Therapy sought to reduce major risk from minor bleeding that can follow stroke

May 12, 2014

AUGUSTA, Ga. - Bleeding into the brain following a stroke doesn't have to be big to be bad, says a researcher exploring a therapy to eliminate the major risk of minor bleeding.

The main problem with a minor bleed is the Iron in the blood , which is essential to transporting oxygen to the brain and body, but can be lethal when it comes in direct contact with brain tissue, said Dr. Adviye Ergul, vascular physiologist at the Medical College of Georgia at Georgia Regents University.

"We need iron in our blood, but we don't want it in our brain," said Ergul, who recently received a $1.8 million grant from the National Institutes of Health to better understand how a relatively small amount of blood and iron are bad for the brain and whether an agent that mops up iron can help.

Her focus is diabetes, which puts patients at higher risk of stroke, bleeding, and poor recovery. As with the general population, people with diabetes are at greatest risk for a clot-based stroke that interrupts blood and oxygen supplies to the brain, much as a heart attack does to the heart.

But the damage diabetes does to blood vessels - making existing vessels leaky and prompting proliferation of new, leaky ones - also means these patients may subsequently experience bleeding from the miles of tiny blood vessels in their brain.

"Patients with diabetes are more likely to bleed into the brain following an ischemic stroke," Ergul said. "It happens spontaneously; it also happens with tPA." Tissue plasminogen activator, or tPA, is a clot-busting agent and the only currently approved medical therapy for stroke. Bleeding is a known risk of tPA that increases in diabetes.

"Patients with diabetes are some of the highest risk patients to bleed with tPA," Ergul said. In fact, while no such recommendations exists in the United States, in Europe, patients with prior stroke and diabetes are not given tPA when they have a recurrent stroke.

From observations in her animal models as well as humans, Ergul suspects many patients with diabetes who have a stroke likely could benefit from rapid removal of iron from the brain.

She is looking at the iron chelating agent, deferoxamine, which basically binds to iron so it becomes inactive and can be easily eliminated in the urine. Deferoxamine, already used clinically for iron overdoses and certain anemias, is under study for hemorrhagic stroke treatment. Hemorrhagic strokes, which are far less common than clot-based strokes and typically more lethal, result from major bleeding from some of the larger arteries in the brain. The rapid, resulting destruction is caused by a large amount of blood pushing brain tissue aside and up again the skull.

While the bleeding that follows a clot-based stroke likely doesn't produce sufficient volume to put that kind of pressure on the brain, the comparatively small amount of bleeding that occurs still exposes brain cells to iron.

"Iron not only kills neurons, we think it also kills endothelial cells in the brain and it affects how endothelial cells can repair themselves." Ergul said. Endothelial cells, which line all blood vessels, comprise the majority of the tiny capillaries which have only one layer of contractile cells on top. Larger vessels have multiple layers of smooth muscle cells.

Similar to what happens with aging, the tiny vessels don't relax or regenerate normally in diabetes. Ergul has evidence that iron, which shouldn't be in brain tissue, also stimulates inflammation as part of an immune response, which further increases the leakiness of the capillaries.

While attempts to stop bleeding in a hemorrhagic stroke are often unsuccessful, essentially nothing is done for bleeding following a clot-based stroke, Ergul said. In fact, clinicians may view the bleeding as an indicator that blood flow has been reestablished to the struggling tissue.

In her stroke models, she is using the chelation agent daily for two weeks alone or after administering tPA, to see how the drugs interact and look at levels of recovery. Within 14 days, normal animals would have mostly recovered from the stroke. She's also examining further how stroke recovery is impacted by diabetes.

While new blood vessels are a good thing in the heart or legs, "We are making the argument that making new blood vessels is not always a good thing," Ergul said. "We need to find ways to stimulate stable and functional new vessels." Ergul notes that the abnormal blood vessel proliferation that occurs in the brain is very similar to the sight-destroying vessels that proliferate in the eye in diabetic retinopathy.

More than 7 percent of Americans have diabetes which puts them at a two- to six-fold increased risk of an ischemic, or clot-based, stroke and poor recovery. Arteries feed arterioles which feed the 400 miles of capillaries in the brain, which feed back into the venous system.
-end-


Medical College of Georgia at Augusta University

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.