Haemophilia

Introduction

Haemophilia describes a group of rare bleeding disorders caused by a congenital defect in the production of specific clotting factors (1).

Epidemiology

Haemophilia A and B are caused by X-linked recessive mutations and are therefore more common in males (2). 

Haemophilia A affects production of Factor VIII and occurs in approximately 1/5000 males (3). Haemophilia B (aka Christmas disease) affects production of Factor IX and is much less common.

The conditions are most commonly inherited, but can be caused by spontaneous mutation in approximately 1/3 of cases (4).

Pathophysiology

Normally when a blood vessel is injured, a platelet plug forms and the clotting cascade is initiated at the site of injury in order to stop blood loss. The end product of the clotting cascade is fibrin, which helps to stabilise the platelet plug.

Factor VIII is one of many clotting factors that contributes to the production of thrombin via the intrinsic pathway of the clotting cascade. The intrinsic pathway is activated in response to endothelial collagen exposure (5).

Due to deficiency of factor VIII in haemophilia A, the patient will also be deficient in thrombin at the site of injury. Insufficient thrombin results in insufficient production of fibrin for clot stabilisation (6). 

The severity of haemophilia A depends on the plasma concentration of factor VIII. Severity is categorised into mild, moderate and severe. Patients with severe disease may have no measurable factor VIII in the blood (7).

Risk factors

• Male gender
• Family history of haemophilia

Clinical features

Features from the history

Patients with haemophilia may present with prolonged, unexplained bleeding, or with a history of recurrent episodes of bleeding.

Patients with severe disease may suffer from spontaneous bleeding episodes, which refers to bleeding from any site with no apparent cause. Spontaneous bleeds may originate from any organ system; however, they most commonly affect muscles and the joints (haemarthrosis.) When this occurs, the patient may complain of joint pain, swelling and reduced range of movement.

In moderate cases, haemophilia may present as unexplained bruising, nosebleeds that take a long time to stop, or bleeding from mucous membranes such as the gums.

Patients with mild disease often go undiagnosed unless they experience prolonged bleeding following surgery, trauma or dental procedures (1).

Features from the examination

In some patients, there may be no features on clinical examination; this usually depends on the presenting complaint. However, you should look out for the following:

• Active bleeding – Patients may present to emergency settings with episodes of bleeding, for example with a nosebleed that will not stop. 

• Pallor of the skin/conjunctiva – If patients are suffering from frequent or severe bleeding episodes, it is possible that they will be anaemic.

• Bruising – The location and a description of the bruising should be carefully documented, as non-accidental injury (NAI) must be considered.

• Haemarthrosis – On examination you may observe a unilateral joint swelling (most commonly the knee, elbow or ankle). The affected joint may also have a reduced range of movement and is usually painful on passive and active movement. 

Differential diagnoses

In a child presenting with prolonged or unexplained bleeding, you should consider the following differentials:

• Non-accidental injury – it is normal for mobile children to have some bruising. However, injuries or bruising which are extensive, unexplained, or occurring in unusual sites should raise suspicion of NAI.
• Other congenital bleeding disorders – for example von Willebrand disease (8).
• Acquired coagulopathy – for example vitamin K deficiency in the neonate or in early infancy (3).
• Bone marrow dysfunction – Acute lymphoblastic leukaemia (ALL) is one of the most common childhood malignancies, and can present with bleeding as a result of thrombocytopenia (8)

Investigations

Initial screening tests for haemophilia can include:

• Full blood count– Anaemia on the FBC can support a diagnosis of haemophilia; all other components of the FBC should be normal. An important cause of bleeding to rule out is thrombocytopenia, so it is important to look at the platelet count.
• Coagulation screen
  • APTT (Activated partial thromboplastin time) – In haemophilia, this is prolonged. APTT demonstrates the speed of coagulation by the intrinsic pathway of the clotting cascade.

• • PT (Prothrobin time) – In haemophilia this should be within the normal range. PT demonstrates the speed of coagulation by the extrinsic pathway of the clotting cascade.
• Factor VIII and IX concentration– In haemophilia A, the plasma concentration of factor VIII will be low. In haemophilia B, factor IX will be low.
• Additional investigations – Examples of these include a CT head if there is a suspected intracranial bleed, or joint imaging and aspiration in suspected haemarthrosis (4).

Management

There are two main components to the management of haemophilia: prevention of bleeds (prophylaxis) and management of bleeding when it occurs. 

For patients with mild to moderate disease, prophylaxis is not usually required. Management for these patients is usually focused on treating bleeds when they occur. If they have a major bleed, they may require a one-off infusion of IV factor VIII (or factor IX in haemophilia B).

Prophylaxis is reserved for patients with severe disease. It involves the patient receiving regular intravenous infusions of the relevant factor in order to prevent the occurrence of spontaneous bleeds (4). The parents, and sometimes the child, can be trained to administer the IV factor, as this is often continued for the duration of the patient’s life (9).

Education for the family on managing bleeding is an extremely important part of managing haemophilia (4). In addition to this, it is important to advise the family about the need for the child to avoid contact sports (for example rugby), and the importance of good dental hygiene to minimise the need for dental procedures (10).

Complications

• Chronic arthropathy– This is a chronic joint disease that occurs secondary to recurrent bleeds into the joints. If severe haemophilia is left untreated, the patient may develop chronic arthropathy by the age of 20 (11).

• Development of factor VIII or IX inhibitors– Sometimes patients who receive clotting factors develop antibodies against the clotting factor. Inhibitors make the treatment of haemophilia less effective (9). Of patients with severe haemophilia, approximately 30% will develop inhibitors (12).
• Transfusion-related complications– For example: allergic reaction, acute haemolytic reaction, bacterial infection and the transmission of blood borne viruses (4).

References