Clues to Blood Clotting

Blood clotting disorder von Willebrand Disease discovery

(RxWiki News) Evolutionary clues have led scientists to a discovery of how a key clotting protein assembles. This could aid in better understanding, and possibly treatments for common bleeding disorders.

Von Willebrand Factor (VWF), the long tube-shaped protein that plays a vital role in blood clotting, is dependent on location within a cell, new research indicates.

"Ask your physician about treatments for bleeding disorders."

VWF circulates within the blood in order to seek out injury, unrolling its helical tube to catch platelets and form blood clots. A defect in this protein causes von Willebrand Disease, the most common inherited bleeding disorder.

Dr. J. Evan Sadler, professor of medicine for the Washington University in St. Louis and senior author of the study, said the challenge is to build the massive protein without clogging the machinery. He said the cell solved that dilemma by making construction of VWF dependent on cell location.

VWF identifies its cell location by pH, which determines how acidic or basic a liquid is, and can vary depending on structure. On the 0 to 14 scale, human blood is slightly basic with a pH of 7.4.

VWF begins construction in a cell with the same pH as blood, then the partially assembled VWF is sent to a more acidic area with a pH of 6.2 that is known for its role in packaging proteins. In the acidic environment, VWF forms its signature long chains.

As this occurs, amino acid histidine gains a positive charge, which the research team suspects may lead to the formation of the long VWF tubules. Hoping to identify which histidine, investigators considered evolution, suspecting that histidine would be present in the same location across many species.

After gathering DNA sequences for humans, birds, a marsupial, an amphibian, a reptile and fish, the sequences were lined up. Only a small number of histidines were found in the same place across species. They were then mutated individually to see if VWF could be prevented from assembling.

Researchers found that out of numerous histidines, two in particular are important for sensing the pH change and assisting the building blocks form chains in an acidic environment. When either of the histidines were replaced with an amino acid with no positive charge, nothing happened. But when researchers forced a positive charge to constantly be present at these locations, the chain formed again.

The investigation is expected to aid researchers is better understanding pathway defects that cause von Willebrand disease and other related conditions.

The research was published in the Journal of Biological Chemistry.

Review Date: 
July 22, 2011