Unblocking our understanding of how cells move in arteries

Blood clots are a major underlying factor for heart attacks, strokes, and similar fatal diseases. For decades, doctors have looked at blood clotting—clinically known as thrombosis—to understand a patient’s likelihood of serious cardiovascular events. But while how clots form has been well studied in smaller blood vessels such as arterioles, few researchers have explored this same process in our much larger arteries.

This gap spurred Noelia Grande Gutiérrez, an assistant professor of mechanical engineering, and Arnav Garcha, a Ph.D. candidate, to research a theoretical basis for better understanding mechanisms that influence thrombosis in arteries, research that could influence how doctors diagnose and treat blood clots in the future. The work was recently published in Physics of Fluids.

As a member of Grande Guitérrez’s lab, Garcha focuses on computational methods for studying cardiovascular diseases. “With research, we have a unique opportunity to dive into assumptions and establish whether they are valid or not,” Garcha said. “A simple question people overlook—for sometimes valid reasons—can completely shift the way we look at a problem.”

“What we know from the clinical perspective is blood in the arteries moves much faster than the blood vessels that are downstream,” he said. He compared our blood vessels to a tree structure, starting off with a big trunk, then branching and tapering off. “We want to know basically: How are these cells moving across those scales, from the largest branch to the smallest at the end of this structure?” he said.

But it’s more than just the speed of blood flow that affects whether a clot forms. To simulate the process of clot formation, scientists have typically focused on interactions between red blood cells and the miniscule pieces that actually create clots: platelets.

When a blood vessel is cut, platelets serve a bodily need by clumping together near that cut to start the healing process. If platelets are not in the right place to serve as these quick Band-Aids, cuts can fester, letting blood out while letting disease in. Platelets can also clump together when there is no cut or vessel injury, a problematic accumulation that can lead to thrombosis.

Platelets are tiny compared to red blood cells, and they also make up only a fraction of total blood volume. Red blood cells comprise up to 50% of our blood’s volume, whereas platelets make up less than 1%. Because red blood cells are so large and numerous, they often push platelets near the walls of small blood vessels, a process called margination. Margination has been identified as a key catalyst for blood clots in arterioles, since it allows platelets to accumulate near the vessel wall in high numbers.

However, platelets are next to impossible to observe in a lab, complicating how doctors are able to study their interaction with red blood cells in larger blood vessels. Even so, researchers have tended to assume red blood cells were pushing platelets in arteries the same way they were in arterioles, despite some experimental evidence to the contrary.

A simple question people overlook—for sometimes valid reasons—can completely shift the way we look at a problem.

Arnav Garcha, Ph.D. Candidate, Mechanical Engineering

In developing this new model, Garcha found that margination in the arteries is actually not prevalent. One major reason why: our biggest blood vessels are simply shorter. “The platelets only have so much time to move through these large arteries” compared to smaller blood vessels, according to Garcha. “By the time the platelets reach the end, these red blood cells didn’t push them in any way. There is simply not enough length for this to happen.”

Instead, Garcha found that how platelets come together in arteries has much more to do with these vessels’ geometry. Arteries can be 10 times bigger in diameter than arterioles, changing how the fluid in blood flows. This arterial fluid has more inertia than it does in arterioles. Arteries are also turning, twisting, and dividing across their paths. This geometry creates more complexity in arteries than it does in arterioles, changing how the blood might otherwise flow. These two attributes—higher inertia and winding, multiplying paths—can push platelets away from the center to clump near an artery’s walls. The curvature and branching of arteries therefore play a larger role in how blood clots form than previously understood.

Thrombosis is hard to predict in part because each person has a unique vascular anatomy. Even so, researchers have not always tested clotting in ways that represent different blood vessels’ individual characteristics. Testing for arterial thrombosis in the past has involved long, straight glass tubes, with researchers photographing cells after 25 centimeters (about 10 inches) or more of blood flow. As Garcha and Grande Gutiérrez note in the paper, this kind of testing does not reflect the flow of actual arteries, which “are tortuous, branch frequently, and rarely exceed 5 centimeters (2 inches) in segment length.”

Garcha believes these findings can thus inform how researchers create new tests to more accurately study how clots form in our biggest blood vessels. And if real-world testing backs these methods up, they can even be applied to how doctors treat patients. Computer simulations based on these findings could signal a patient’s likelihood for arterial thrombosis in ways amenable to a clinical setting, taking only hours or a few days to diagnose someone’s risk compared to no physical test today.