A possible diagnostic use for clot-dissolving drugs such as tPA has been found by Medical College of Georgia researchers working to improve a test that identifies potentially deadly blood clots in the legs.
"This study is a fairly simple concept," says Dr. Vincent J.B. Robinson, nuclear cardiologist at MCG and the Veterans Affairs Medical Center in Augusta and lead author of a study in the February issue of CHEST detailing how clot-busting drugs such as tPA, already used to treat strokes and heart attacks, may help find clots as well.
When patients go to their doctor with symptoms such as swollen legs with tender spots, shortness of breath or passing out, they may get a simple blood test called the latex d-dimer, says Dr. Robinson.
The d-dimer test is a screening test that checks the blood for evidence that the body is trying to break down a clot. The body forms blood clots, impermeable masses of elastic fibrin and platelets and other cells, to stop bleeding. But clots also can form for no apparent good reason, particularly in areas such as the legs where blood pools.
"It's just how we are built; dependency and immobility shifts the balance to clotting inside our veins," says Dr. Robinson. This risk is the main reason flight attendants remind passengers to stretch their legs on long flights and hospitals put intermittent inflatable devices on the legs of bedridden patients. Some people have an inherited predisposition to forms these clots, a condition called thrombophilia.
Each year, 250,000 hospitalizations and 200,000 deaths in the United States result from these clots moving to the lungs, where they can prevent sufficient oxygen from getting to the body, the researchers says. About 10 percent of hospital deaths are linked to the potentially preventable scenario of clots forming in the venous system, then breaking loose.
Amazingly, the body already has tPA in the lining of blood vessels to help dissolve clots; the d-dimer tests looks for the breakdown products of that effort. While the standard d-dimer test has been shown highly efficient at detecting a clot once it has reached the lungs, called a pulmonary embolism, it's not as efficient at finding clots deep in the leg veins where many of them start.
MCG researchers, led by Dr. Robinson, wondered if they could improve the effectiveness of clot detection by giving small amounts of tPA before the test.
They hypothesized that the lower part of the legs has lower rates of clot dissolution because a clot large enough to occlude a vessel in the leg would minimize contact between the clot and the blood.
Using pigs as their animal model, the researchers first performed d-dimer studies to get a baseline, then caused a clot in the femoral vein in the groin. An hour later, there were no significant changes in the d-dimer levels even though, if the natural clot-busters were working as might be expected, the levels should have risen rapidly.
So they gave five progressively higher doses of tPA – the highest of which was well below the therapeutic level given for stroke or heart attack treatment – and d-dimer levels increased within 30 minutes of each dose, with significant changes at the highest two doses.
"There are some groups of people, especially those with deep-vein thrombosis in their lower limbs, who don't show positive with the standard d-dimer test. How can we improve the ability of the d-dimer test to detect clots in these groups? The answer may be to add a miniscule dose of tPA so that it would break down a small amount of the clot," says Dr. Robinson. "There is also a group of patients who are false positive. I had one in my clinic today. Those people have higher levels of d-dimer and we don't know why. It may be they have confounders, such as antibodies that mimic d-dimers," says Dr. Robinson.
Adding tPA or some other clot-dissolving drug right before the test may clear up those positives and negatives, he says, hypothesizing that measuring the difference between the standard and the new 'provoked' d-dimer test will allow the clinician to better determine whether the clot was present in the first instance.
A better d-dimer test also could help some patients avoid more costly and potentially more risky tests, such as a computerized tomography scan with a radiographic dye, he says.
Dr. Robinson recently applied for an American Heart Association grant to fund clinical studies in which humans get two d-dimer tests: one without tPA and the second after a tiny dose. "Then, we may have a gold standard technique for looking at clots in people which will work for nearly everyone."
Co-authors on the study include Dr. Guillermo E. Pineda, former MCG cardiology fellow who is now on the faculty at the University of South Carolina in Columbia; Dr. Ali K. Salah, MCG internal medicine resident; Dr. Walter L. Pipkin, former MCG general surgery and vascular surgery fellow who is now a pediatric vascular surgery fellow at the University of Alabama; James H. Corley, nuclear pharmacist and associate professor of radiology at MCG; Mary H. Jonah, supervisor of the MCG Hematology Lab in the Department of Pathology; and Dr. James R. Gossage, MCG pulmonologist.
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