into joints, muscles, or organs can cause significant long-term damage. Haemophilia is the most common severe hereditary haemorrhagic disorder, though it is not limited to inherited cases alone.

Genetic haemophilia: the inherited form

The most well-known form of haemophilia is genetic – present from birth and caused by mutations in specific genes responsible for producing clotting factors. Most people who have haemophilia are born with it, inheriting the condition from a parent. The specific gene that is mutated determines which type of haemophilia a person has.

How the genetics work

Haemophilia A and B are both inherited in an X-linked recessive pattern. The genes for clotting factors VIII and IX are located on the X chromosome. Since males have only one X chromosome (XY), a single mutated copy of the gene is enough to cause the disorder – there is no second X chromosome to compensate. Females, having two X chromosomes (XX), are typically carriers: they carry one mutated copy but usually do not develop the full condition because their second X chromosome can still produce sufficient clotting factor.

A carrier mother has a 50% chance of passing the mutated gene to each of her sons, who would then develop haemophilia. Spontaneous mutations account for about 33% of all haemophilia A cases, meaning a significant number of those diagnosed have no known family history of the condition.

Haemophilia A: the most common type

Haemophilia A, also called classic haemophilia, is caused by a lack or low level of clotting Factor VIII. It is the most frequently occurring type, affecting approximately 1 in 5,000 males. The underlying cause is a mutation in the F8 gene on the X chromosome, which impairs or prevents the production of functional Factor VIII. Variants that cause severe haemophilia almost completely eliminate the activity of Factor VIII, while those associated with mild or moderate disease reduce – but do not eliminate – its function. Factor VIII plays a critical role in activating Factor X, a key step in the clotting cascade; without it, the cascade stalls and clot formation fails.

Haemophilia B: Christmas disease

Haemophilia B, sometimes called Christmas disease, is caused by changes to the F9 gene, which is responsible for clotting Factor IX. The name comes from Stephen Christmas, the first patient in whom this distinct form was identified. Haemophilia B affects approximately 1 in 40,000 males and follows the same X-linked recessive inheritance pattern as Haemophilia A. Although less common, its clinical symptoms – prolonged bleeding after injury, spontaneous joint bleeds in severe cases – are very similar to those of Haemophilia A, and the two are distinguished through clotting factor blood tests.

Haemophilia C: the autosomal form

Haemophilia C is a considerably rarer and distinctly different form. It is caused by changes to the F11 gene, which controls clotting Factor XI. What makes Haemophilia C unique is its inheritance pattern: unlike A and B, the F11 gene is located on chromosome 4, not on the X chromosome. This means it follows an autosomal recessive pattern – both parents must carry the mutated gene for a child to be significantly affected, and it affects males and females equally.

People who inherit a normal F11 gene and an abnormal one will carry haemophilia C but typically will not experience symptoms. Haemophilia C is also notably milder than A or B – affected individuals generally do not experience spontaneous bleeding into joints or muscles. Bleeding tends to occur following surgery, dental procedures, or significant trauma. The condition is estimated to affect around 1 in 100,000 people in the general population, though it is substantially more common among people of Ashkenazi Jewish descent, occurring in up to 8% of that population in Israel due to historical intermarriage patterns.

Acquired haemophilia: the autoimmune disorder

While genetic haemophilia is present from birth, acquired haemophilia is a completely different condition – one that can emerge in people with no personal or family history of any bleeding disorder. It is not inherited and cannot be passed to children. Instead, it is classified as an autoimmune disorder, where the body’s own immune system turns against itself.

What causes acquired haemophilia?

Acquired haemophilia results when the body makes specialised proteins called autoantibodies that attack and disable coagulation Factor VIII. These autoantibodies – sometimes referred to as inhibitors – interfere with Factor VIII’s ability to function in the clotting process, leading to potentially serious, uncontrolled bleeding. Acquired haemophilia is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies directed against plasma coagulation factors, most frequently Factor VIII.

Unlike congenital haemophilia, which typically causes bleeding into joints, acquired haemophilia more commonly presents as large haematomas, extensive bruising, or severe mucosal bleeding such as nosebleeds, gastrointestinal bleeding, and blood in the urine. Because the condition appears suddenly in people with no bleeding history, it is frequently misdiagnosed or overlooked – particularly in elderly patients.

Who is most affected?

Acquired haemophilia has a bimodal age distribution. It shows a small peak among individuals aged 20 to 30 years – predominantly women who develop the disorder in the postpartum period – and a much larger peak at age 60 and older. The annual incidence is approximately 1 case per million individuals in the general population, rising to 3 to 4 cases per million among those aged 60 years and older. Data from large US studies places the median age of hospital admission at 73 years, firmly establishing this as predominantly a condition of older adults.

Known triggers and associated conditions

More than half of acquired haemophilia cases are idiopathic – meaning no clear underlying cause can be identified. In the remaining cases, the condition is associated with a range of identifiable triggers. Known associated conditions include autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis, as well as malignancies and inflammatory bowel disease. Cases linked to certain drugs – including penicillins, interferons, and clopidogrel – as well as to COVID-19 infection and vaccination have also been reported.

In postpartum women, the immune changes that accompany pregnancy are thought to trigger autoantibody development in rare instances. The majority of acquired haemophilia cases that occur in middle-aged or elderly people, or in young women who have recently given birth, often resolve with appropriate treatment. Treatment typically focuses on suppressing the immune system to stop autoantibody production, alongside controlling acute bleeding episodes.

Key differences at a glance

The table below summarises the essential distinctions between the two major forms of haemophilia.

Genetic haemophilia is caused by mutations in the F8, F9, or F11 genes, is present from birth, and follows predictable inheritance patterns. Acquired haemophilia, by contrast, develops during a person’s lifetime as a result of the immune system mistakenly producing autoantibodies against Factor VIII. It has no genetic basis, can appear in anyone, and is particularly associated with older age and, to a lesser extent, the postpartum period. Both forms can cause serious bleeding, but they require very different diagnostic approaches and management strategies.

What do you think? Given that acquired haemophilia can develop spontaneously in the elderly with no prior bleeding history, how important is it for educators and healthcare workers supporting older adults to be aware of its signs? And considering that around one in three cases of genetic haemophilia arise from spontaneous mutations rather than family inheritance, how might this change the way we approach genetic counselling for families with no known history of the condition?

References

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Table of Contents

What is haemophilia? 🔗

Genetic haemophilia: the inherited form 🔗

How the genetics work 🔗

Haemophilia A: the most common type 🔗

Haemophilia B: Christmas disease 🔗

Haemophilia C: the autosomal form 🔗

Acquired haemophilia: the autoimmune disorder 🔗

What causes acquired haemophilia? 🔗

Who is most affected? 🔗

Known triggers and associated conditions 🔗

Key differences at a glance 🔗