A number of studies have shown that patients with haemophilia A are more likely to develop certain medical conditions than the healthy population. These findings have urged the scientific community to investigate whether factor VIII plays other important roles inside the body. If it does, a deficiency of factor VIII would not merely expose patients with haemophilia A to the risk of haemorrhages, but also to the onset of conditions that are not related to haemostasis.
Recent studies have started to shed light on the matter, by suggesting that factor VIII may have a role to play in a number of contexts, such as keeping the bones healthy.
One of the medical conditions most commonly observed in patients with haemophilia is low bone mineral density, which makes the bones frailer and at a high risk of fractures: it is estimated that 43% of patients with haemophilia have low bone mineral density and that 27% have osteoporosis, which often develops as early as childhood.
This reduced bone mineral density was initially thought to be the indirect consequence of two conditions usually associated with haemophilia, namely the acute inflammatory state caused by haemorrhages, which leads to a deterioration of the bone and cartilage involved in the bleed and a lack of exercise.
However, it was recently discovered that factor VIII has a direct role in bone health, in that it plays an active part in regulating bone remodelling, a process that takes place throughout the life of an individual.
Bone remodelling is the result of a delicate balance between two events:
- the production of bone tissue by cells called osteoblasts;
- and the reabsorption or breakdown of bone tissue by cells called osteoclasts;
Factor VIII plays an active role in the regulation of bone remodelling through two different mechanisms:
- the complex that factor VIII forms with von Willebrand factor, another element involved in the clotting cascade, is able to inhibit the activity of the osteoclasts, whose task is to break down bone tissue;
- active factor VIII permits the production of thrombin, which promotes both the formation and the activity of the osteoblasts, whose task is to produce bone tissue.
The deficiency of factor VIII typical of haemophilia A, is therefore thought to cause an imbalance in bone metabolism, leading to an increase in the destructive activity of the osteoclasts and a reduction in the productive activity of the osteoblasts, with a consequent reduction in bone mineral density.
It has also been observed that mice in which the factor VIII gene has been inactivated present abnormalities in the production of collagen, which forms part of the structure of bone tissue.
In any case, it has also been seen that the adequacy of the prophylactic factor VIII supplementation taken by patients with haemophilia A produces an increase in bone density.
Prophylactic factor VIII therapy as treatment for haemophilia A is therefore a valid strategy not only for preventing bleeds, but also for preventing the osteoporosis that often accompanies the condition.
- Bannow B. S. et al, (2019). Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood Reviews, 35, 43–50.
- Rodriguez-Merchan E. C. et al, (2019). Increased bone resorption in hemophilia. Blood Reviews, 33, 6–10.
- Aronovich A. et al, (2013). A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure. Blood, 122(15), 2562–2571.