New research is set to expand the therapeutic time window for stroke treatment, while also contributing to the basic research understanding that stroke pathogenesis involves much more than acute disruption of blood flow.

Strokes affect nearly 1 million people every year in the U.S., and the vast majority (80-90%) are of the ischemic variety, that is, due to blood clots. Strokes are the fifth leading cause of adult death and disability, resulting in over USD 72 billion in annual cost.

Treatment of acute ischemic stroke is highly time dependent, requiring the intravenous administration of tissue plasminogen activator (TPA) within 4.5 hours of the event. Ultimately however, only roughly 2% of stroke patients get TPA, because hospitals to which stroke patients are initially delivered are not set up for administering TPA, requiring transfer to an additional hospital.

Researchers working at the Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University reported in the August 25, 2020, issue of Nature Communications that blood replacement could rescue mice from an otherwise lethal stroke.

Most significantly, the researchers observed rescue even when treatment was administered as late as 7 hours after they induced a stroke through middle cerebral artery occlusion.

First author and co-principal investigator, Xuefang "Sophie" Ren, Director of the Experimental Stroke Core at the Rockefeller Neuroscience Institute, West Virginia University, told BioWorld Science, "I think our study is of great translational significance because if we can replace stroke patient blood with healthy blood, it can save lives, improve stroke outcome, reduce stroke infarct volume, improve neurological scores, and reduce mortality for stroke patients."

Co-principal investigator James W. Simpkin, director and professor at the Center for Basic and Translational Stroke Research, West Virginia University, explained, "From a basic science perspective, this study demonstrates as well as any study that's ever been published, that stroke is a whole-body condition not just a brain-vascular condition. The peripheral system becomes involved with what's happening in the brain and this leads to exacerbation of damage of blood vessels. Sophie's study showed very elegantly that there is a profound immune response to the event and Sophie has started to identify the white blood cells component that is involved in the beneficial response."

The brain normally is protected by the blood-brain barrier (BBB) that blocks most of the white blood cells from getting into the brain, but after stroke, because the BBB is damaged, white blood cells can go into the brain.

The investigators observed that part of the mechanism involves the ability of healthy blood to seal off the BBB quickly, thus reducing the continual entry of pathogenic peripheral white blood cells.

Simpkins pointed out that this works primarily through neutrophils initiating attack from these extracellular molecules produced from the event. Thereafter, neutrophils get into the brain and begin attacking brain tissue.

Another mechanism of the protective activity of blood replacement therapy involved the reduction in the amount of those inflammatory signaling molecules, which ultimately reduced the number of entering neutrophils attacking the brain.

Translationally, the investigators aim next to define exactly which cellular component(s) of the blood gives the positive effect when replacing stroke blood with non-stroke blood. They know it is not the plasma component, but rather a yet to be identified cell or cell fragment component. Then the goal will be to collect those cells and store them in banks for use in the acute setting.

In the U.S., blood replacement therapy is only rarely used because of the variety of side effects. Accordingly, researchers need to define the minimal cellular component of the blood needed for the improved outcome. Only then, do they feel they will be ready to talk to physicians and stroke neurologists about doing blood replacement therapy clinical trials.

Initially Simpkins had hoped the magic would be in the fluid part of the blood, because then dialysis could be used as a very simple route of administration. Unfortunately, this does not appear to be a possibility, since the beneficial activity is not in the plasma fluid. Accordingly, their next goal is to determine exactly which cell type is mediating the life-saving activity.

Ren explained that they have examined a variety other compounds in this animal model and some of them showed a little improvement, but this study showed significant improvement. "It was a dramatic change after we treated the mice," Ren emphasized.

Simpkins said that two impressions from the study that really stood out for him. Firstly, the 70-80% reduction in stroke infarction volume was never witnessed by him previously with any neuroprotective drug or therapy. Secondly, it was most impressive how long it was possible to wait before performing the blood replacement therapy in the stroke mice. This approach may dramatically extend the therapeutic window, and "that's really where the rubber hits the road in the clinic." (Ren, X. et al. Nat Commun 2020, 11(1): 4078).