Etiology

Congenital hemophilia has an X-linked recessive pattern of inheritance.[8] Therefore, boys/men are exclusively affected, although many female carriers have clotting factor levels in the hemophilia 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 hemophilia are described, such as those seen due to lyonization (random inactivation of the normal X chromosome), homozygosity, mosaicism, or Turner syndrome. Up to one third of patients with congenital hemophilia have no family history, as the condition may also result from spontaneous germline mutations and/or somatic mosaicism during early embryogenesis.[9] 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.[10][11]

Factor VIII and IX genes are located on the long arm of chromosome X. About 50% of severe hemophilia A cases are due to intrachromosomal inversions involving regions in introns 1 and 22 of the factor VIII gene.[12] The remaining cases are due to other genetic alterations such as deletions, insertions, missense or nonsense point mutations, or abnormal splicing. Most cases of hemophilia 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.[13] 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 hemophilia is a much rarer condition that has an autoimmune-related etiology and no genetic inheritance pattern. It results from the development of auto-antibodies to coagulation factors, most commonly factor VIII. The cause of acquired hemophilia is unknown; however, it may occur in association with autoimmune disorders, inflammatory bowel disease, diabetes, hepatitis, pregnancy and the postpartum period, malignancy, monoclonal gammopathies, and use of certain drugs.[3][14][15][16] Acquired hemophilia occurs more commonly postpartum 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 hemophilia, 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.[17]

Classification

Types of hemophilia according to inheritance

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

  • Acquired hemophilia: a rare condition with an autoimmune etiology and no genetic inheritance pattern

Types of hemophilia according to type of factor deficit

  • Hemophilia A: reduced or absent factor VIII

  • Hemophilia B: reduced or absent factor IX

Severity of hemophilia 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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