Scientists Discover Promising New Way To Treat Uncontrolled Internal Bleeding

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Main Category: Blood / Hematology
Also Included In: Cardiovascular / Cardiology;  Infectious Diseases / Bacteria / Viruses;  Immune System / Vaccines
Article Date: 26 Oct 2009 - 2:00 PDT

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Scientists in the US have discovered that antibodies can block the action of proteins that contribute to uncontrolled internal bleeding following traumas like those sustained in car crashes and battlefield injuries, and have done pre-clinical trials showing promising results as potential life-saving treatments with no side-effects. They said their discovery may also lead to effective treatments for severe infectious diseases and diabetes.

The discovery, which was funded by the Howard Hughes Medical Institute, was the work of researcher Dr Charles Esmon and colleagues Drs Florea Lupu and Jun Xu from the Oklahoma Medical Research Foundation (OMRF). Together with other colleagues from OMRF and the Temple University School of Medicine in Philadelphia, they wrote a paper about it that was published online on 25 October in the journal Nature Medicine.

Esmon and colleagues found out how following severe physical trauma, proteins called histones go into the bloodstream and destroy the lining of blood vessels which leads to uncontrolled bleeding. They then found an antibody that counteracts this process.

Esmon, who holds the Lloyd Noble Chair in Cardiovascular Biology at OMRF and is also a member of the National Academy of Sciences, told the media that:

"This discovery could open the door to new ways to treat soldiers hurt in IED [improvised explosive device] attacks, gunshot wound victims and people who suffer a traumatic injury."

He explained that:

"When we realized that histones were so toxic, we immediately went to work looking for a way to stop their destructive tendencies."

Under normal circumstances histones do an important job of keeping DNA tightly coiled and packed inside the nuclei of cells.

But the researchers discovered that when cells burst, such as through injury, infection or diseases like diabetes, these histones enter the bloodstream and kill blood vessel linings. This leads to uncontrolled bleeding and build up of fluid in tissues, both life-threatening conditions.

However, they then, with the help of Temple University's Dr Marc Monestier, found antibodies to histone, including one called activated protein C (APC), were able to block their ability to kill.

Esmon said:

"When a patient is suffering from severe bleeds, these antibodies could prevent multi-organ failure."

They have already tested the antibodies in pre-clinical trials using tissue culture and animal models of trauma, infections and other conditions. They showed promising results and no adverse effects.

For example, they found that baboons infected with E. coli had histone in their bloodstream and that increased levels of histone were accompanied by the onset of kidney failure. But co-infusion of APC with E. coli in baboons "prevented lethality", they wrote.

In another test, using mice treated with gram-negative bacterial lipopolysaccharide (LPS), a frequently used model of severe infection in humans, they showed that blocking protein C activation increased likelihood of death ("exacerbated sublethal LPS challenge into lethality"), and this was reversed by treatment with antibody to histone.

Esmon and colleages concluded that:

"Extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases."

The researchers predict that the next step is likely to be human trials.

OMRF President Dr Stephen Prescott described the implications of the discovery as "staggering". He said Esmon and colleagues:

"Have not only found a new key player in cardiovascular injuries and disease, but they've taken this work and transformed it into a potential treatment for severe trauma, diabetes, pneumonia and any other condition that results in tissue death."

The work also lays the foundation for future studies that could look for example at why "people suffering from one traumatic injury often experience a catastrophic 'cascade' of secondary traumatic events", said Prescott, suggesting that figuring out what happens in the initial trauma might help stop the "domino effect" that so often follows.

"Extracellular histones are major mediators of death in sepsis."
Jun Xu, Xiaomei Zhang, Rosana Pelayo, Marc Monestier, Concetta T Ammollo, Fabrizio Semeraro, Fletcher B Taylor, Naomi L Esmon, Florea Lupu, Charles T Esmon.
Nature Medicine, published online 25 October 2009.
DOI:10.1038/nm.2053

Additional sources: OMRF.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today