Factor VIII and haemophilia

Haemophilia A (classical haemophilia, often simply termed haemophilia) is an X-linked recessive disorder caused by a deficiency of factor VIII. Von Willebrand disease is a related disorder, also caused by a defect in the factor VIII complex, as discussed below.

Intact factor VIII, as usually purified from the blood, consists of two distinct gene products: factor VIII and (multiple copies of) von Willebrand's factor (vWF; Figure 12.6). This complex displays a molecular mass ranging from 1 to 2 MDa, of which up to 15 per cent is carbohydrate. The fully intact factor VIII complex is required to enhance the rate of activation of factor IX of the intrinsic system.

The factor VIII polypeptide portion of the factor VIII complex is coded for by an unusually long gene (289 kb). Transcription and processing of the mRNA generates a shorter, mature, mRNA that codes for a 300 kDa protein. Upon its synthesis, this polypeptide precursor is subsequently proteolytically processed, with removal of a significant portion of its mid region. This yields two fragments: an amino terminal 90 kDa polypeptide and an 80 kDa carboxyl terminal polypeptide. These associate non-covalently (a process requiring Ca2+ ions) to produce mature factor VIII (sometimes called factor VIII:C). This mature factor VIII is then released into the plasma where it associates with multiple copies of vWF forming the biologically active factor VIII complex. vWF stabilizes factor VIII in plasma (particularly against proteolytic degradation). It also can associate with platelets at the site of vascular damage and, hence, presumably plays a role in docking the factor VIII complex in an appropriate position where it can participate in the coagulation cascade.

Persons suffering from haemophilia A exhibit markedly reduced levels (or the complete absence) of factor VIII complex in their blood. This is due to the lack of production of factor VIII:C.

Liver cell Endothelial cell

Liver cell Endothelial cell

Liver cell Endothelial cell

Liver cell Endothelial cell

vWF

Liver cell Endothelial cell

Factor VIII

complex (VIII C: vWF)

Figure 12.6 (a) Synthesis of factor VIII complex as occurs in healthy individuals. (b) In the case of persons suffering from haemophilia A, synthesis of factor VIII:C is blocked, thus preventing constitution of an active factor VIII complex in plasma. (c) Persons suffering from von Willebrand's disease fail to synthesize vWF. Although they can synthesize VIII:C, this is rapidly degraded upon entering the blood due to lack of its vWF stabilizing factor

Persons suffering from (the rarer) von Willebrand's disease lack both components of mature factor VIII complex (Figure 12.6). The severity of the resultant disease is somewhat dependent upon the level of intact factor VIII complex produced. Persons completely devoid of it (or expressing levels below 1 per cent of normal values) will experience frequent, severe and often spontaneous bouts of bleeding.

Persons expressing 5 per cent or above of the normal complex levels experience less severe clinical symptoms. Treatment normally entails administration of factor VIII complex purified from donated blood. More recently, recombinant forms of the product have also become available. Therapeutic regimens can require product administration on a weekly basis, for life. About 1 in 10 000 males are born with a defect in the factor VIII complex and there are approximately 25 000 haemophiliacs currently resident in the USA.

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