Researchers have discovered how do clots become firm in the presence of blood flow


Blood clotting is one of the most critical, protective processes in human physiology.

When something goes wrong with clotting, either because there is too much clotting, leading to a stroke, or not enough, leading to internal bleeding, the outcome can be catastrophic.

Now, University at Buffalo researchers have established an in vitro model of this process that will help clinicians improve presurgical planning and care for patients with certain bleeding disorders, especially defects in platelets (the blood cells that form clots) and those affecting the patient’s ability to form clots.

The work is also providing a picture of what might happen between platelets and blood vessels with unprecedented detail.

Published in May in Nature Communications, the paper reveals how the model the UB bioengineers constructed mimics the complexity of what happens when blood clots at an injury site.

Shear stress

“Blood flow – and the shear stress on the walls of blood vessels – are big factors in the cardiovascular system,” said Ruogang Zhao, Ph.D., corresponding author on the paper and assistant professor in the Department of Biomedical Engineering, a joint department between the School of Engineering and Applied Sciences and the Jacobs School of Medicine and Biomedical Sciences at UB.

He collaborated with researchers from other UB departments, including co-corresponding author Sriram Neelamegham, Ph.D., professor of chemical and biological engineering.

Before performing surgery, surgeons need to know a patient’s history with regard to bleeding and the capacity of their blood to clot.

Hematologists treating various blood disorders also need to understand how specific treatments will alter the patients’ ability to form clots.

Currently, there are devices that can be used in a clinical and home-care setting to help characterize how a patient’s blood clots.

But, Zhao noted, these devices lack the ability to realistically model how clots form and how shear flow affects them, which limits their utility.

He explained that shear stress is the result of the force of blood flow against blood vessel walls, similar to the way that water flowing through pipes in a house exerts force and stress on those pipes over time.

“For the past several decades, it’s been known that the shear force along vessel walls affects how platelets adhere to the injury site,” said Zhao, “but we haven’t known exactly how that affects the clotting process and outcome.”

“That’s important because normal clotting is directly dependent on the stiffness of a clot,” he said. “If a clot is too soft, it will just wash away.

If it’s too stiff, then it can form a thrombus, obstructing blood flow and potentially leading to complications, including stroke and heart attack.”

Maintaining that delicate balance becomes even more challenging in the presence of the shear force of blood flow.

Zhao said that platelets, the clotting cells, are very smart. When there’s no injury, they quietly circulate.

But if they are exposed to collagen, meaning there’s been an injury, they activate. They rush to the site, but different blood flow rates can change their activity.

Modeling both flow and stiffness

“The innovation of our system is that we can model both flow conditions and the stiffness of the clot, which gives the most realistic picture of what’s happening. No other model can do that,” said Zhao.

This diagram demonstrates how the engineered tissue model works to mimic the clotting upon blood vessel injury. Platelets adhere to the collagen microtissue that represents the collagen layer in the blood vessel. The micropillars that support the microtissue sense the stiffness of the microclots that form when exposed to different flow rates, which mimic venous or arterial flow in the body.​ Credit: Zhao, Neelamegham, et al/Nature Communications

The system imitates the dynamic process of how platelets adhere to the injured blood vessel walls and form clots while providing real-time information on the mechanical properties of the clot that has formed.

It thereby models both clot formation and clot mechanics during shear flow.

Zhao and his colleagues did this using microfabrication technology, creating mechanical sensing platforms that allow simultaneous control of both the formation of the clot and the clot mechanics, mimicking the stiffening process.

The key innovation of the UB system is the development of flexible micropillars that allow the stiffness of clots to be measured.

“These micropillars support the microcollagen as the platelets adhere to it,” said Zhao.

“The micropillars serve as force sensors, they can sense the contraction and stiffness of the microclots.

No other system can measure the stiffness of clots and therefore, how soft or stiff they are.”

The model that he and his colleagues developed integrates engineered microchannels that mimic the blood vessel with micropillar force sensors to measure the stiffness of a clot.

The system was tested using blood samples from human volunteers.

The UB team has used the device to mimic how clotting occurs in people who have inherited bleeding disorders compared to normal clotting.

The team plans to further validate the clinical utility of the system by testing more samples from patients with diverse clotting disorders.

When we injure ourselves and start to bleed, our bodies make sure that the bleeding soon stops by forming a clump of blood (a blood clot) that closes the wound.

This reaction is very important, because it ensures that we lose as little blood as possible, stops germs from getting into the wound, and allows the wound to heal.

But sometimes blood clots form in the bloodstream even though there are no external injuries, and blood vessels may become blocked as a result. This can lead to dangerous complications such as a heart attack or stroke.

These kinds of blood clots only occur very rarely in healthy people. But certain illnesses and genetic factors can increase the risk of blood clots forming. Many people who have this higher risk take anti-clotting medication as prevention.

When we injure ourselves and start to bleed, this is what happens:

  1. Our blood vessels become narrower. This reduces the flow of blood to the injured tissue, limiting the loss of blood.
  2. Blood platelets in the bloodstream, known as thrombocytes, attach to the damaged area of the blood vessel and clump together to reduce the bleeding.
  3. The body then activates a number of substances in the blood and the tissue. These substances solidify the clump by forming a special protein and fix the clump at the wound. These substances are called clotting factors or coagulation factors. There are 13 clotting factors in human blood and tissues. Most of them are made in the liver. The liver needs vitamin K to make some of these clotting factors. Our bodies cannot make their own vitamin K, so people have to get it in their diet.

Blood clots can also form even if the person does not have any external injuries. For instance, if blood flows too slowly and it starts to build up, large numbers of blood platelets may group together and stick to each other, forming a blood clot.

It is also not uncommon for them to form because the inner walls of blood vessels are damaged, for example in atherosclerosis.

If clotting factors are stronger, that can also increase the risk of blood clots forming for no identifiable reason.

There are a number of reasons that this can happen, including a genetic predisposition, a tumor, or because somebody is taking a particular kind of medication.

The medical term for a blood clot is “thrombus”.

When can blood clots become dangerous?

If a blood clot forms in a vein it is called venous thrombosis. Venous thrombosis usually affects the veins in the legs.

The main reason people get this kind of thrombosis in the legs is because they do not get enough movement over a long period of time – perhaps because they have had major surgery, or have a serious illness or injury.

A blood clot in the legs can become dangerous if part of the clot (called an embolus) breaks off and blocks a blood vessel in the lungs. The medical term for this condition is pulmonary embolism. Typical signs of pulmonary embolism include sudden breathing difficulties, coughing, coughing up blood, and chest pain.

If blood clots form in arteries, the tissues and organs that they usually supply no longer get enough blood, or might not get any blood at all.

This kind of thrombus usually develops in the coronary (heart) arteries or inside the heart. If a thrombus blocks a coronary artery, it can cause a heart attack.

Blood clots that develop in the heart itself could cause a stroke if they move to the brain and block blood vessels there.

People who have atrial fibrillation have a higher risk of blood clots in the heart.

Atrial fibrillation is a particular type of irregular heartbeat, where two of the chambers (called atria) beat very fast and irregularly.

This means that blood does not flow through the heart as quickly and steadily. Artificial heart valves also increase the risk of a thrombus: Their surface is not as smooth as that of natural valves, so blood platelets are more likely to attach to them and form a blood clot.

Particular medications or illnesses such as cancer or genetic coagulation disorders can also increase the risk of blood clots developing.

More information: Zhaowei Chen et al. Microclot array elastometry for integrated measurement of thrombus formation and clot biomechanics under fluid shear, Nature Communications (2019). DOI: 10.1038/s41467-019-10067-6

Journal information: Nature Communications
Provided by University at Buffalo


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