June 2001

From Schepens Eye Research Institute

Blood clots are found in retinas of patients with diabetic retinopathy

Findings suggest aspirin therapy for diabetic patients to stave off blindness

BOSTON — Diabetic patients may benefit from aspirin therapy to reduce their risk of developing diabetic retinopathy – the damage to tiny blood vessels in the back of the eye that causes many diabetic patients to go blind, according to a new study at The Schepens Eye Research Institute.

In diabetic patients, the narrow capillaries that nourish the retina –the tissue-thin back of the eye onto which light is focused – become marked by hundreds of tiny, microscopic blood clots that impede the flow of nutrient-rich blood, the researchers have found. While this has been suggested previously, this is the first time it has been demonstrated.

Aspirin, already recommended by the American Diabetes Association to reduce cardiovascular disease in diabetic patients, might help prevent the aggregation of platelets and clotting in retinal capillaries because it is an anti-platelet agent and anti-inflammatory agent as well.

"The study, done by Drs. Boeri and Maiello in my laboratory, has shown that there is a process in retinopathy that is likely to benefit from anti-platelet intervention," said Mara Lorenzi, M.D., Senior Scientist at The Schepens. "This study gives added impetus to the incorporation of aspirin in the treatment regimen of diabetic patients, as early and chronic use of the drug may help prevent retinopathy."

Dr. Lorenzi, Associate Professor of Ophthalmology at Harvard Medical School and Director of the Center for Diabetic Retinopathy at The Schepens, and her colleagues, Drs. Daria Boeri and Michele Maiello, Assistant and Associate Professor Internal Medicine, respectively, at the University of Genoa, Italy, found that diabetic patients had a four-fold increase in these tiny blood clots, called microthrombi, over patients without diabetes. The scientists report their findings in the June issue of the journal Diabetes (50:1432-1439, June 2001). The study was funded by the National Eye Institute.

Retinopathy is the most common complication from diabetes and is the leading cause of blindness in this country for people aged 20 to 74. The damaging changes to the eye are initially without symptoms but lead to an estimated 12,000 to 24,000 new cases of blindness each year.

The blood clots that form in the retinal vessels, similar to the clots that form in larger blood vessels that carry blood to and from the heart and cause heart disease, eventually can become so numerous that blood cannot properly reach the retina. When that happens, the retina starves for oxygen and nutrients, and eventually produces growth factors that stimulate abnormal growth of new blood vessels. In this advanced, or proliferative, stage of retinopathy, new blood vessels grow along the retina and in the vitreous, the clear, gel-like substance that fills the inside of the eye. These blood vessels can bleed, cloud vision, and destroy cells in the retina, causing blindness.

But knowing that minuscule blood clots are damaging the narrow retinal capillaries and impeding blood flow in the disease’s very early stages means that perhaps an intervention could interfere with that process. That intervention, the authors suggest, may well be as simple as a daily dose of aspirin in the 81-325 milligram range, if begun well before any sign of retinopathy has developed.

They write: "The American Diabetes Association has recently issued recommendations for the use of aspirin in diabetic patients, targeted to both secondary and primary prevention of large vessel disease. When implemented early, such strategy may extend its benefits to retinopathy."

The story of blood clots in the retina is complex. Capillary walls are made of endothelial cells, which die or are damaged due to high glucose in people with diabetes. When this happens, platelets and blood cells stick to the inner walls of capillaries, forming a clot, or occlusion. When enough of the clots are sufficiently big to interfere with blood flow, vision can be compromised because the retina is not getting enough oxygen from the blood and retinal cells can become damaged.

The scientists found that the clots that block retinal vessels in diabetic patients often were in the same places where cells of the capillary walls were damaged and the endothelial cells had died. They also found that the clots were made of platelet clumps and fibrin, leading them to conclude that aspirin may be of benefit.

"The treatment would, most likely, need to be started early on, because even small and transient blood clots have the potential to do their damage on retinal vessels," Dr. Lorenzi said.

While aspirin is one possible intervention, tight glucose control is the very first line of defense, Dr. Lorenzi noted. "Aggressive control of the high blood glucose before retinopathy develops always is the first and best defense," she said. "But it’s difficult to achieve, and there is a risk of diabetic patients experiencing hypoglycemia. That’s why something else is needed." In addition, tight control of high blood pressure also will be of benefit, she said.

Dr. Lorenzi directs the new Center for Diabetic Retinopathy at The Schepens, funded by the Juvenile Diabetes Research Foundation. It is the first such center funded by the Foundation. The Schepens investigators in the Center plan to study the interplay of changes induced by diabetes in many cell types of the retina: neural cells, glial cells that provide support to both neurons and vessels, and the vascular cells themselves. One of the goals is to devise a combination of drugs that can be coupled to anti-diabetic regimens in order to prevent retinopathy.

The Schepens Eye Research Institute, an affiliate of Harvard Medical School, is the largest independent eye research center in the nation, both in size of faculty and support from the National Eye Institute. The Institute, begun in 1950, has a renowned faculty of more than 60 scientists, including immunologists, molecular and cell biologists and physicists who investigate cures for blinding diseases and aids for people with low vision.

EDITORS: The research paper is available online at http://diabetes.diabetesjournals.org/cgi/content/full/50/6/1432.












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