American Heart reports on acute ischemic stroke and increased risk of bleeding in the brain

May 27 2004

High blood levels of a cell-regulating protein in patients with acute ischemic stroke can identify those with an increased risk of bleeding in the brain, according to a report in today’s rapid access issue of Stroke: Journal of the American Heart Association.

Identifying which patients are at risk for the bleeding – the most feared complication of clot-busting stroke therapy – can improve the risk-benefit ratio.

Researchers investigating the mechanisms behind such bleeding found high blood levels of a protein called cellular fibronectin (c-Fn) predicted bleeding risk.

“This study demonstrates that blood c-Fn levels are significantly higher in patients in whom bleeding develops after clot-busting therapy.  Therefore it might be a useful marker of those patients who are at greatest risk of thrombolytic treatment,” said lead author Mar Castellanos, M.D., a neurologist at the Hospital Universitari Doctor Josep Trueta in Girona, Spain. 

The results suggest that c-Fn levels of 3.6 micrograms per milliliter or greater can predict the development of bleeding with 100 percent accuracy.

The clot-busting drug tissue plasminogen activator (tPA) can reduce the severity of an ischemic stroke and thus, reduce debilitating effects.  It is the only U.S. Food and Drug Administration-approved treatment for ischemic stroke and must be given within three hours of symptom onset. 

However, tPA could also increase risk of bleeding in the brain.  Evidence suggests that tPA may indirectly cause damage to the cells that line the inner walls of blood vessels.

Fibronectins promote cell-to-cell and other interactions.  C-Fn is largely confined to the cells that line blood vessels, where it mediates the interactions between those cells and blood cells.  It also plays an important role in blood-clot formation.

Castellanos and his colleagues studied 87 ischemic stroke patients (average age 67, 59 percent men) treated with intravenous tPA at two university hospitals in Spain within six hours after their symptoms began.  Seventy-one were treated within three hours.  Giving tPA within three hours is the time frame considered the most effective for treating ischemic stroke.  Prior to tPA treatment, the researchers drew blood samples and did CT scans, which they examined to learn the amount of neurological injury already caused by the stroke.

In their study, the researchers looked for hemorrhagic transformation – the point when damaged brain tissue begins to leak blood.  Twenty-six (30 percent) of the patients developed bleeding.  Blood levels of c-Fn before tPA-administration were significantly higher in patients with hemorrhagic transformation (4.8 micrograms per milliliter) than those who did not develop bleeding (1.7 ug/mL).

The greater the severity of the bleeding, the higher the levels of c-Fn, researchers said.

Among the study’s other findings:

• Blood c-Fn levels were significantly higher in patients with early signs of ischemia.
• Patients who suffered bleeding had more severe neurological damage when admitted to the hospital.
• Those who bled also had greater volumes of brain tissue damage on their next CT scan.
• It confirmed previous findings that those who suffered bleeding after tPA have higher levels of MMP-9, an      enzyme that can degrade the basal membrane.  However, after adjusting for other factors, only c-Fn proved to be an independent predictor of brain bleeding.
• Plasma MMP-9 levels were higher before tPA treatment in patients who later bled.
• No interaction was found between c-Fn and MMP-9.

Vessel damage following treatment for ischemic stroke may be the result of several mechanisms including the activation of MMPs, which is secondary to reduced blood flow and the administration of tPA, Castellanos added.

Because the study size was small, the results need to be replicated in larger studies.

“This manuscript provides important information which may significantly change the manner in which patients with acute ischemic stroke are treated,” said Marc Mayberg, M.D., chairman of the American Heart Association Stroke Council, and chairman of the department of neurosurgery at Cleveland Clinic Foundation. “Tissue plasminogen activator (tPA) is an effective, proven therapy for acute stroke when administered in the first three hours, but its administration is associated with a significant risk of hemorrhagic conversion and bleeding into the brain.   By identifying a blood marker for patients with a higher risk of hemorrhagic conversion after tPA, it should be possible to give tPA with a greater level of confidence and reduce the overall risk profile.”

Ischemic strokes account for about 80 percent of the 700,000 new or recurrent strokes that occur annually in the United States.  They are caused by a blockage of an artery supplying blood to the brain, usually as the result of a blood clot.