Platelets are unsung heroes in the human body. When a person suffers an injury that causes bleeding, platelets rush to the scene to work with proteins to form a blood clot that stems the flow of blood. Scientists are still debating whether these tiny disks — a mere two micrometers wide — are even full cells or just fragments. However they may be classified, though, they are lifesavers.

Physicians know firsthand that platelet function is a matter of life or death, whether a person falls or undergoes heart surgery. However, current methods to assess platelet function often fall short. These methods require large amounts of blood, and they do not provide specific insights into how or why platelets may be dysfunctional. “The technology that we're using to measure [platelet function] is like a big old hammer,” said Roman Sniecinski, a cardiac anesthesiologist at Emory University.

This need has spurred a new wave of technologies to more precisely assess platelet functions by focusing on the force that these tiny cells produce. These forces can be as small as one billionth of a paper clip’s weight, requiring engineers to bring creative, out-of-the-box strategies to a problem that has existed for over a century.

Clotting concerns

Platelets were first described as early as 1882, when Italian physician Giulio Bizzozero observed platelets under a microscope and deduced that they emerged from bone marrow and played a role in clotting (1). Later researchers tied platelets to a wide range of diseases where people bleed or bruise easily — all without knowing how platelets work.

The mechanisms underlying clotting were only deciphered in the late 1900s, when researchers began to tease out the role that platelets played in the process. Injured blood vessels attract platelets within seconds (2). There, the platelets attach to the blood vessel walls. Once in place, a chemical signal must activate them. At this point, the platelets become much more dynamic: changing their shape, releasing clotting factors, and clumping together. 

When people have platelet diseases, steps of this process fail, and the clot does not form. Drugs can also halt clotting — and sometimes, this is used for a patient’s benefit. During heart surgery, for example, physicians want to temporarily stop platelets from forming unnecessary clots, so they give patients anti-coagulation drugs. After the surgery, though, it is critical for physicians to reverse this effect.

The prior ways in which we looked at platelet behavior did not mimic the actual actions of the platelets inside the body. 
– Rachael Callcut, University of California, Davis

“We always have to deal with this platelet defect in the operating room,” Sniecinski said. “We have to make the patient clot after the surgery.” That makes it essential for cardiac anesthesiologists like Sniecinski to measure platelet function. Other physicians also need this capability when they have a patient who has undergone a major trauma, for example, or when deciding what drugs are safe to give a patient.

Some common tests measure the concentration of platelets in a person’s blood. Others focus on the final step in the process of platelet response, called aggregation, which has long been the hallmark characteristic of platelet function. These aggregometry tests measure how well platelets stick together as a proxy for their function. Thromboelastography tests assess the physical characteristics of the clot itself.

Physicians have argued that these tests don’t tell the whole story. Having a high platelet count doesn’t mean the platelets are actually promoting clotting. Studies have also revealed that aggregometry and thromboelastography do not always provide reliable guidance on when patients require interventions for impaired platelet function (3).

“The prior ways in which we looked at platelet behavior did not mimic the actual actions of the platelets inside the body,” said Rachael Callcut, a trauma surgeon at the University of California, Davis.

However, platelets may offer other insights into their function. For example, during aggregation, the platelets contort and squeeze together. To move like this, structural proteins within the platelets must generate force. Some researchers think measuring this force could be the key to identifying dysfunctional platelets.

Arm-wrestling a platelet

To Nathan Sniadecki, a mechanical engineer at the University of Washington, force is the key to understanding all of a platelet’s functions.

“If the platelets can't attach, they can't make force. If they can't activate, they can't make force. If they can't aggregate, they can't make force,” he said.

Sniadecki has spent much of his career thinking about forces at the cellular and molecular level. Forces may determine how cells move around, interact with each other, and form larger-scale structures. His team has designed flexible microscopic structures to measure these forces. One is a cantilever, or a post that is anchored at one end. When a cell exerts enough force on the exposed end, it can bend the post like a diver standing on the end of a diving board.

In 2011, Sniadecki learned about the military’s interest in measuring platelet function to figure out how to treat injured, bleeding soldiers. As he mulled over a Department of Defense grant proposal, he realized his cantilever posts might provide a way to accomplish this. “It is sort of like having an arm-wrestling match with a cell,” he said. “You can see how strong it is by how far it bends the pillar.”

However, measuring these forces one platelet at a time was too slow. He wanted to accumulate multiple platelets and measure their force altogether — similar to how they might actually act at the site of a clot. The solution came to him serendipitously, when a speck of dust accidentally made its way into their experiment. Looking under the microscope, he could see that the platelets began to gather behind the dust particle.

That inspired the final piece of the puzzle: a block positioned in front of the post to encourage platelets to aggregate. His team placed these structures within tiny channels on a plastic card. Scientists could inject blood into the channels, and when the platelets encountered the block and post, the amount that the post bent would reflect the force that the platelets exerted. They created a tiny microscope to take pictures of the bent posts and created software to calculate the force.

In a 2019 study in Nature Communications, Sniadecki’s team demonstrated that this platform could test how drugs such as aspirin affect clotting abilities (4). They also used the tool to predict which trauma patients needed blood transfusions. Unlike other technologies, this platform requires less than one milliliter of blood, which Sniadecki hopes makes it easier to use in clinical practice.

The cool part is to see the technology work in the wild. … It has been really impactful to see that it actually has utility in many different areas. 
– Nathan Sniadecki, University of Washington

Sniadecki has now formed a company called Stasys Medical Corporation to commercialize the tool. They have developed a desktop microscope system, disposable cartridges to run the blood through the channels, and analysis software. Other researchers are already demonstrating interest in the nascent technology. In a 2022 study, researchers used Stasys’ tool to evaluate the restoration of platelet function after a common method to stop and restart clotting in heart surgery (5). In a 2024 study, Callcut’s team used the tool to estimate platelet function and blood transfusion needs in trauma patients (6).

Sniadecki isn’t just excited about the interest in the tool. He is especially eager to see the actual data produced by the system on diverse patient populations, which he hopes will inform better algorithms to predict the health consequences of abnormal platelet forces.

“The cool part is to see the technology work in the wild,” he said. “It has been really impactful to see that it actually has utility in many different areas.”

From force to fluorescence

While Sniadecki has concentrated on forces generated by platelet aggregates, other researchers focus on much smaller-scale forces within platelets.

Khalid Salaita, a chemist at Emory University, has also thought about forces throughout his career, but his focus has been at the subcellular level. Cells are full of proteins that can move, bend, and push their way around the cell. In platelets, the forces seen outside the cell start deep within.

“At a macroscopic scale, you see a group of cells shrink and collectively pull,” he said. “But where that pulling is coming from, ultimately, is the cytoskeleton of the cell.”

Salaita had previously developed a series of molecules that can measure force within cells. By folding molecules into spring-like structures, he could measure how intracellular machines deformed these springs and calculate the corresponding force.

When Salaita met Sniecinski, they realized that these force-measuring molecules could be the perfect match for the task of assessing platelet function. Salaita’s team developed a prototype with a folded-up piece of DNA as the spring that would be pulled by the cytoskeleton proteins. To measure how far the cytoskeleton proteins pulled the spring, they used a fluorescent protein that would only emit energy when close to another protein. By placing the two proteins at opposite ends of the spring, the protein’s fluorescence would decrease as the spring expanded.

However, this system wasn’t enough. As a physician, Sniecinski knew that for this assay to be part of routine clinical workflows, it would have to be easy to run in the relatively austere setting of a clinical laboratory, without any specialized equipment or expertise. Some of the chemistry in Salaita’s first version wouldn’t work in that context.

Salaita’s team went back to the drawing board to come up with a new way to measure the spring. “All this work was really blood, sweat, and tears,” Salaita said. He meant this literally: Some of the blood samples used in the study came from laboratory members working on the experiments, and one sample was even Salaita’s own blood.

They realized they could create fluorescent signals that would emit light when a DNA linker connecting them was cut by the protein Cas12a. They rigged Cas12a to only activate when the spring expanded. This would trigger a flood of glowing light easy to measure with simple lab equipment.

In their 2023 study published in Nature Biomedical Engineering, Salaita and Sniecinski showed that the system — dubbed Mechano-Cas12a Assisted Tension Sensor (MCATS) — could detect forces in as few as 1,000 platelets in less than five milliliters of blood (7). Similarly to Stasys’ tool, MCATS could also predict the need for a platelet transfusion after heart surgery, but Sniecinski thinks the tool has even more potential applications. With such low blood volumes, it could be especially helpful for diagnosis of platelet conditions in babies.

“As we go down the road of personalized medicine, this is something that could become useful,” Sniecinski said.

A new tool for physicians

For trauma surgeons like Callcut, it is common to see patients who are bleeding. These surgeons often have to make decisions about if a person is bleeding too much and needs a blood transfusion, but current methods to inform those decisions often feel imprecise to Callcut. “We have always assumed that if a patient’s platelet counts are low, then we should transfuse platelets, but that really oversimplifies what's happening,” she said.

That is why she jumped at the opportunity to test drive Stasys’ new technology. She reached out to the company when she read about the tool and, as an early adopter, provided early feedback on technical issues and analysis challenges. She appreciates the modular cartridge structure of the tool, although she hopes that the company releases more specific guidelines on interpreting results in the future. Ultimately, she sees the advantages of Stasys’ tools over the standard tests. 

“Each technology offers something unique, but this particular technology allowed us to identify stronger signals predicting outcomes in patients,” she said. “It gives us a much more reliable way of looking at what's actually happening.”

Since then, she has seen more interest in force-measuring tools among her physician colleagues. Increasing demand has motivated Sniadecki to scale up production of the physical components — although his own lab is still using their home-brewed version so that they can continue tinkering to improve it. The system is currently only approved for research use, so they are generating data to garner Food and Drug Administration approval for clinical use.

Scaling up is also on Salaita and Sniecinski’s minds. They haven’t yet formed a company, but they have thought about potential changes to MCATS to make it a viable clinical lab test. For example, their test is run in a 96-well plate but is still largely manual. They are brainstorming ways to automate it and to ensure that it is easy for even a novice lab technician to run and get reliable results.

Callcut hopes that tools like these can guide physicians who need to make fast decisions about bleeding patients. Salaita’s dream is to get a real-time readout, but to Sniecinski, even a world in which a laboratory could run the test in as little as 60 minutes would provide invaluable insights.

“That is a big step forward for diagnosing a lot of different platelet disorders and medication effects,” he said.

References

1. Coller B.S. Historical Perspective and Future Directions in Platelet Research. J Thromb Haemost  9, 374–395 (2012).
2. Eisinger F. et al.  The Platelet Response to Tissue Injury. Front Med (Lausanne)  5, 317 (2018).
3. Schmidt A.E. et al.  The Utility of Thromboelastography to Guide Blood Product Transfusion: An ACLPS Critical Review. Am J Clin Pathol  152, 407–422 (2019).
4. Ting L.H. et al.Contractile forces in platelet aggregates under microfluidic shear gradients reflect platelet inhibition and bleeding risk. Nat Commmun  10, 1204 (2019).
5. Mazzeffi M. et al. In Vitro Treatment of Extracorporeal Membrane Oxygenation Coagulopathy with Recombinant von Willebrand Factor or Lyophilized Platelets. J Cardiothorac Vasc Anesth  37, 522–527 (2022).
6. Vuoncino L.H. et al.  Using microfluidic shear to assess transfusion requirements in trauma patients. Trauma Surg Acute Care Open  9, e001403 (2024).
7. Duan Y. et al.  Detection of cellular traction forces via the force-triggered Cas12a-mediated catalytic cleavage of a fluorogenic reporter strand. Nat Biomed Eng  7, 1404-1418 (2023).