Factor VIIIa and its von Willebrand factor carrier
Pathway · Haemophilia A APTT Not vitamin K
Factor VIII circulates bound to von Willebrand factor; thrombin cleaves it to VIIIa, which is released from vWF and becomes the cofactor of the intrinsic tenase, raising the catalytic efficiency of IXa on factor X by orders of magnitude. Activated protein C then destroys VIIIa and switches the complex off. Factor VIII is not vitamin K dependent and is made largely by liver sinusoidal endothelium, so it stays normal or high in liver disease.
Traced from the start
- Subendothelial collagen and von Willebrand factor
- Factor VIIIa and its von Willebrand factor carrier
Detail
- Cofactor for
- Factor IXa within the intrinsic tenase complex
- Carried by
- Von Willebrand factor, which shields it from activated protein C and from clearance
- Activated by
- Thrombin (and factor Xa); inactivated by activated protein C with protein S
- Not vitamin K dependent
- Synthesised by liver sinusoidal endothelial cells; an acute-phase reactant that rises in inflammation, pregnancy and after exercise
- Measured by
- APTT and a factor VIII activity assay; a persistently high factor VIII is itself a venous thrombosis risk factor
When it goes wrong
Haemophilia A — X-linked recessive factor VIII deficiency, about 1 in 5000 male births, roughly 45% of severe cases from the intron 22 inversion
Spontaneous haemarthrosis, muscle and intracranial haemorrhage; prolonged APTT with normal PT and platelet count. Desmopressin for mild disease, recombinant factor VIII or emicizumab (a bispecific antibody that bridges IXa and factor X in place of VIIIa) for severe disease
An anti-factor VIII inhibitor after repeated factor exposure, or arising spontaneously in the elderly, postpartum or with autoimmune disease
Acquired haemophilia A: the APTT is prolonged and fails to correct on 50:50 mixing with normal plasma, unlike simple factor deficiency; treat bleeding with bypassing agents such as recombinant VIIa or FEIBA plus immunosuppression
Type 2N von Willebrand disease, a defective factor VIII binding site on vWF
Low factor VIII with normal vWF antigen — mimics mild haemophilia A but is autosomal, so it appears in women and does not follow an X-linked pedigree
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