Queen Victoria famously bequeathed haemophilia, a disease whose sufferers bleed uncontrollably after even minor injuries, to a number of her descendants as an unwelcome genetic inheritance. A century on, we are far better able than the Victorians to alleviate the symptoms of this disease. But as two Nature reports1,2 -- on the atomic structures of two closely related blood-clotting proteins -- demonstrate, we still have a lot to learn about its cause.

Haemophilia occurs because of failures in any one of a number of proteins that attach to the membranes of the type of blood cells called 'platelets' when blood vessels are damaged. The mechanisms by which these blood-clotting 'factors' help to produce the fibrous protein 'fibrin' from which clots are chiefly made are well understood; however, why they stick to platelet membranes in the first place is more mysterious.

Now two groups have solved the structures of the membrane-binding portions of the two blood-clotting proteins, Factors V and VIII, providing some new clues about clotting in health and disease.

The membrane-binding region of Factor VIII, whose structure has been determined by Barry L. Stoddard and colleagues of the Fred Hutchinson Cancer Research Center, Seattle, contains 24 places where mutations are known to cause disease. Apparently, these vulnerable sites are either deep within the region's core or on two outer faces. These faces, the authors propose, interact with other parts of the Factor VIII molecule, or with the so-called 'von Willebrand Factor' which collaborates with Factor VIII to bring about clotting.

Many haemophiliacs receive regular injections of Factor VIII as part of their treatment, but there is always a danger of the patient's own immune system raising antibodies against the foreign protein -- much the same as when transplanted organs are rejected. Most often this abreaction is against the very region Stoddard's group have studied. The authors suggest that mapping the surface of this protein could help find the areas responsible for triggering the immune response and so help avoid its consequences.

Stoddard's team also determined the surface of Factor VIII that binds to platelet membranes, but surprisingly this contains only one site where mutations are known to cause haemophilia. Fortunately, the structure of the analogous region of the closely related Factor V, determined by Wolfram Bode and colleagues of the Max-Planck Institute for Biochemistry, Martinsreid, Germany, helps explain why the detailed make-up of this surface is less important than its overall shape.

Bode's group have determined the structure of the folded up or 'closed' version of the Factor V domain, as did the Seattle group for Factor VIII. Hence both groups see regions that would be extremely efficient at adhering to outer surface of platelet membranes. But, by studying the protein under slightly different conditions, the German team have also observed the 'open' conformation of Factor V in which three loops extend out from this surface. These are all water-repellent, or to put it technically 'hydrophobic', and would therefore be far more stable inserted into the depths of the platelet cell membrane than in contact with the watery environment of the blood.

Thus the group proposes that both Factor V and Factor VIII circulate in the blood folded-up. Then, when guided to platelet membranes, they open up and anchor themselves down with their hydrophobic 'spikes'. In other words, Factors V and VIII bind to platelet membranes thanks not to individual component parts but to the concerted movement of an entire region.