One of the most crucial physiological processes in clotting. The recognition of a site of vascular injury, followed by recruitment of pro-coagulation proteins and eventual restoration of integrity of the vascular wall occurs every time we suffer a significant injury and prevents excessive bleeding into tissues.
One of the crucial components of this process is Factor VIII, referred to here as F8. Also known as anti-haemophilic factor (AHF), F8 plays a crucial role along with fibrin and platelets in plugging any vascular sites of injury. F8 and fibrin are both generated from inactive forms by the action of thrombin. The main interaction that occur at the site of injury are between platelets and fibrin, which together form a network that prevents further bleeding. The main role of F8 is to stabilise this interaction.
Factor VIII is involved in the pathogenesis of Haemophilia A, an X-linked recessive bleeding disorder. As a result, it only affects males with an incidence of around 1 in 5,000. The majority of the mutations result in deficient levels of F8, while some mean that F8 is still produced, but in dysfunctional forms. As a result, those affected suffer from severe bleeding to the extent that severe haemhorrhage can occur as a result of even the most innocuous injuries. As far as disease management is concerned, a common strategy is simply the avoidance of anything that might lead to bleeding. Patients can also be given recombinantly produced F8 therapeutically, though this is far from a perfect strategy – antibody mediated rejection of the ultimately foreign protein is relatively common and the injected F8 has a relatively short half-life, meaning that booster doses are required.
Much of the current research into the treatment and potential cure of haemophilia A lies in gene therapy. It is hoped that by treating haematopoietic stem cells, the cells from which all blood cells are derived, with a normal (wild type) F8 gene at a relatively early developmental stage, individuals will not go on to develop disease. A recent study has highlighted a potentially novel mechanism for F8 gene therapy in dogs, that may be of human significance. The researchers in this study introduced the wild type F8 gene into the haematopoietic stem cells that eventually give rise to all cells of the blood, including platelets. Packaged into this therapy was a sequence that means the F8 is expressed and stored in platelets. Since activated platelets are the primary mediators of clotting, expression and storage of F8 in these cells should reconstitute the clotting mechanism that is lost in haemophilia A. This group found that this mechanism did indeed induce haemostasis, a term referring to the cessation of bleeding, in dogs and that this protection from haemhorrhage last significantly longer than the current levels of protection seen in patients undergoing recombinant F8 therapy. It remains to be seen whether these findings can be shown to have relevance to human disease, but studies such as this are providing encouraging results in the treatment and potential prevention of disease in haemophilia A patients.