COLLEGE STATION, Texas—Researchers in the Department of Biomedical Engineering at Texas A&M University are working on a new way to detect blood clots, particularly in pediatric patients. Their study was recently published in Nature Scientific Reports.
Unlike biology textbook illustrations, blood vessels aren’t straight cylinders. They are tortuous, with complex curves, spirals and bends. When blood reaches these curves, it makes changes to its fluid mechanics and interactions with the vessel wall. The fluid mechanics change with the tortuous microenvironment, in a healthy person. But when diseased, these environments could lead to incredibly complex flow conditions, which activate proteins and cells that eventually lead to blood clots.
Abhishek Jain, assistant professor in the Department of Biomedical Engineering at Texas A&M, noted a large challenge in medicine — the medical devices used to detect clots and assess anti-blood clotting drug effects are entirely chemistry-based.
“They do not incorporate the flow through the naturally turning and twisting blood vessels, which are physical regulators of blood clotting,” pointed out Jain. “Therefore, the readouts from these current static systems are not highly predictive, and often result in false positives or false negatives.”
“… current monitoring devices do not measure the effects of hemodynamic forces that contribute significantly to coagulation, platelet function and fibrin formation. This limits the extent to which current assays can predict clotting status in patients,” adds the article.
Researchers in Jain’s lab at Texas A&M approached the problem from a new angle, and designed a microdevice that mimics tortuous blood vessels, creating a diseased microenvironment in which blood may rapidly clot under flow. They showed that this biomimetic blood clotting device could be used to design and monitor drugs that are given to patients who suffer from clotting disorders.
Jain added that he can see several applications for the device, including critical care units and military trauma care units. “It can be used in detection of clotting disorders and used in precision medicine where you would want to monitor pro-thrombotic or anti-thrombotic therapies and optimize the therapeutic approach,” he stated.
After developing the device, the team took it into the field for a pilot study. Working with Dr. Jun Teruya, chief of transfusion medicine at Texas Children’s Hospital and Baylor College of Medicine, the team coordinated with clinicians to test the device with pediatric patients in critical care whose heart and lungs were not functioning properly.
These patients needed an extracorporeal membrane oxygenation (ECMO) machine, which provides cardiac and respiratory support in the exchange of oxygen and carbon dioxide. A common complication in ECMO is blood clotting, so patients are administered anticoagulants to prevent clotting. But ECMO machines are also known to “eat” clotting proteins and platelets, which puts anti-coagulated patients at further risk of bleeding. Anti-coagulated pediatric patients on ECMO are especially prone to bleeding.
“Another major advantage of this tortuosity-activated device is that when connected to a pressure sensor, blood clots can be quantified,” the article says. The clotting time derived from the pressure curve can detect differences in blood spiked with clinically-relevant doses of anticoagulants (thrombin inhibitors) and antifibrinolytics (tranexamic acid) in-vitro, and it shows sensitivity to platelet count under stenosed and tortuous flow, making this device potentially well suited to explore whether anticoagulants, antifibrinolytics and anti-platelet drug candidates that produce different behaviors in clotting dynamics. Importantly, we were able to confirm that pediatric patients on ECMO as well as anticoagulants did not clot within our device. Therefore, this data provides a proof-of-feasibility that device may be used to identify changes in hemostasis at bedside and guide therapy.”
Current chemically based blood clotting tests are expensive, time-consuming, require a skilled technician, and can be unreliable. The Jain team’s tortuosity-based microfluidic system doesn’t require expensive chemicals. It provides results within 10-15 minutes, uses low blood sample volume and is easy to operate.
“The margin for error is essentially zero for these patients. Therefore, it’s imperative that all the tests, not just clotting tests, must work and provide clinicians with quick and reliable information about their patient so they can provide the best care possible,” Jain explained.
With the opportunity to test their system with real patients, Jain said his team was able to demonstrate that their design could detect bleeding in anticoagulated patients with low platelet counts. This can help guide doctors to make better evidence-based clinical decisions for their patients.
“First, when we added clinically-relevant doses of UFH [unfractionated heparin] (0–1 IU mL−1)18 to whole blood samples fluorescently labelled to track fibrin formation, and perfused the blood though the device while monitoring fibrin using fluorescence microscopy, we found decrease in fibrin area coverage as concentration of heparin was increased. These results suggested that this device can potentially detect differences in heparin dosage within blood samples in-vitro. Next, we explored if our device can also detect differences in doses of bivalirudin, a direct thrombin inhibitor, when added to blood samples,” the article continues. “When we followed the same methodology as described above for heparin, but instead added clinically relevant doses of bivalirudin (0–100 ng mL−1) to whole blood, we again observed reduced fibrin with nearly complete clearance at 75 ng mL−1, demonstrating a potentially unique advantage over current monitoring tools that have limited sensitivity to bivalirudin.”
The team plans to continue clinical studies in order to compare their approach to standard methods and hopefully demonstrate key performance advantages.
