Why some stroke patients can recover better than others

A clot forms. Blood flow to the brain is blocked. Starved of oxygen, neurons begin to die. This scenario, known as an ischemic stroke, plays out in roughly 21,000 people worldwide each day, threatening them with long-term disability or even death. In recent decades, the advent of drugs and mechanical tools for removing clots has revolutionized stroke care.
Yet, even with the clot gone and the vessel clear, up to 50% of patients never recover neurologically.
Doctors have long known that removing a stroke-causing clot cannot always restore full blood flow to the brain. But why this phenomenon, known as "no reflow," occurs has remained a mystery.
But this new research helps explain why.
After clot removal, irregular cerebral blood flow can stretch von Willebrand factor, promoting platelet-rich micro-clots that sustain “no reflow” and tissue injury. Inflammatory signalling may impair normal regulation of this protein; higher interleukin-6 levels were associated with greater von Willebrand factor activity and poorer outcomes.
The study, published in the journal PNAS, reveals in unprecedented detail how the brain's own defense mechanisms against stroke can backfire, triggering yet more micro-clots in small vessels and damaging tissue long after the primary culprit is gone.

We now have a way to explain why so many of these patients are not seeing neurological improvements. These new findings also point to a new potential target for therapeutics that could be extremely impactful for stroke patients.
To examine what, precisely, goes on in the brain after a clot is removed, the research team first turned to mice.

Using a technique called intravital microscopy, they observed in real time how blood flowed in the brain and how cells behaved in the hour after mice that had suffered strokes underwent endovascular thrombectomy—a procedure in which a tool is threaded through a blood vessel to remove an obstructive clot.

While blood quickly started flowing again after the procedure, the researchers were stunned to see that in many mice, it flowed haphazardly, in fits and starts, even reversing course at certain points.
They saw it happening with their own eyes. Blood that was flowing left all of a sudden flowed right and vice versa.

An even closer look revealed that, as the brain tried to divert blood around the original obstruction, tiny clots formed where the haphazard channels converged.

To drill down on why those clots formed, the researchers recreated this scenario using computer simulations. In other research, they also recreated similar scenarios using a 3D artificial brain filled with fake blood.

These experiments implicated von Willebrand factor—a protein best known for stopping us from bleeding when we get a cut.

In its resting state, von Willebrand factor is coiled up like a ball of string inside blood vessels, waiting for distress signals from the body that make it stretch out and start forming clots to stop bleeding.

In a brain experiencing a stroke, something else unfolds the ball.

If there is some kind of fluid motion induced after the clot is removed, it can stretch out that ball into an extended thread that attracts platelets, forms new clots and blocks flow even after the original culprit clot is gone.

Meanwhile, the study showed, the brain's inflammatory response to stress interferes with safeguards that normally keep the protein's clotting efforts in check, creating what the researchers call "a perfect storm" of collateral damage.

Other experiments, looking at blood from stroke patients at the University of Washington in St. Louis, suggest a similar phenomenon happens in humans, too.

These researchers are the first to really show in this hyperacute phase of stroke what is happening with these cells inside blood vessels. "Seeing is believing."

More research is necessary to determine why no reflow happens in some stroke patients but not others. But the study did find that stroke patients with higher blood levels of a pro-inflammatory compound called interleukin-6 had more overactive von Willebrand factor and worse long-term outcomes.

The researchers envision a day when therapeutics targeting von Willebrand factor, or the inflammatory compounds that exacerbate its clotting capabilities, could be given to stroke patients alongside clot-busting drugs and surgery.

Notably, several drugs targeting the von Willebrand factor already exist and are approved for use for other disorders.

Audrée Laroche et al, Mechanisms of von Willebrand factor activation driving no reflow in ischemic stroke, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2610397123