Computer model predicts red blood cell flow

Rendering of stream of blood cells. Credit: © Witold Krasowski / Fotolia

Adjacent to the walls of our arterioles, capillaries, and venules -- the blood vessels that make up our microcirculation -- there exists a peculiar thin layer of clear plasma, devoid of red blood cells. Although it is just a few millionths of a meter thick, that layer is vital. It controls, for example, the speed with which platelets can reach the site of a cut and start the clotting process.

"If you destroy this layer, your bleeding time can go way up, by 60 percent or more, which is a real issue in trauma," said Eric Shaqfeh, the Lester Levi Carter Professor and a professor of chemical engineering and mechanical engineering at Stanford University. Along with his colleagues, Shaqfeh has now created the first simplified computer model of the process that forms that layer -- a model that could help to improve the design of artificial platelets and medical treatments for trauma injuries and for blood disorders such as sickle cell anemia and malaria.

The model is described in a paper appearing in the journal Physics of Fluids.

The thin plasma layer, known as the Fåhræus-Lindqvist layer, is created naturally when blood flows through small vessels. In the microcirculation, the layer forms because red blood cells tend to naturally deform and lift away from the vessel walls. "The reason they don't just continually move away from the wall and go far away is because, as they move away, then also collide with other red blood cells, which force them back," Shaqfeh explained. "So the Fåhræus-Lindqvist layer represents a balance between this lift force and collisional forces that exist in the blood."

Because the deformation of red blood cells is a key factor in the Fåhræus-Lindqvist layer, its properties are altered in diseases, such as sickle cell anemia, that affect the shape and rigidity of those cells. The new model, which is a scaled-down version of an earlier numerical model by Shaqfeh and colleagues that provided the first large-scale, quantitative explanation of the formation of the layer, can predict how blood cells with varying shapes, sizes, and properties -- including the crescent-shaped cells that are the hallmark of sickle cell anemia -- will influence blood flow.

The model can also help predict the outcome of -- and perfect -- treatments for trauma-related injuries. One common thing to do during treatment for trauma injuries is to inject saline, which among other things reduces the hematocrit, the blood fraction of red blood cells. With our model, Shaqfeh said, "we can predict how thick the Fåhræus-Lindqvist layer will be with a given hematocrit, and therefore how close the platelets will be to the periphery of the blood vessels -- and how quickly clotting will occur.

Source: American Institute of Physics (AIP)

Anemia: One-minute point-of-care test shows promise in new study

Erika Tyburski is shown with a prototype device for point-of-care testing of anemia. The device could enable more rapid diagnosis of the common blood disorder and allow inexpensive at-home self-monitoring of persons with chronic forms of the disease. Credit: Gary Meek

A simple point-of-care testing device for anemia could provide more rapid diagnosis of the common blood disorder and allow inexpensive at-home self-monitoring of persons with chronic forms of the disease.

The disposable self-testing device analyzes a single droplet of blood using a chemical reagent that produces visible color changes corresponding to different levels of anemia. The basic test produces results in about 60 seconds and requires no electrical power. A companion smartphone application can automatically correlate the visual results to specific blood hemoglobin levels.

By allowing rapid diagnosis and more convenient monitoring of patients with chronic anemia, the device could help patients receive treatment before the disease becomes severe, potentially heading off emergency room visits and hospitalizations. Anemia, which affects two billion people worldwide, is now diagnosed and monitored using blood tests done with costly test equipment maintained in hospitals, clinics or commercial laboratories.

Because of its simplicity and ability to deliver results without electricity, the device could also be used in resource-poor nations.

A paper describing the device and comparing its sensitivity to gold-standard anemia testing was published August 30 in The Journal of Clinical Investigation. Development of the test has been supported by the FDA-funded Atlantic Pediatric Device Consortium, the Georgia Research Alliance, Children's Healthcare of Atlanta, the Georgia Center of Innovation for Manufacturing and the Global Center for Medical Innovation.

"Our goal is to get this device into patients' hands so they can diagnose and monitor anemia themselves," said Dr. Wilbur Lam, senior author of the paper and a physician in the Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and the Department of Pediatrics at the Emory University School of Medicine. "Patients could use this device in a way that's very similar to how diabetics use glucose-monitoring devices, but this will be even simpler because this is a visual-based test that doesn't require an additional electrical device to analyze the results."

The test device was developed in a collaboration of Emory University, Children's Healthcare of Atlanta and the Georgia Institute of Technology -- all based in Atlanta. It grew out of a 2011 undergraduate senior design project in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. In 2013, it was among the winners of Georgia Tech's InVenture Prize, an innovation competition for undergraduate students, and won first place in the Ideas to SERVE Competition in Georgia Tech's Scheller College of Business.

Using a two-piece prototype device, the test works this way: A patient sticks a finger with a lance similar to those used by diabetics to produce a droplet of blood. The device's cap, a small vial, is then touched to the droplet, drawing in a precise amount of blood using capillary action. The cap containing the blood sample is then placed onto the body of the clear plastic test kit, which contains the chemical reagent. After the cap is closed, the device is briefly shaken to mix the blood and reagent.

"When the capillary is filled, we have a very precise volume of blood, about five microliters, which is less than a droplet -- much less than what is required by other anemia tests," explained Erika Tyburski, the paper's first author and leader of the undergraduate team that developed the device.

Blood hemoglobin then serves as a catalyst for a reduction-oxidation reaction that takes place in the device. After about 45 seconds, the reaction is complete and the patient sees a color ranging from green-blue to red, indicating the degree of anemia.

A label on the device helps with interpretation of the color, or the device could be photographed with a smartphone running an application written by Georgia Tech undergraduate student Alex Weiss and graduate student William Stoy. The app automatically correlates the color to a specific hemoglobin level, and could one day be used to report the data to a physician.

To evaluate sensitivity and specificity of the device, Tyburski studied blood taken from 238 patients, some of them children at Children's Healthcare of Atlanta and the others adults at Emory University's Winship Cancer Institute. Each blood sample was tested four times using the device, and the results were compared to reports provided by conventional hematology analyzers.

The work showed that the results of the one-minute test were consistent with those of the conventional analysis. The smartphone app produced the best results for measuring severe anemia.

"The test doesn't require a skilled technician or a draw of venous blood and you see the results immediately," said Lam, who is also an assistant professor in the Coulter Department of Biomedical Engineering. "We think this is an empowering system, both for the general public and for our patients."

Tyburski and Lam have teamed up with two other partners and worked with Emory's Office of Technology Transfer to launch a startup company, Sanguina, to commercialize the test, which will be known as AnemoCheck™. The test ultimately will require approval from the FDA. The team also plans to study how the test may be applied to specific diseases, such as sickle cell anemia -- which is common in Georgia.

The device could be on pharmacy shelves sometime in 2016, where it might help people like Tyburski, who has suffered mild anemia most of her life. "If I'd had this when I was kid, I could have avoided some trips to the emergency room when I passed out in gym class," she said.

About a third of the population is at risk for anemia, which can cause neurocognitive deficits in children, organ failure and less serious effects such as chronic fatigue. Women, children, the elderly and those with chronic conditions such as kidney disease are more likely to suffer from anemia.

Source: Georgia Institute of Technology

Hormone that controls supply of iron in red blood cell production discovered by researchers

This is a microscopic image of erythroblasts, which are the bone marrow cells that secrete erythroferrone. Credit: Leon Kautz/UCLA

A UCLA research team has discovered a new hormone called erythroferrone, which regulates the iron supply needed for red blood-cell production.

Iron is an essential functional component of hemoglobin, the molecule that transports oxygen throughout the body. Using a mouse model, researchers found that erythroferrone is made by red blood-cell progenitors in the bone marrow in order to match iron supply with the demands of red blood-cell production. Erythroferrone is greatly increased when red blood-cell production is stimulated, such as after bleeding or in response to anemia.

The erythroferrone hormone acts by regulating the main iron hormone, hepcidin, which controls the absorption of iron from food and the distribution of iron in the body. Increased erythroferrone suppresses hepcidin and allows more iron to be made available for red blood-cell production.

"If there is too little iron, it causes anemia. If there is too much iron, the iron overload accumulates in the liver and organs, where it is toxic and causes damage," said senior author Dr. Tomas Ganz, a professor of medicine and pathology at the David Geffen School of Medicine at UCLA. "Modulating the activity of erythroferrone could be a viable strategy for the treatment of iron disorders of both overabundance and scarcity."

The early findings were reported online June 1 in the journal Nature Genetics.

"Our previous work anticipated that a regulator of hepcidin could be secreted by the bone marrow," said the study's first author, Leon Kautz, a postdoctoral fellow at UCLA. "In this research, we searched for new substances that were made in bone marrow that could fill that role."

Researchers first focused on what happens in the bone marrow after hemorrhage. From there, they focused on a specific protein that was secreted into the blood. This protein attracted their attention because it belonged to a family of proteins involved in cell-to-cell communication. Using recombinant DNA technology, they showed that the hormone suppressed the production of hepcidin and demonstrated the effect it had on iron metabolism.

The team foresees that the discovery could help people with a common congenital blood disorder called Cooley's anemia, also known as thalassemia, which causes excessive destruction of red blood cells and of their progenitors in the bone marrow. Many of these patients require regular blood transfusions throughout their lives. Most iron overload is attributed to the iron content of transfused blood. However, even patients who are rarely, or never, transfused can also develop iron overload.

"Overproduction of erythroferrone may be a major cause of iron overload in untransfused patients and may contribute to iron overload in transfused patients," said study author Elizabeta Nemeth, a professor of medicine at the David Geffen School of Medicine at UCLA and co-director of the UCLA Center for Iron Disorders. "The identification of erythroferrone can potentially allow researchers and drug developers to target the hormone for specific treatment to prevent iron overload in Cooley's anemia."

The discovery could also lead to treatments for other common anemia-related conditions associated with chronic kidney disease, rheumatologic disorders and other inflammatory diseases. In these conditions, iron is "locked up" by the effect of the hormone hepcidin, whose levels are increased by inflammation. Erythroferrone, or drugs acting like it, could suppress hepcidin and make more iron available for red blood-cell production.

The next stage of research is to understand the role of the new hormone in various blood diseases and study the molecular mechanisms through which erythroferrone regulates hepcidin.

Additional study authors included Grace Jung and Erika Valore of UCLA and Stefano Rivella of Weill Cornell Medical College in New York.

The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung and Blood Institute.

The Board of Regents of the University of California is the owner of patent applications and uses directed at erythroferrone, which are managed by UCLA's Office of Intellectual Property and Industry Sponsored Research. This intellectual property is the subject of license negotiations with a company for which authors Ganz and Nemeth are scientific advisors and equity holders. Other disclosures are available in the manuscript.

Source: University of California, Los Angeles (UCLA), Health Sciences