Factor VIII and haemophilia A

Published on October 1, 2007 Updated on May 31, 2016   31 min

A selection of talks on Clinical Practice

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My name is Geoff Kemball-Cook and I work in the hemostasis and thrombosis group of the Clinical Sciences Center in London. My talk is on Factor VIII and hemophilia A.
I'd like to touch on three main areas. First is to review the normal coagulant function of factor VIII. The second is to move on to describe the molecular pathology that we find in patients with hemophilia A. And lastly, to briefly mention a rare bleeding disorder, combined factor V- factor VIII deficiency.
So a brief review of factor VIII function in coagulation. The cartoon in this slide shows blood flowing from left to right in the upper part within a vessel. This is demarcated by the endothelial cell layer, marked as ECs in the slide, which presents an anticoagulant surface to flowing blood, including the soluble coagulation factors shown. For example, factor VIII, VII, X, et cetera. And the various blood cells, which are also immersed in plasma. Outside the endothelial cell layer, in the vascular tissue, are found cells bearing tissue factor, or TF, which is a potent initiator of coagulation.
In the event to vascular damage, blood flows out under pressure through a breach in the endothelial cell layer and contacts the extravascular tissues. In particular, coagulation factor VII forms a tight complex with tissue factor, and this constitutes the initiates of coagulation.
What part does FVIII play in amplifying this initial stimulus? Well, tissue factor VIIa complex is capable of producing small amounts of factor Xa and factor IXa, which are activated serine proteases, from their zymogen forms. However, the levels of factor Xa produced by this direct route are inadequate to produce the amount of thrombin needed to produce a solid clot from fibrinogen. Hence, factor VIII and the related molecule, factor V, are activated by trace amounts of thrombin to their active cofactor forms, factor VIIIa and factor Va. In the case of factor VIIIa, this assembles with trace amounts of factor IXa to produce an extremely potent complex for increasing the rate of cleavage of factor X to Xa. This enormously increased amount of factor Xa is then able to produce the large amounts of thrombin which are necessary to make a solid clot.