Robert A. S. Roubey, MD

University of North Carolina at Chapel Hill, NC

2004 Biomarkers, Cardiovascular System, Human Lupus Biology

People with lupus are at an increased risk for blood clots that can result in stroke, heart attack, and miscarriage.

The blood clots are associated with the presence of antiphospholipid antibodies. These antibodies are present in one-third of people with lupus and interfere with the normal function of blood vessels.

Researchers are on the hunt for markers of this clotting risk, so that they can determine who might benefit from potentially life-saving treatment, such as blood thinners, to prevent clots from forming.

“About 1/3 of people with lupus have these antibodies, but only a third of that number will go onto have a major blood clot causing stroke, heart attack or miscarriage. So if we can determine who is at greatest risk, we have a chance to intervene.” – Dr. Roubey

With LRI funding, Dr. Roubey set out to develop new tests to predict which lupus patients with antiphospholipid autoantibodies are at increased risk for developing clots.

He evaluated a new blood test that reflects levels of a substance called tissue factor (TF) on blood cells and blood vessel walls. TF can be assessed by measuring complexes of two proteins involved in coagulation—factor VIIa and antithrombin (VIIa-AT)—using a blood test developed by collaborator Dr. James Morrissey, PhD, at the University of Illinois.

Currently, there are no good tests to measure the overall level of tissue factor activity, “but we think this test will be a general measure of total tissue factor exposure throughout blood vessels,” Dr. Roubey said.

To evaluate the effectiveness of the test, Dr. Roubey and colleagues ran it on a group of approximately 300 patients from the Antiphospholipid Syndrome Collaborative Registry (APSCORE), which includes people with APL antibodies.

“If we can prove that certain people are at much greater risk of blood clots, the next thing to do would be to figure out the best way to treat them before a blood clot occurs,” he said. “The new test may open up that realm.”

“If this new biomarker proves that tissue factor activity is high in patients at risk for developing clots, drugs aimed at reducing levels of tissue factor may be effective. Further, these drugs may be safer than current blood thinners,” he added. “For example, cholesterol lowering drugs known familiarly as statins, certain blood pressure lowering drugs, and some antiplatelet drugs may decrease tissue factor activity in addition to their other effects.”

Studies to date have found that VIIa-AT complexes are elevated in a significant proportion of patients with antiphospholipid antibodies, including those with and without lupus.

“Long-term studies are needed to see whether this test predicts which patients are at greatest risk for blood clots in the future,” Dr. Roubey said.

Translating Lupus Research
A story of inspiration from North Carolina in Science journal's Science Careers by Karyn Hede

Select publications:

Tissue factor in the antiphospholipid syndrome. Kinev AV, Roubey RA. Lupus. 2008; 17:952-958.

Warfarin and the antiphospholipid syndrome: does one size fit all? Kasthuri RS, Roubey RA. Arthritis Rheum. 2007; 15:1346-1347.

Q&A

Blood clots are a health hazard that all people with systemic lupus erythematosus (SLE) have to contend with, especially if they are among the thirty-three percent with antiphospholipid antibodies (aPL) in their blood.

Some people with these abnormal antibodies go on to develop an autoimmune condition called the antiphospholipid syndrome—a constellation of serious blood clotting problems associated with heart attacks, strokes, deep vein clots, and pregnancy losses. There are powerful medicines that people with antiphospholipid antibodies can take to prevent blood clots. Unfortunately, these medicines also can cause severe bleeding and other complications.

Robert A. S. Roubey, M.D. and his team at the University of North Carolina at Chapel Hill have been exploring a way to determine who among those with antiphospholipid antibodies will get the syndrome linked to the serious clots—and therefore may benefit from more aggressive treatment.

With help from the Lupus Research Institute's (LRI) 2004 Jane Luke Murphy Memorial Grant, Dr. Roubey is making exciting strides in finding a key biomarker (a disease-predicting alteration in cellular, molecular, or genetic material) that will show this distinction. The research award honors the late Jane Luke Murphy, who suffered from lupus and the antiphospholipid syndrome.

LRI: How would you describe your current research project?

Dr. Roubey: With the LRI grant we are testing for our proposed biomarker in blood samples from approximately 300 people in the Antiphospholipid Syndrome Collaborative Registry—also known as APSCORE. This multicenter NIH-funded registry is collecting detailed clinical information from volunteers with aPL, as well as blood and DNA specimens. Our prediction is that some people will have elevated levels of the proposed biomarker, and that these high levels will identify those who are at the greatest risk of developing a blood clot.

LRI: How will this biomarker make a difference in the lives of people with lupus?

Dr. Roubey: Currently we treat most people with antiphospholipid antibodies (anticardiolipin, anti-ß2GPI, lupus anticoagulant) who have not yet had blood clots with low-dose aspirin, which is a mild blood thinner. This probably helps reduce the risk, but it does not prevent clots altogether. If we could identify the people at very high risk for blood clots—those who will develop the antiphospholipid syndrome—we could treat them with potent blood thinners or other drugs before the first (and potentially devastating) clot occurs. That could make an enormous difference in the lives of the 10 to 15 percent of people with SLE who develop the syndrome.

LRI: Do people without lupus benefit?

Dr. Roubey: Yes, the antiphospholipid syndrome is very under-recognized. Many people with antiphospholipid antibodies (aPL) don't have lupus, or appear healthy. Yet an estimated 15 to 20 percent of all people with blood clots in their veins, up to a third of stroke patients under age 50, and approximately 5 to15 percent of women who miscarry repeatedly suffer from the antiphospholipid syndrome.

LRI: How did you develop the idea of testing this biomarker?

Dr. Roubey: Tissue Factor (TF) is a protein on cell surfaces that triggers not only normal but many types of abnormal blood clotting. Normally TF is not present on cells in contact with flowing blood. We started thinking of TF when research from our lab and several others indicated that aPL cause TF to appear on certain blood cells and cells lining blood vessels. By measuring TF on cells in contact with blood, we think we can determine who with aPL is at risk for serious clots.

LRI: Is there a dependable blood test to measure TF activity?

Dr. Roubey: There hasn't been one so far, but we think we've found one. Although some TF circulates freely in the blood, the TF of greatest interest to clotting risk is on cell surfaces. To tackle the problem of how to best measure TF, we turned to James H. Morrissey, PhD, a biochemist at the University of Illinois at Urbana-Champagne and an internationally known TF expert. Dr. Morrissey recently devised the VIIa-AT test that is thought to reflect the total level of TF exposed to circulating blood. This test is our proposed biomarker.

LRI: How hopeful are you that this biomarker will be effective in predicting antiphospholipid syndrome?

Dr. Roubey: We are cautiously very hopeful. If it's on target, drugs aimed at reducing or inhibiting TF might one day offer effective and safer alternatives to standard blood thinners. For example, some laboratory data in animals indicate that commonly used cholesterol-lowering drugs (statins) and certain antiplatelet drugs may decrease TF activity in addition to their other effects. By the end of 2005 we expect to complete the testing of blood from our subset of patients, and have some answers on the value of our biomarker.

LRI: Can you describe the day-to-day workings of your laboratory?

Dr. Roubey: We're a relatively small lab, with two post-doctoral fellows, two technicians, an undergraduate student, and the study coordinator for APSCORE. We meet formally once a week, but we discuss results, plan experiments and so forth on a daily, if not hourly, basis. My office is adjacent to the lab, which is very helpful. I devote my clinical practice almost exclusively to people with SLE or the antiphospholipid syndrome.

As the coordinating center for the registry as a whole, we also communicate with the nation's seven other APSCORE sites. Investigators around the world can apply to use the registry's database and samples for their studies—the information there should be incredibly valuable to researchers and, before long, to patients as well.

LRI: Why did you choose autoimmunity as a research focus?

Dr. Roubey: During medical school, I became fascinated with the idea that the immune system could go awry and make auto-reactive antibodies to various organs or specific parts of cells. Before starting my rheumatology fellowship, I had the opportunity to spend about seven months in London working with Dr. Graham Hughes, an internationally known SLE expert. This was during the mid-1980s, and Dr. Hughes' seminal work on the antiphospholipid syndrome was just beginning. Intellectually, it was an exciting place to be. Also, the patients I saw in London made a big impression. They included very sick lupus patients with blood clots or strokes, and women who'd had many miscarriages and desperately wanted children. We were just beginning to link many of these problems to aPL.

About Robert A. S. Roubey, MD

Dr. Robert Roubey is an Associate Professor of Medicine at the Thurston Arthritis Research Center at the University of North Carolina at Chapel Hill. He is an internist and a rheumatologist who specializes in lupus and the antiphospholipid syndrome. His clinical and basic research focuses on antiphospholipid antibodies. Dr. Roubey is the Principal Investigator of APSCORE. For more information on the registry, visit www.apscore.org, call the staff at 919-966-0572, or e-mail them at apscore@med.unc.edu.