Bond Kinetics Underlie von Willebrand's Disease

The results, published in the July 2002 issue of Biophysical Journal, suggest that the disease occurs because a defective form of vWF allows vWF-platelet complexes to last longer than they should.

Until recently it was thought that substitution of one amino acid in defective vWF caused a conformational change that stabilized the bond between the protein and platelets. The findings of the current study support a different explanation, however. Investigators from the Washington University School of Medicine (St. Louis, MO, USA) found that bond kinetics, the rate at which chemical bonds form and dissociate, rather than a conformational change, is responsible.

"This is the first time that a naturally occurring disease has been linked to an alteration in the kinetic properties of a chemical bond,” explained study leader Dr. Thomas G. Diacovo, assistant professor of pediatrics, pathology, and immunology. "The finding should give us a better understanding of how normal platelets function and of the delicate balance that exists between these blood-clotting elements. Disturb that balance, and the whole system falls apart.”

The importance of bond kinetics had previously been demonstrated for a family of proteins called selectins, which are involved in the recruiting of white blood cells to inflamed blood vessel walls. Working with platelets in the current study, the researchers found that in normal individuals a few transient bonds form between circulating platelets and vWF. In type IIb von Willebrand's disease, however, the bonds last significantly longer than normal. That extra time allows many additional bonds to form, which stabilizes the interaction.

"It is not just a brief touch-and-go,” said Dr. Diacovo. "Rather, one bond forms and before it breaks, two, three, and four more have formed.” As more bonds form, small aggregates of platelets and vWF develop. These aggregates are removed from the blood, which reduces the amount of vWF and the number of platelets in circulation. Consequently, people with von Willebrand's disease have a mild-to-moderate bleeding disorder. They bruise easily and simple nosebleeds can continue for several hours or days before finally healing.