The reason why intracerebral hemorrhage, a common cause of stroke, has worse consequences in diabetics than in non-diabetic patients, appears to be because high blood sugar increases the ability of a protein called plasma kallikrein to stop blood from clotting near injured vessels, say US scientists who hope the discovery will lead to new treatments that control such bleeding.
You can read about the study, led by the Joslin Diabetes Center, Boston, Massachusetts, in a paper published online on 23 January in the journal Nature Medicine.
Strokes are a leading cause of death and disability in adults; according to the American Heart Association, they killed over 137,000 people in 2006.
Strokes occur when blood flow to a part of the brain is blocked, often killing off brain tissue.
There are two main types of stroke: ischemic and hemorrhagic, the first caused by a blockage in a blood vessel supplying blood to the brain, and the second, the subject of this study, caused by intracerebral hemorrhage, when blood vessels rupture and blood escapes into the surrounding tissue, causing a hematoma.
When intracerebral hemorrhage occurs in patients with diabetes or who are discovered to have have hyperglycemia (high blood glucose), the hematoma expansion is usually greater, and the outcomes are often much worse, lead Joslin Investigator Dr Edward Feener and colleagues wrote in their background information.
Feener’s team had done some work with plasma kallikrein in diabetic eye complications and decided to investigate its effect in stroke.
Although we have known about the protein for decades, this is the first study to show that it increases brain bleeding through a previously unknown mechanism: it stops platelets forming near damaged blood vessels, and this is boosted by high blood glucose.
“We show that PK [plasma kallikrein] inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations,” Feener and colleagues wrote.
They started the study with a test where they injected a small amount of blood into the brains of rats with diabetes and rats without diabetes (the controls). The blood they used came from the rats themselves (“autologous blood”).
The results were dramatic: the “hematoma expansion” (the spread of blood outside blood vessels) covered a much greater area of brain in the diabetic rats than in the non-diabetic controls.
They did the test again, but this time pre-treated the diabetic rats with a molecule that inhibits the effect of plasma kallikrein: the hematoma expansion in the diabetic rats was on a par with that of the non-diabetic rats.
And when they injected the rats with pure plasma kallikrein, the non-diabetic rats showed little effect, but the diabetic rats then experienced rapid increases in major bleeding.
The researchers then did further tests that showed by bringing blood glucose levels to normal in the diabetic rats, they could inhibit the effect of the plasma kallikrein, and by rapidly increasing the blood glucose in non-diabetic rats, they could produce the hemorrhage results seen in the brains of the diabetic rats.
They concluded this means it was the level of sugar in the blood at the time of the hemorrhage, rather than the presence of diabetes per se, that caused the increased bleeding.
Feener, who is also an associate professor of medicine at Harvard Medical School, told the press that given the high rate of strokes and the damage they cause, these findings are exciting because:
“… they suggest the possibility that rapid control of blood sugar levels may provide an opportunity to reduce intracerebral hemorrhage, which is a clinical situation that has very limited treatment options.”
“This work could have broad implications since about half of patients with acute hemorrhagic stroke have hyperglycemia, whether or not they have pre-existing diabetes,” he added.
Another avenue this study opens up is to develop drugs that target plasma kallikrein to protect people with diabetes or others at high risk of stroke. These treatments could also benefit people at high risk of certain types of ischemic stroke that start as blocked blood vessels but then burst and become hemorrhages.
“Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein.”
Jia Liu, Ben-Bo Gao, Allen C Clermont, Price Blair, Tamie J Chilcote, Sukanto Sinha, Robert Flaumenhaft & Edward P Feener.
DOI:10.1038/nm.2295
Source: Joslin Diabetes Center (press release, 23 Jan 2011), American Heart Association.
Written by: Catharine Paddock, PhD