Red blood cells found to squeeze clots tight using physical force

Ever since William Harvey outlined the circulation of the blood, textbooks have assigned distinct roles to blood’s cellular cast.

Platelets served as the tiny workhorses that pulled clotting protein threads tight, white cells patrolled for infection, and red blood cells (RBCs) mostly hauled oxygen while passively filling space inside a forming clot.

A collaborative study from the University of Pennsylvania now overturns that familiar picture. Using a blend of biochemical tricks, high-resolution imaging, and mathematical modeling, the investigators show that red blood cells actively generate the forces that make a clot shrink and toughen once it has sealed a wound.

“This discovery reshapes how we understand one of the body’s most vital processes,” said senior author Rustem Litvinov from the Perelman School of Medicine (PSOM).

The project drew on expertise that spans hematology, cell biology, and soft-matter mechanics, illustrating how interdisciplinary science can upend long-held assumptions.

Clots shrink without platelets

John Weisel, a professor of cell and developmental biology at PSOM, has spent decades probing fibrin – the insoluble, rope-like protein network that glues a clot together.

In previous studies, he and Litvinov had dissected how platelets tug on fibrin fibers. So when they decided to revisit that system without platelets, they expected an inert mass.

Professor Weisel said the team did not expect anything to happen. “Instead, the clots shrank by more than 20 percent.”

To rule out platelet activity, the team used blood treated to block the platelets’ ability to contract. Once again, the clots pulled inward. At that point, the researchers confronted the unanticipated culprit.

“Red blood cells were thought to be passive bystanders,” Weisel said. Far from passive, the cells appeared to be doing mechanical work.

“That’s when we realized red blood cells must be doing more than just taking up space,” Litvinov explained.

Red cells act like gels

How could flexible discs with no contractile proteins of their own produce force? The Penn biologists enlisted Prashant Purohit, a professor of mechanical engineering and applied mechanics who specializes in the behavior of gels and other squishy materials.

“Red blood cells have been studied since the 17th century,” noted Purohit. “The surprising fact is that we’re still finding out new things about them in the 21st century.”

Purohit constructed a mathematical model grounded in colloid physics. As a clot forms, fibrin polymerizes into a porous mesh. This mesh traps RBCs along with plasma proteins such as albumin and fibrinogen.

When the mesh compacts, large protein molecules are squeezed out of the tight spaces between adjacent red cells faster than they can leave the surrounding fluid. That imbalance, known as an osmotic depletion force, produces an external pressure that pushes the trapped cells into even closer contact.

Packed blood cells shrink the clot

“Essentially, the proteins in the surrounding fluid create an imbalance in pressure that pushes red blood cells together,” Purohit said.

The packed cells transmit the pressure back to the fibrin scaffold, making the entire clot shrink and stiffen.

“This attractive force causes them to pack more tightly, helping the clot contract even without platelets,” he added.

The model also permitted the team to quantify a second, previously proposed mechanism: molecular bridging. In this process, complementary molecules on neighboring RBC membranes bind together.

Clot behavior matches math

Study first author Alina Peshkova, now a postdoctoral researcher in pharmacology at Penn, designed a series of clotting assays to test the model head-on.

When she blocked the membrane molecules required for bridging, clots still contracted robustly. When she manipulated the chemical environment to eliminate the osmotic pressure gradient, contraction was largely abolished.

“We experimentally confirmed what the model predicted,” Peshkova said. “It’s an example of theory and practice coming together to support each other.”

Findings may impact stroke care

Most acute clotting problems in medicine trace back to an imbalance between clot formation and dissolution.

If RBC-driven contraction proves to be a major determinant of clot strength in vivo, it could help explain why patients with anemia or sickle cell disease sometimes experience unusual clotting complications.

Conversely, individuals with very low platelet counts (thrombocytopenia) might still achieve adequate clot retraction if their red cells provide compensatory force.

A better grasp of clot mechanics is also relevant to thromboembolism. A clot that retracts too vigorously can become so dense that fragments break off and travel downstream, lodging in the lungs, coronary arteries, or brain.

Understanding how osmotic forces affect clot architecture may therefore inform strategies to prevent strokes or pulmonary emboli.

“Ultimately, our model is going to be helpful in understanding, preventing, and treating diseases related to clotting inside the bloodstream,” Purohit said.

Physical forces reshape biology

The Penn study showcases the power of looking at a biological question through a physical lens. Osmotic depletion had long been recognized in industrial colloids – pigment particles in paint, milk proteins in dairy science – but had received little attention in hemostasis research.

By merging classic hematology with contemporary soft-matter theory, the investigators revealed that an abundant, well-studied cell type still harbors surprises that matter for human health.

“This attractive force causes them to pack more tightly, helping the clot contract even without platelets,” Purohit emphasized.

The remark captures the study’s dual message: mechanical laws operate inside living tissues, and basic science can still revise what clinicians think they already know.

With platelet-free contraction now firmly established, the field can move on to explore how genetic diseases, pharmaceuticals, or blood storage conditions influence this newly recognized RBC function.

Researchers can also investigate whether tweaking it might tip the balance between life-saving hemostasis and life-threatening thrombosis.

The study is published in the journal Blood Advances.

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