Suppressing immune system reverses otherwise untreatable case of blood disease

Treatment with two medications that suppress the immune system, rituximab and cyclophosphamide, appears to have cured one woman of an otherwise untreatable case of the blood disease known as thrombotic thrombocytopenic purpura (TTP). The findings support the theory that TTP is an autoimmune disease, and not only provide insight into diagnosis and treatment, but also reveal clues about blood clotting and autoimmune diseases in general.

“In this particular patient who did not respond to standard therapy, immunosuppression seems to have been successful,” says Morey A. Blinder, M.D., associate professor of medicine and of pathology and immunology at Washington University School of Medicine in St. Louis. “These results are promising for others suffering from similarly resistant cases of TTP.”

Blinder led the study, in conjunction with J. Evan Sadler, M.D, Ph.D., professor of medicine and of biochemistry and molecular biophysics. Their findings appear in the Jan. 21 issue of the journal Annals of Internal Medicine.

TTP is a blood disorder that affects an estimated 3,000 Americans each year, most of whom are women of childbearing age. Prior to the early 1980s, the prognosis was grim: The risk of dying from complications of the disease such as heart attack or stroke was as high as 90 percent. And because the disease is so rare, it continues to be misdiagnosed and untreated.

Today, most patients who are diagnosed accurately with TTP are successfully treated with plasmapheresis, in which an individual’s blood is swapped for healthy blood in a daily process similar to dialysis for kidney failure. But plasmapheresis does not target the underlying problem, which is believed to be similar to autoimmune diseases such as lupus, in which the immune system attacks a person’s own tissues. Therefore, even with daily plasmapheresis, the disease returns in about 25 percent of patients.

In 2000, Sadler’s team, in collaboration with investigators at the University of Washington in Seattle, identified a protein in the bloodstream called von Willebrand factor-cleaving protease and found that it either is missing or abnormal in people with TTP, presumably as a result of disruption by the immune system. Without it, the protein called von Willebrand factor is not regulated and therefore sticks to itself, forming large clumps, or blood clots, that often lead to stroke or heart attack.

“The discovery of this protein really helps us understand the mechanism of blood clotting in general and how important von Willebrand factor is,” says Blinder. “Also, we hope to use this knowledge to develop a definitive test for TTP so that it can be more easily diagnosed and more effectively treated. It also may be possible to genetically engineer the protein for infusion, similar to the use of insulin for diabetes.”

To prevent the immune system from destroying or disrupting this essential cleaving protease, the Washington University team tested two drugs already shown to suppress the immune system. In October 2001, after 19 months of relapsing disease despite extensive plasmapheresis, the team gave one 42-year-old woman with severe TTP two drugs – rituximab and cyclophosphamide, both known anti-cancer drugs. Her symptoms and blood levels improved and continue to be stable to date.

“This may not be a public health issue like AIDS or breast cancer, but the fact that first this disease was almost always life-threatening and now may be curable is really important,” says Blinder. “And now that we’re really beginning to understand the disease itself, it will help us diagnose and treat TTP and will provide insight into blood clotting and how immune diseases work in general.”

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Zheng X, Pallera AM, Goodnough LT, Sadler JE, Blinder MA. Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab. Annals of Internal Medicine, vol. 138, Jan. 21, 2003.

Funding from the National Institutes of Health and the Howard Hughes Medical Institute supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.