Scientists solve long-standing mystery about hemophilia protein

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Scientists solve long-standing mystery about hemophilia protein

Scientists have long wondered where blood clotting factor is stored in the body. This clotting factor is not made in large enough quantities by those with hemophilia. It is now known that clotting factor VIII is stored in cells that line the walls of blood vessels.

Rice University scientists have solved a long-standing mystery about where the body stores and deploys blood-clotting factor VIII, a protein that about 80 percent of hemophiliacs cannot produce due to genetic defects.

For years, conventional medical doctrine was that factor VIII was made in the liver, but studies over the past 10 years showed it was made in endothelial cells — the cells that line the walls of blood vessels — in the liver, heart, intestines and other organs. The new study, which is available online in the journal PLOS ONE, offers the first clear images of where factor VIII is stored within those cells. Researchers found the protein is both stored and secreted from a specialized organelle inside the cells that is also known to store and deploy another important blood-clotting protein called “von Willebrand factor” or VWF.

Hemophilia A, a bleeding disorder that affects almost one in 5,000 men, is caused by genetic defects that eliminate or reduce a person’s ability to make factor VIII. The protein is one of several that are required for effective blood clotting; without it, patients can suffer prolonged bleeding and death even from minor cuts.

“Great clinical advances have been made over the past 50 years in spite of our lack of understanding of where factor VIII was made and stored,” said study co-author Dr. Joel Moake, a hematologist with appointments in Rice’s Department of Bioengineering and at Baylor College of Medicine in the Texas Medical Center. “Understanding how the body makes, stores and deploys the protein will be increasingly important in the future as physicians look to develop gene therapies that could free patients from a reliance on regular injections of factor VIII.”

Hemophilia is caused by recessive genetic defects on the X chromosome, which means that men typically suffer from hemophilia, and women usually act as carriers. Hemophilia A, the more common form of the disease, accounts for about 80 percent of known cases. Hemophilia B, the less common form, is caused by defects in clotting factor IX; the disorder is widely known to have affected Queen Victoria’s descendants.

Factor VIII is a prominent component of a variety of specialized proteins involved in clot regulation. Some of these signal where wounds occur, others attract clot-initiating cells called platelets and many act only to break up clots or destroy their clot-forming relatives. Factor VIII, a signaling protein, is one of several that act in concert to produce a signaling “cascade,” an amplification process that allows the body to quickly transform a weak signal from a tiny cut into a blaring clarion call to rapid action.

Factor VIII was identified in the 1950s, and clinicians have used it to treat patients for decades, both by isolating it from donated blood and by producing it through biotechnology. Today, many hemophiliacs live symptom-free, thanks to regular injections of factor VIII.

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