New Study Uncovers Key to Varying Sickle Cell Severity

A new study led by University of Minnesota Twin Cities researchers may explain why patients with the same genetic sickle cell mutation experience varying levels of pain, organ damage, and treatment response.

The study indicates that the severity of sickle cell disease is not best predicted by the average "thickness" of a patient's blood. Instead, it is predicted by the specific behavior of a small population of highly "stiff" red blood cells. These stiff cells reorganize themselves within the blood flow, moving to the edges of blood vessels—a process called margination—creating significantly more friction and resistance compared to flexible cells.

Understanding Sickle Cell Disease

Sickle cell disease is an inherited disorder affecting millions globally. It causes normally flexible, doughnut-shaped red blood cells to become stiff and crescent-shaped in low-oxygen environments. This leads to painful blockages, organ damage, and a reduced life expectancy. Previously, blood testing typically used "bulk" measurements, which averaged out the properties of all cells, potentially missing critical individual cell differences.

David Wood, a professor in the University of Minnesota Department of Biomedical Engineering and senior author of the study, stated that the research bridges the gap between single-cell behavior and overall blood supply flow. By using an engineering approach to measure individual cell properties and whole blood dynamics, the team found that patients with diverse clinical profiles follow a consistent physical relationship governed by the fraction of stiff cells.

How Stiff Cells Disrupt Blood Flow

Using advanced microfluidic "chips" designed to mimic human blood vessels, the team identified two main ways blood flow is disrupted:

• Margination: Even a small number of stiff cells can relocate to vessel walls, significantly increasing wall friction.
• Localized Jamming: At higher concentrations, stiff cells can cause blood to "jam" in specific areas, leading to a sudden and substantial increase in flow resistance.

The research also found that these stiff cells begin to appear at oxygen levels as high as 12 percent. These oxygen levels are typically present in the lungs and brain, suggesting that the physical processes leading to vessel blockages can start earlier in the oxygen-depletion process than previously thought.

Hannah Szafraniec, a Ph.D. candidate and lead author on the paper, noted that these insights could support the development of more effective, personalized therapies and new testing methods for early symptom detection. This research may also be applicable to other blood-related disorders, including malaria, diabetes, and certain cancers.

The study involved collaborations with University College of London, University of Edinburgh, Harvard University, Massachusetts General Hospital, and Princeton University. Funding was provided by the National Heart, Lung, and Blood Institute, a part of the U.S. National Institutes of Health.