Investigators have tracked down the gene mutated in patients with a deadly blood disorder, a feat they said points the way to developing treatments and gene therapy strategies and to understanding in more detail the nature of blood clotting.
The gene ADAMTS13 appears to be the culprit in thrombotic thrombocytopenic purpura, a mysterious malady that once was nearly always fatal and that, without treatment which carries its own hazards, still can claim 90 percent of those it strikes within weeks or even days, the scientists said in the British journal Nature.
The finding bodes well not only for those with the disorder, which, like hemophilia, affects about one in 100,000 to 200,000 people, but also for those suffering from other more common conditions that share some of the blood characteristics of TTP, including anemia and even food poisoning resulting from ingestion of ground beef or strawberries contaminated with E. coli bacteria, scientists told United Press International.
By unraveling the genetic underpinnings of TTP, researchers can pave the way for developing diagnostic tools and treatment strategies, researchers said.
The new study, which builds upon previous partial identifications of the gene, tells a significant part of the story, tying TTP to clumps of red blood cells and a large protein called von Willebrand factor -- implicated in von Willebrand disease, a special form of hemophilia -- that amass in the small blood vessels of the brain, kidneys and other organs, leading to fever, bleeding and other severe complications.
Under normal circumstances, VWF acts as traffic cop for the interactions among platelets -- the smallest of the blood vessels that are critical to coagulation -- and between them and the blood vessel walls, maintaining the balance between bleeding and clotting. In TTP, the gene is defective and the mechanisms go haywire, said the researchers, led by David Ginsburg of the Howard Hughes Medical Institute at the University of Michigan Medical Center in Ann Arbor, Mich.
"Dr. Ginsburg's studies show the (ADAMTS13) gene is essential for normal health and prove that TTP can be caused directly by defects in this gene," said Dr. J. Evan Sadler of Washington University in St. Louis, who collaborated on an earlier project that sequenced the same gene and protein, using a different approach.
Ginsburg's study "goes significantly further by identifying mutations in the (ADAMTS13) gene that actually cause a serious, often fatal, human disease," Sadler told UPI. "This is an important advance in understanding TTP, and may help to understand a group of potentially related diseases with similar clinical features," including diarrhea, anemia, kidney failure and E. coli-related food poisoning.
TTP is marked by potentially deadly destruction of red blood cells, apparently by shearing them over abnormal strands of protein that block their passage through small blood vessels, akin to "the way guitar strings might slice an egg," Sadler said.
"This process produces characteristic deformed red cell fragments that we see when we examine the blood. The disease process also consumes platelets, the very small cells that are in the front line of defense against bleeding. Cuts and scratches, or normal wear and tear, break blood vessels and allow the blood to escape," Sadler told UPI.
"At sites of bleeding, platelets coat the surface and clump together, which is sufficient to seal many small leaks. In TTP, the platelets participate in the blockage of small blood vessels that causes the destruction of red cells. The obstruction of small blood vessels can damage tissues throughout the body, causing heart attacks, strokes, kidney failure and ultimately death. The consumption of platelets sometimes is sufficiently serious to also cause bleeding, which may be life threatening."
Most often, the patients -- two-thirds of whom are women -- suffer fever, kidney failure, headache, trouble seeing, mental upheavals, weakness or loss of sensation similar to that produced by stroke, nausea, vomiting and abdominal pain.
"As a practicing hematologist, I think that all of us are excited to learn more about the pathogenesis of a killer disease in the hope that that knowledge will lead to additional breakthroughs in the diagnosis and treatment," Dr. Lawrence Brass of the University of Pennsylvania in Philadelphia told UPI.
Plasma exchange therapy -- in which a portion of the patient's blood is removed and replaced with plasma from normal blood donors -- has an 80 percent to 90 percent remission rate. If treatment fails, however, the patient generally dies within days or weeks. Of those who go into remission, 10 percent to 35 percent relapse at least once. Each episode carries with it some risk of death, and the therapy itself may lead to serious complications.
The plasma treatment "saves many lives, but also carries significant risks of disease transmission, allergic reaction and septic complications, " senior study author Dr. Han-Mou Tsai of Montefiore Hospital at Albert Einstein Medical School in New York, who collaborated on the work, told UPI.
"The (findings) should make it possible to provide a specific DNA diagnosis for patients with the relatively rare hereditary form of the disease. Having the gene in hand should also lead to the development of improved diagnostic tools for the more common acquired form of the disease and for monitoring therapy in all patients. Most importantly, the production of recombinant ADAMTS13 protein should provide a more effective and safer treatment for TTP patients," Ginsburg told UPI.
"Understanding the biological function of ADAMTS13 and the pathophysiology of TTP may lead to other novel approaches to therapy, not only for TTP but potentially for other bleeding and clotting disorders."
These might include gene therapy that transfers the gene to provide a cure for individuals with the familial form of TTP, measures to decrease the activity of ADAMTS13 to minimize bleeding in some patients with von Willebrand disease and perhaps even new treatments for cardiovascular diseases such as heart attack, Sadler said.
"Because the exact location of the ADAMTS13 gene within the human genome has been mapped, gene therapy -- along the lines being explored for treating hemophiliacs -- may be a realistic option in the future for patients with inherited TTP," said Amanda Fosang and Peter Smith of the University of Melbourne in Australia, who co-authored an accompanying commentary.
Doctors have long puzzled over thrombotic thrombocytopenic purpura, a mysterious blood disease that claimed 90 percent of its victims when it was first described at the beginning of the last century. Suddenly striking otherwise healthy young people -- the average patient is 40 years old -- the disorder robs them of precious red blood cells and platelets. As the cell counts plummet, the devastating symptoms start to appear. The plasma exchange therapy has been successfully used for the past 20 years, but until now doctors did not understand why.
Some studies had suggested the key was the removal of a toxic factor from the blood and others, the replacement of a missing factor. The missing factor, it turns out, could be the protease that may mince another blood clotting factor, VWF, scientists said.
"This gene was previously unknown, though two other groups recently independently identified part of the gene," Ginsburg told UPI. "Taken together, our work and theirs identifies this gene as an important part of our blood clotting system that was previously unrecognized. It may also play a role in other bleeding diseases, including von Willebrand Disease, and possibly others that we don't yet understand. There's obviously a lot more work to do."
