Scientists find gene for clotting disorder.

People with venous thrombosis suffer from blood that forms clots aggressively. This week, Dutch researchers report finding a mutant gene that underlies this clotting disorder.

Researchers had long known that venous thrombosis runs in families. In people with the condition, blood pools in the veins of the legs, causing clots to form. Those jellylike clots can cause pain, inflammation, and even death if they break off and travel to the lungs.

In February, a team of Swedish investigators discovered that the action of activated protein C (APC), a naturally produced anticlotting substance, seems to be blocked in people with a family history of this disorder.

That finding spurred the hunt for the genetic cause of this overzealous clotting. Biochemist Rogier M. Bertina of University Hospital in Leiden, the Netherlands, and his colleagues focused on chromosome 1, one of the 23 pairs of human chromosomes and a likely location for the faulty clotting gene. After comparing the DNA of family members whose blood formed clots normally to that of members whose blood clotted too much, the researchers found that the difference came down to this: Relatives with clot-prone blood showed a single mutation, or flaw, in the gene that codes for Factor V, a protein that dramatically accelerates the body's clotting process.

The Factor V that this mutant gene codes for is identical to the normal protein except for one thing: A single amino acid is out of place. That seemingly minor goof, like a typo in an otherwise clean manuscript, results in a souped-up Factor V. Normally, this factor helps the body form beneficial blood clots, such as those aiding in the repair of an injury. Once the clots have done their job, the body sends APC to destroy Factor V and thus dampen the clotting cascade. But for people with the genetic defect, there's no brake on this process. The mutant Factor V remains impervious to APC's attack. This results in blood that keeps on clotting long after it should have stopped.

Bertina suspects, but has yet to prove, that people who inherit two copies of the mutant Factor V gene show an even greater tendency to form clots than those who carry just one such gene.

The discovery of the flawed gene makes the Factor V defect the most common genetically determined clotting disorder, the authors write in the May 5 NATURE. About half the people with a family history of venous thrombosis carry the mutant gene, they say. Bertina estimates that 2 to 4 percent of the Dutch population carries it. The mutation probably occurs at the same rate in the United States, he says.

This high frequency suggests that the mutation conferred some evolutionary advantage upon people who inherited it, Bertina says. Perhaps those with a hyper-charged clotting system were more likely to survive injuries, he speculates.

Although "remarkably" common, the flawed gene doesn't underlie every case of venous thrombosis, points out Kenneth A. Bauer of Harvard Medical School in Boston. Other genes, as well as environmental factors, probably contribute to an individual's risk of developing these blood clots, he says.

Clinical applications of this genetic find are unclear. Most people who carry the mutant gene will never suffer from a dangerous clotting episode, asserts hematologist Philip W. Majerus at the Washington University School of Medicine in St. Louis. Physicians have yet to devise a foolproof method of preventing clots from forming or identifying people at high risk of developing such blood clots.

"Thus the risks of lifelong treatment with anticoagulants must be weighed against the benefit of preventing infrequent, but potentially devastating, thrombotic attacks," Majerus writes in a commentary that accompanies the Dutch report.