In these microscopic close-ups, samples of pink blood cells mixture from left to proper, turning into extra compact regardless of the absence of platelets, lengthy thought important to clotting. Credit score: Rustem Litvinov
Crimson blood cells, lengthy regarded as passive bystanders within the formation of blood clots, truly play an lively function in serving to clots contract, in accordance with a brand new research by researchers on the College of Pennsylvania.
“This discovery reshapes how we understand one of the body’s most vital processes,” says Rustem Litvinov, a senior researcher on the Perelman Faculty of Drugs (PSOM) and co-author of the research. “It also opens the door to new strategies for studying and potentially treating clotting disorders that cause either excessive bleeding or dangerous clots, like those seen in strokes.”
The discovering, revealed in Blood Advances, upends the long-standing concept that solely platelets, the small cell fragments that originally plug wounds, drive clot contraction. As a substitute, the Penn crew discovered that pink blood cells themselves contribute to this significant technique of shrinking and stabilizing blood clots.
“Red blood cells have been studied since the 17th century,” says co-author Prashant Purohit, Professor of Mechanical Engineering and Utilized Mechanics inside Penn Engineering. “The surprising fact is that we’re still finding out new things about them in the 21st century.”
An sudden discovering
Till now, researchers believed that solely platelets have been liable for clot contraction. These tiny cell fragments pull on rope-like strands of the protein fibrin to tighten and stabilize clots.
“Red blood cells were thought to be passive bystanders,” says co-author John Weisel, Professor of Cell and Developmental Biology inside PSOM and an affiliate of the Bioengineering graduate group inside Penn Engineering. “We thought they were just helping the clot to make a better seal.”
That assumption started to unravel when Weisel and Litvinov ran a take a look at they anticipated to fail. They created blood clots with out platelets. “We expected nothing to happen,” says Weisel. “Instead, the clots shrank by more than 20%.”
To double-check their outcomes, the crew repeated the experiment utilizing common blood handled with chemical compounds to dam platelet exercise. The clots nonetheless contracted. “That’s when we realized red blood cells must be doing more than just taking up space,” says Litvinov.
Modeling the mechanics of blood clots
To determine how pink blood cells have been driving this sudden conduct, the crew turned to Purohit, a mechanical engineer by coaching.
An knowledgeable on delicate supplies like blood clots and gels, Purohit developed a mathematical mannequin that recommended that pink blood cells compact collectively primarily resulting from “osmotic depletion.”
This course of additionally explains how particles in colloids—mixtures like paint, milk or muddy water—can collect and type clusters when the circumstances round them change.
“Essentially, the proteins in the surrounding fluid create an imbalance in pressure that pushes red blood cells together,” says Purohit. “This attractive force causes them to pack more tightly, helping the clot contract even without platelets.”
On this timelapse, a blood clot (in white) contracts, regardless of being engineered to haven’t any platelets. Credit score: Rustem Litvinov
How clotting works with out platelets
As blood begins to clot, a web-like protein referred to as fibrin kinds a mesh that traps pink blood cells and pulls them shut collectively. “That packing sets the stage for osmotic depletion forces to take over,” says Purohit.
As soon as the pink blood cells are packed tightly throughout the fibrin mesh, proteins within the surrounding fluid are squeezed out from the slim areas between the cells. This creates an imbalance: The focus of proteins is greater outdoors the packed cells than between them, which ends up in a distinction in “osmotic pressure.”
That strain distinction acts like a squeeze from the skin, pushing the pink blood cells even nearer collectively.
“This attraction causes the cells to aggregate and transfer mechanical forces to the fibrin network around them,” provides Purohit. “The result is a stronger, more compact clot, even without the action of platelets.”
Validating the mannequin
Prior analysis recommended one other potential clarification: bridging, wherein the attraction between small molecules on the floor of pink blood cells causes them to stick.
“Our model suggested the bridging effect was real,” says Purohit, “but much smaller than the effect of osmotic depletion.”
To check the mannequin, first writer Alina Peshkova, now a postdoctoral researcher in Pharmacology inside PSOM, carried out a collection of experiments on modified blood clots.
Within the absence of the molecules that trigger the bridging impact, the clots nonetheless contracted, however little contraction occurred in an atmosphere designed to stop osmotic depletion.
“We experimentally confirmed what the model predicted,” says Peshkova. “It’s an example of theory and practice coming together to support each other.”
Combating clotting illnesses and strokes
Gaining a greater understanding of the function pink blood cells play within the formation and maturation of clots may result in new remedies for circumstances like thrombocytopenia, wherein low platelet counts may cause uncontrolled bleeding.
The findings may additionally make clear how clots break into fragments that journey by means of the bloodstream and trigger blockages—often called embolisms—that may set off strokes.
“Ultimately, our model is going to be helpful in understanding, preventing and treating diseases related to clotting inside the bloodstream,” says Purohit.
Extra co-authors embrace Ekaterina Okay. Rednikova, Rafael R. Khismatullin and Vladimir R. Muzykantov of PSOM, and Oleg V. Kim of PSOM and Virginia Tech.
Extra info:
Alina D. Peshkova et al, Crimson blood cell aggregation inside a blood clot causes platelet-independent clot shrinkage, Blood Advances (2025). DOI: 10.1182/bloodadvances.2024015533
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