UC Irvine-led study is first to find brain hemorrhage cause other than injured blood vessels

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“Our study offers new insights into the formation of brain microhemorrhages and may pave the way for innovative approaches to treating them in the future,” says co-corresponding author Dr. Mark Fisher, professor of neurology in UCI’s School of Medicine. Steve Zylius / UCI

A first-of-its-kind study led by the University of California, Irvine has revealed a new culprit in the formation of brain hemorrhages that does not involve injury to the blood vessels, as previously believed. Researchers discovered that interactions between aged red blood cells and brain capillaries can lead to cerebral microbleeds, offering deeper insights into how they occur and identifying potential new therapeutic targets for treatment and prevention.

The findings, published online recently in the Journal of Neuroinflammation, describe how the team was able to watch the process by which red blood cells stall in the brain capillaries and then observe how the hemorrhage happens. Cerebral microbleeds are associated with a variety of conditions that occur at higher rates in older adults, including hypertension, Alzheimer’s disease and ischemic stroke.

“We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” said co-corresponding author Dr. Mark Fisher, professor of neurology in UCI’s School of Medicine. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

The team exposed red blood cells to a chemical called tert-butyl hydroperoxide that caused oxidative stress; the cells were then marked with a fluorescent label and injected into mice. Using two different methods, the researchers observed the red blood cells getting stuck in the brain capillaries and then being cleared out in a process called endothelial erythrophagocytosis. As they moved out of the capillaries, microglia inflammatory cells engulfed the red blood cells, which led to the formation of a brain hemorrhage.

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development,” said co-corresponding author Xiangmin Xu, UCI professor of anatomy & neurobiology and director of the campus’s Center for Neural Circuit Mapping. “We need to examine in detail the regulation of brain capillary clearance and also analyze how that process may be related to insufficient blood supply and ischemic stroke, which is the most common form of stroke, to help advance the development of targeted treatments.”

Leveraging the broad, collaborative infrastructure and robust resources of the Center for Neural Circuit Mapping, other team members were Rachita Sumbria, co-first author/co-corresponding author and associate professor in the Chapman University School of Pharmacy; Hai Zhang, co-first author and postdoctoral researcher in UCI’s Department of Anatomy & Neurobiology; Rudy Chang, co-first author and Chapman University School of Pharmacy graduate student; Jiahong Sun, postdoctoral researcher at Chapman University; David Cribbs, professor-in-residence at UCI’s Institute for Memory Impairments and Neurological Disorders; and Todd Holmes, UCI professor of physiology & biophysics.

This work was supported by the National Institute on Aging under award numbers R01AG062840, R01AG072896, R35127102, RF1 AG065675 and R01NS121246 and by National Institute of Neurological Disorders and Stroke grant R01NS20989.

UCI’s Brilliant Future campaign: Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for UCI. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UCI seeks to reach new heights of excellence in student success, health and wellness, research and more. The School of Medicine plays a vital role in the success of the campaign. Learn more by visiting https://brilliantfuture.uci.edu/uci-school-of-medicine.

Click here to read the full article in the UCI School of Medicine News and Events website.

Newly discovered mechanism behind microhaemorrhages

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Findings about how erythrocytes interact with brain capillaries offers new potential treatments for brain microhaemorrhages.

New research has revealed a novel contributor to the formation of brain haemorrhages. The study, co-authored by Rachita Sumbria, Associate Professor in the Chapman University School of Pharmacy, has found that increased interactions between aged red blood cells and brain capillaries can lead to brain microhaemorrhages, contrasting to previous thought that these haemorrhages were only linked to blood vessel injuries.

This discovery improves the understanding of the mechanisms behind these microhaemorrhages and offers new possibilities for therapeutic targets for treatment and prevention.

The research details how aged red blood cells stall in brain capillaries of mice, resulting in cerebral microhaemorrhages. Increased red blood cell stalling in brain capillaries was linked to the activation of the immune cells of the brain and brain microhaemorrhages in the absence of brain capillary rupture.

Dr Sumbria explained: “The recent work is a culmination of experiments that we started about a decade ago using cell culture systems. We showed for the first time that brain endothelial cells are capable of engulfing aged/stressed iron-rich erythrocytes, a process known as brain endothelial erythrophagocytosis, and the recent collaborative work shows this process in mice.”

Rudy Chang, co-first author and PhD student at Chapman University, began the foundational work leading to the current study with Dr Sumbria and University of California, Irvine (UCI) researcher, Dr Mark Fisher.

The team, which was led by Dr Mark Fisher and Dr Xiangmin Xu, also from UCI, then conducted experiments by injecting aged red blood cells into mice and tracking their interactions with the brain capillaries in real-time followed by postmortem imaging.

“Our findings show that age-related changes to erythrocytes, and how erythrocytes interact with the brain capillaries, are important underlying factors contributing to brain microhaemorrhage. This represents a novel mechanism distinct from the traditional view of a blood vessel rupture as the cause of brain microhaemorrhages,” Dr Sumbria said.

This research denotes a substantial advancement in the understanding of brain microhaemorrhages and offers paths for new approaches to their treatment.

This study was published in the Journal of Neuroinflammation.

Click here to read full Drug Target Review article.

The Hidden Culprit: Old Red Blood Cells and Capillary Brain Hemorrhage

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Investigating the Causes of Capillary Brain Hemorrhage

By Gordon Jeong, Science Columnist, News Directory 3

Brain hemorrhage is a severe condition that can occur without warning, posing a life-threatening risk. While trauma, high blood pressure, cerebral aneurysms, and cerebrovascular malformations are known to be common causes, there are cases where the exact cause remains unknown.

A research team at the University of California, Irvine, USA has made strides in uncovering the root of capillary brain hemorrhage. Their findings suggest that old red blood cells may be to blame. As these cells age, their function declines, increasing the likelihood of blockage in narrow blood vessels.

Interestingly, the human body possesses its own mechanism for addressing this issue. Vascular cells are able to process old red blood cells trapped in narrow capillaries through a process akin to removing a jammed paper in a copy machine. However, this regulatory function also diminishes with age, leading to an accumulation of old, dysfunctional red blood cells.

The research team conducted an experiment using drugs to simulate the effects of old red blood cells and injected them into mice. The results revealed that the inflammatory response caused by inflammatory microglia leads to blood vessel damage, ultimately resulting in the disposal of the trapped red blood cells. This buildup of damage can lead to blood vessel rupture and subsequent bleeding, ultimately causing harm to cerebral blood vessels and brain tissue.

Capillary hemorrhage of this nature can result in an increased risk of other brain diseases such as stroke or Alzheimer’s disease. While this study sheds light on a new mechanism of cerebrovascular damage, further research is needed to develop effective prevention and treatment methods for cerebrovascular diseases.

This groundbreaking research underscores the importance of ongoing efforts to address cerebrovascular diseases, which pose a significant threat to countless lives each year.

Contact the author at jjy0501@naver.com.

▲ Data photo (123rf) Brain hemorrhage is a serious brain disease that can strike anyone without warning, and can sometimes lead to life-threatening emergencies. Trauma, high blood pressure, cerebral aneurysm, and cerebrovascular malformation are known to be the main causes of cerebral hemorrhage, and although they can be treated or managed and prevented, there are many cases of cerebral hemorrhage that are not is their exact cause known. Scientists are continuing research to find a more accurate cause.

A research team at the University of California, Irvine, USA investigated the causes of capillary brain hemorrhage. Old red blood cells were the culprit the research team suspected. Red blood cells are shaped like donuts with an indentation in the middle to carry oxygen effectively but are not trapped in narrow capillaries and are very flexible. However, as red blood cells age, their function declines and the likelihood of blockage in narrow blood vessels increases.

Fortunately, the human body has the ability to repair these problems on its own. Old red blood cells stuck in the narrow part of the capillaries are processed by vascular cells through the red blood cell phagocytic process, like removing jammed paper in a copy machine. However, this regulatory function also declines with age. And old, bad red blood cells can also increase in older people.

The research team used drugs to make red blood cells look like old red blood cells, then added a fluorescent tag to them and injected them into mice. As a result, it was observed that blood vessel damage accumulates due to the inflammatory response caused by inflammatory microglia, which eventually dispose of the trapped red blood cells. And when this damage builds up, blood vessels can easily burst and cause bleeding.

This type of capillary hemorrhage eventually causes damage not only to cerebral blood vessels but also to brain tissue, which appears to increase the risk of other brain diseases such as stroke or Alzheimer’s disease. This study is significant as it has revealed a new mechanism of cerebrovascular damage. However, developing prevention and treatment through this is still work for the future. Through ongoing research, effective prevention and treatment methods must be developed for cerebrovascular disease, which threatens the lives of countless people every year.

Click here to read full News Directory 3 article.

Best of Last Week—Bronze Age megastructure found, Apple MacBook Pro hacked, the brain is not rewireable

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TSG site of Kačarevo 2 showing: A) Low-lying land, B) raised sand-plateau, C) enclosure ditch, D) activity areas. Photograph and key by Barry Molloy and Darja Grosman. Credit: PLOS ONE (2023). DOI: 10.1371/journal.pone.0288750

By Bob Yirka, ScienceX

It was an interesting week for human behavior and history as a team of climate scientists affiliated with several institutions in China, working with a colleague from the U.S., found evidence that human-produced aerosols may overtake greenhouse gases in the atmosphere, leading to a warmer climate and more weather extremes toward carbon neutrality by 2050. Also, a team of archaeologists from University College Dublin, working with colleagues from Portugal, the U.K., Serbia and Slovenia, uncovered a European hidden Bronze Age megastructure in the southern Carpathian Basin in Romania. And a behavioral economist at the University of Bath in the U.K., Chris Dawson, found evidence linking higher levels of unwarranted financial optimism with lower levels of cognitive ability.

In technology news, a team of robotics engineers at Chung-Ang University in South Korea demonstrated a wearable robot that can assist people with walking. And a team of cybersecurity researchers at Georgia Tech broke Apple’s new MacBook pro just weeks after its release. They successfully evaded security measures on the latest MacBook Pro by capturing private information. Also, a team of engineers at the Korea Electrotechnology Research Institute developed a stretchable and efficient wearable thermoelectric energy harvester. And a team at Google’s DeepMind are seeking a consensus on what constitutes artificial general intelligence by publishing a paper on the preprint server arXiv asking other researchers to help them come up with a framework that could be used by everyone in the scientific community.

In other news, a team led by a group of medical researchers at the University of California, Irvine, found that not all brain hemorrhages are caused by injured blood vessels—some, they found, are caused by aged red blood vessels interacting in brain capillaries in ways that can lead to cerebral microbleeds. Also, a team working at the Telescope Array detected the second-highest-energy cosmic ray ever in data recorded back in 2021. And finally, a pair of brain researchers, Tamar Makin with the University of Cambridge, and John Krakauer with Johns Hopkins University School of Medicine, claimed that the human brain is not able to “rewire” itself, despite what many scientists believe.

© 2023 Science X Network

Click here to read full ScienceX article.

Chapman University Researcher, Dr. Rachita Sumbria, Plays a Key Role in Groundbreaking Study on Brain Hemorrhages

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By Carley Murphy, Chapman News

A groundbreaking study co-authored by Rachita Sumbria, associate professor in the Chapman University School of Pharmacy, has uncovered a new contributor to the formation of brain hemorrhages. Contrary to previous beliefs that such hemorrhages were solely linked to blood vessel injuries, the research reveals that increased interactions between aged red blood cells and brain capillaries can lead to brain microhemorrhages. This discovery not only enhances new understandings of the mechanisms behind these microhemorrhages but also opens up new possibilities for therapeutic targets in treatment and prevention.

Published online in the Journal of Neuroinflammation, the study details how aged red blood cells stall in brain capillaries of mice, leading to cerebral microhemorrhages. Increased red blood cell stalling in brain capillaries was associated with activation of the immune cells of the brain and brain microhemorrhages in the absence of brain capillary rupture.

“The recent work is a culmination of experiments that we started about a decade ago using cell culture systems. We showed for the first time that brain endothelial cells are capable of engulfing aged/stressed iron-rich erythrocytes, a process known as brain endothelial erythrophagocytosis, and the recent collaborative work shows this process in mice”, Sumbria, co-corresponding author, said.

Rudy Chang, co-first author and Ph.D. student at Chapman University, started the foundational work leading to the current study with Rachita Sumbria and University of California, Irvine (UCI) researcher, Dr. Mark Fisher. The team, which was also led by UCI researchers, Drs. Mark Fisher and Xiangmin Xu, conducted experiments by injecting aged red blood cells into mice and tracking their interactions with the brain capillaries in real-time followed by postmortem imaging.

“Our findings show that age-related changes to erythrocytes, and how erythrocytes interact with the brain capillaries, are important underlying factors contributing to brain microhemorrhaging. This represents a novel mechanism distinct from the traditional view of a blood vessel rupture as the cause of brain microhemorrhages,” Sumbria said.

The study, funded by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, marks a significant advancement in the understanding of brain microhemorrhages and offers potential avenues for innovative approaches to their treatment.

Click here to read full Chapman News press release.

A fresh study discovers a novel reason for brain hemorrhages, not just blood vessel injury

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BY AARON ROTTENBERG, List23

The discovery that cerebral microbleeds can be caused by mature red blood cells interacting with brain capillaries is the result of recent research, which contradicts the belief that these bleeding events occur solely due to blood vessel damage.

A new finding from the University of California, Irvine has revealed that cerebral microbleeds can be caused by a combination of older red blood cells and brain capillaries.

The discovery contributes to a better understanding of the mechanisms behind these bleeding, which can lead to the development of new therapeutic interventions to manage and prevent these conditions.

Recent research published in the Journal of Neuroinflammation reveals that the team observed how red blood cells stall in brain capillaries and analyzed the process of hemorrhage.

Dr. Mark Fisher, a neurology professor at UCI’s School of Medicine, emphasized the importance of this study in extending our understanding of the mechanism behind cerebral microbleeds.

After tert-butyl hydroperoxide was exposed to them, the team used a fluorescent label to mark the cells and inject them into mice. They observed that the red blood cells became trapped in the brain capillaries and then cleared out in endothelial erythrophagocytosis, leading to hemorrhage in the brain as microglia engulfed the cells as they moved out of the capillaries.

It has long been thought that blood vessels must be injured or disrupted to cause cerebral hemorrhage, but additional research suggests that increased red blood cell interactions with brain capillaries offer a unique means of development.

The findings, published in the democratic college in New York on October 18, 2017, suggest that learning or movement through connections between retinal and cynical nerves may result in milder symptoms, which could indicate cancer progression.

Rachita Sumbria, Hai Zhang, Rudy Chang, Jiahong Sun, David Cribbs, and Todd Holmes worked together to maximize the benefits of the Center for Neural Circuit Mapping’s comprehensive infrastructure and robust resources.

The National Institute on Aging and the National Institute of Neurological Disorders and Stroke donated their support for this work.

Click here to read full List23 article.

TEAM FINDS NEW CULPRIT BEHIND BRAIN HEMORRHAGE FORMATION

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Photo: “Our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” says  Mark Fisher. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.” (Credit: Lisa Yount/Unsplash)

POSTED BY 

A first-of-its-kind study has revealed a new culprit in the formation of brain hemorrhages that does not involve injury to the blood vessels, as previously believed.

Researchers discovered that interactions between aged red blood cells and brain capillaries can lead to cerebral microbleeds, offering deeper insights into how they occur and identifying potential new therapeutic targets for treatment and prevention.

The findings, published in the Journal of Neuroinflammation, describe how the researchers were able to watch the process by which red blood cells stall in the brain capillaries and then observe how the hemorrhage happens.

Cerebral microbleeds are associated with a variety of conditions that occur at higher rates in older adults, including hypertension, Alzheimer’s disease, and ischemic stroke.

“We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” says co-corresponding author Mark Fisher, professor of neurology in the University of California, Irvine School of Medicine. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

The team exposed red blood cells to a chemical called tert-butyl hydroperoxide that caused oxidative stress; the cells were then marked with a fluorescent label and injected into mice.

Using two different methods, the researchers observed the red blood cells getting stuck in the brain capillaries and then being cleared out in a process called endothelial erythrophagocytosis. As they moved out of the capillaries, microglia inflammatory cells engulfed the red blood cells, which led to the formation of a brain hemorrhage.

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development,” says co-corresponding author Xiangmin Xu, professor of anatomy and neurobiology and director of the campus’s Center for Neural Circuit Mapping.

“We need to examine in detail the regulation of brain capillary clearance and also analyze how that process may be related to insufficient blood supply and ischemic stroke, which is the most common form of stroke, to help advance the development of targeted treatments.”

The National Institute on Aging and the National Institute of Neurological Disorders and Stroke funded the work.

Source: UC Irvine

Revolutionary Study Unveils New Cause of Brain Hemorrhages Beyond Blood Vessel Injury

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Photo: New research has revealed that aged red blood cells interacting with brain capillaries can cause cerebral microbleeds, a finding that upends the traditional belief that these hemorrhages only result from blood vessel injury. This breakthrough offers new avenues for understanding and treating conditions related to aging and brain health.

By UNIVERSITY OF CALIFORNIA, IRVINE

The discovery improves our understanding of cerebral microbleeds and may offer new therapeutic targets.

A groundbreaking study conducted by the University of California, Irvine has uncovered a novel factor contributing to the development of brain hemorrhages. Contrary to previous assumptions that linked hemorrhages solely to blood vessel injury, this research found that the interplay between older red blood cells and brain capillaries can cause cerebral microbleeds.

This discovery provides a deeper understanding of the mechanisms behind these bleeds and opens up new avenues for therapeutic interventions aimed at treating and preventing them.

Study Methodology and Observations

The findings, recently published in the Journal of Neuroinflammation, describe how the team was able to watch the process by which red blood cells stall in the brain capillaries and then observe how the hemorrhage happens. Cerebral microbleeds are associated with a variety of conditions that occur at higher rates in older adults, including hypertension, Alzheimer’s disease, and ischemic stroke.

“We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” said co-corresponding author Dr. Mark Fisher, professor of neurology in UCI’s School of Medicine. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

Mechanism Behind Brain Hemorrhages

The team exposed red blood cells to a chemical called tert-butyl hydroperoxide that caused oxidative stress; the cells were then marked with a fluorescent label and injected into mice. Using two different methods, the researchers observed the red blood cells getting stuck in the brain capillaries and then being cleared out in a process called endothelial erythrophagocytosis. As they moved out of the capillaries, microglia inflammatory cells engulfed the red blood cells, which led to the formation of a brain hemorrhage.

Implications and Future Research Directions

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development,” said co-corresponding author Xiangmin Xu, UCI professor of anatomy & neurobiology and director of the campus’s Center for Neural Circuit Mapping. “We need to examine in detail the regulation of brain capillary clearance and also analyze how that process may be related to insufficient blood supply and ischemic stroke, which is the most common form of stroke, to help advance the development of targeted treatments.”

Reference: “Erythrocyte–brain endothelial interactions induce microglial responses and cerebral microhemorrhages in vivo” by Hai Zhang, Rachita K. Sumbria, Rudy Chang, Jiahong Sun, David H. Cribbs, Todd C. Holmes, Mark J. Fisher and Xiangmin Xu, 15 November 2023, Journal of Neuroinflammation.
DOI: 10.1186/s12974-023-02932-5

Leveraging the broad, collaborative infrastructure and robust resources of the Center for Neural Circuit Mapping, other team members were Rachita Sumbria, co-first author/co-corresponding author and associate professor in the Chapman University School of Pharmacy; Hai Zhang, co-first author and postdoctoral researcher in UCI’s Department of Anatomy & Neurobiology; Rudy Chang, co-first author and Chapman University School of Pharmacy graduate student; Jiahong Sun, postdoctoral researcher at Chapman University; David Cribbs, professor-in-residence at UCI’s Institute for Memory Impairments and Neurological Disorders; and Todd Holmes, UCI professor of physiology & biophysics.

This work was supported by the National Institute on Aging and by the National Institute of Neurological Disorders and Stroke.

Click here to read full SciTech Daily article.

Study identifies new cause of brain bleeds, new treatment target

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What we think we know about brain hemorrhages is only part of the story

Photo: This photo from University of California, Irvine shows red blood cells clogging a capillary in the brain of a mouse. The researchers say the blocking and then clearing of the capillary can lead to microbleeds and brain hemorrhage | University of California, Irvine

By Lois M. Collins, Deseret News, Lcollins@deseretnews.com

New research from the University of California, Irvine, could change the thinking on what causes brain bleeds — and offer the potential to develop new therapies.

Experts have long believed that injury to blood vessels causes brain hemorrhage. But the Irvine team has found that “interactions between aged red blood cells and brain capillaries” can spark microbleeds in brain tissue, too.

The findings were just published in the Journal of Neuroinflammation.

Tiny brain bleeds are associated with stroke, cognitive decline and normal aging, the study says. The authors noted that their own previous work has found that interaction between oxidatively stressed red blood cells and brain capillaries can underlie the development of cerebral microhemorrhages. Such microbleeds are associated with high blood pressure, Alzheimer’s disease and ischemic strokes.

The researchers watched the process in which red blood cells stall in brain capillaries and saw hemorrhage unfold. A news release from UC Irvine said they exposed red blood cells to a chemical that caused oxidative stress, then marked the cells with a fluorescent label and injected them into mice. They then used two methods to watch the fluorescent cells get stuck in the brain capillaries, and how the capillaries were cleared. As the red blood cells moved out of the capillaries, inflammatory cells “engulfed the red blood cells,” leading to a brain hemorrhage.

Capillaries are the body’s tiniest blood vessels. As New Atlas reported, they “employ a clever membranous mechanism to push out any blockages, (but) it’s a system that begins to falter with age.”

Per New Atlas, “The 2010 study that identified this mechanism also found that it becomes 30% to 50% slower in an aging brain and also results in the death of more capillaries.”

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development,” said co-corresponding author Xiangmin Xu, professor of anatomy and neurobiology and director of Irvine’s Center for Neural Circuit Mapping.

He said detailed examination of how the brain capillaries are cleared and a possible relationship between that process and insufficient blood supply and ischemic stroke is needed to help develop targeted treatments.

Said co-corresponding author Dr. Mark Fisher, professor of neurology in UCI’s School of Medicine, “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

Click here to read full Deseret News article.