Definition

Rare haematological disease characterised by spontaneous haemorrhage or prolonged bleeding due to factor VIII or IX deficiency.

Summary

Epidemiology

Prevalence in the general population is estimated at 1/12,000 and in boys, prevalence at birth is estimated at 1/5,000.

Clinical description

Haemophilia mainly affects boys, and can also present in generally minor forms in girls who carry the mutation. In most cases, coagulation anomalies appear in affected children at the start of learning to walk. However, newborns with haemophilia are at risk of intra- or extracranial haemorrhage and other haemorrhagic complications. The severity of the clinical manifestations depends on the extent of the coagulation factor deficiency: if the biological activity of the coagulation factor is less than 1 IU/dL, haemophilia is severe and manifests itself by frequent spontaneous haemorrhages and abnormal bleeding following minor injuries or trauma, surgery or dental extraction (severe haemophilia A and B). If it is between 1 and 5 IU/dL, haemophilia is moderate with abnormal bleeding following minor injuries or trauma, surgery or tooth extraction, but spontaneous bleeding is rare (moderate haemophilia A and B). If it is between 5 and 40 IU/dL, haemophilia is minor and is characterised by abnormal bleeding following minor injuries or trauma, surgery or tooth extraction, in the absence of spontaneous haemorrhage (mild haemophilia A and B). In patients with severe haemophilia, bleeding most often occurs in the joints (haemarthrosis) and muscles (haematomas), but can occur in any area of the body following trauma or injury. Spontaneous haematuria is a frequent and highly characteristic sign of the disease.

Etiology

The disease is caused by mutations in the F8 gene (Xq28) coding for coagulation factor VIII, or the F9 gene (Xq27) coding for coagulation factor IX, involved in haemophilia type A and B respectively.

Diagnostic method(s)

Diagnosis is based on evidence of a prolongation of the blood coagulation time (activated partial thromboplastin time, APTT). The type and severity of haemophilia are determined by specific measurements of factor VIII and IX activity and antigen levels.

Differential diagnosis(es)

The differential diagnosis aims to rule out Willebrand’s disease, combined factor V and VIII deficiency and other coagulation abnormalities that prolong coagulation time.

Prenatal diagnosis

Prenatal diagnosis by chorionic villus sampling or amniocentesis is rapid and informative when the causal family mutation is known. Knowing the family mutation status of the foetus makes it possible to prepare for delivery and anticipate the medical care of the newborn.

Genetic counselling

The mode of transmission is X-linked recessive, and genetic counselling is recommended for affected families. When a woman is a carrier of the mutation, the risk of transmitting the disease to her male offspring is 50%, as is the risk that her female offspring will be carriers. Overall, for each pregnancy, there is a 25% risk of giving birth to a boy with haemophilia and a similar risk of giving birth to a girl who is heterozygous.

Care and treatment

Care is provided by multidisciplinary haemophilia comprehensive care centres. Substitution treatment with factor VIII (haemophilia A) or factor IX (haemophilia B) is the simplest therapeutic approach. Plasma-derived and recombinant factor VIII and factor IX concentrates are available. In addition, factor-free treatments for haemophilia A and new therapeutic approaches, including gene therapy, are currently being developed. Treatment can be administered after a haemorrhage or prophylactically to prevent bleeding. The most frequent complication is the appearance of antibodies directed against the coagulation factor administered. Surgical correction, particularly orthopaedic surgery, is possible in specialised centres.

Prognosis

If left untreated, the disease progresses to a severe form which is generally fatal. Rarely or inadequately treated, recurrent haemarthrosis and haematomas lead to very disabling motor disability, combining stiffness, joint deformity and physical incapacity. However, the prognosis is favourable because current therapeutic approaches (early prophylaxis) make it possible to prevent these complications. Haemorrhage, HIV and HCV infection and liver disease are the main causes of death.