Aetiology

Congenital haemophilia has an X-linked recessive pattern of inheritance.[9] Therefore, boys/men are exclusively affected, although many female carriers have clotting factor levels in the haemophilia range due to lyonization (random inactivation of the normal X chromosome) and may have bleeding symptoms requiring appropriate management. Rare cases of girls/women with severe haemophilia are described because of extreme lyonization, homozygosity, mosaicism, or Turner syndrome. Up to one third of patients with congenital haemophilia have no family history, as the condition may also result from spontaneous germline mutations and/or somatic mosaicism during early embryogenesis.[10] Genetic mutations in the factor VIII gene result in decreased circulating levels of coagulation factor VIII, and genetic mutations in the factor IX gene result in decreased circulating levels of coagulation factor IX.[11][12]

Factor VIII and IX genes are located on the long arm of chromosome X. About 50% of severe haemophilia A cases are due to intrachromosomal inversions involving regions in introns 1 and 22 of the factor VIII gene.[13] The remaining cases are due to other genetic alterations such as deletions, insertions, missense or nonsense point mutations, or abnormal splicing. Most cases of haemophilia B are due to point mutations and deletions.

Databases of genetic variants in the factor VIII and factor IX human coagulation factors are available; access may vary by location.[14] EAHAD Factor VIII Variant Database Opens in new window Factor VIII Variant Database Opens in new window EAHAD Factor IX Variant Database Opens in new window Factor IX Mutation Database Opens in new window

Acquired haemophilia is a much rarer condition that has an autoimmune-related aetiology and no genetic inheritance pattern. It results from the development of auto-antibodies to coagulation factors, most commonly factor VIII. The cause of acquired haemophilia is unknown; however, it may occur in association with autoimmune disorders, inflammatory bowel disease, diabetes, hepatitis, pregnancy and the postnatal period, malignancy, monoclonal gammopathies, and use of certain drugs.[3][15][16][17] Acquired haemophilia occurs more commonly postnatally and in older people.[3]

Pathophysiology

Blood coagulation normally occurs through a series of enzymatic reactions. Both factors VIII and IX are crucial for thrombin generation via the intrinsic pathway of coagulation. In patients with haemophilia, there is delayed clot formation due to reduced thrombin generation. This leads to the formation of an unstable clot that is easily dislodged, causing excessive bleeding.[18]

Classification

Types of haemophilia according to inheritance

  • Congenital haemophilia: an inherited condition with an X-linked recessive pattern of inheritance

  • Acquired haemophilia: a rare condition with an autoimmune aetiology and no genetic inheritance pattern

Types of haemophilia according to type of factor deficit

  • Haemophilia A: reduced or absent factor VIII

  • Haemophilia B: reduced or absent factor IX

Severity of haemophilia A and B based upon plasma levels of factor VIII or IX activity[1][2]

Severity:

  • Severe (<1% clotting factor level [CFL]): frequent spontaneous bleeding (occurring with no apparent cause or trauma), particularly into joints and muscles; severe bleeding with trauma and surgery.

  • Moderate (1% to 5% CFL): occasional spontaneous bleeding (occurring with no apparent cause or trauma); severe bleeding with trauma and surgery.

  • Mild (>5% to 40% CFL): severe bleeding with trauma and injury.

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