Nav: Home

Impeding white blood cells in antiphospholipid syndrome reduced blood clots

April 25, 2019

ANN ARBOR, Mich. - For men and women affected with antiphospholipid syndrome (APS), blood thinners are the main treatment option.

"Unfortunately, treatment with blood thinners does not prevent all cases of blood clotting in APS," says Jason Knight, M.D., Ph.D., an assistant professor of rheumatology at Michigan Medicine. APS is an autoimmune condition characterized by blood clots in both genders and pregnancy loss in women.

"And those blood thinners do very little to impact the neurologic, hematologic and cardiac complications that regularly affect patients with the condition," he adds.

Knight's lab is currently pursuing the idea that anti-inflammatory treatment might provide a more targeted way to treat APS and give patients better control of the condition with fewer side effects.

"Specifically, we have been interested in the role that neutrophils, the most abundant white blood cells in circulation within the body, play in APS," Knight says. "We've had prior studies demonstrate that neutrophils release sticky, spider web-like structures called neutrophil extracellular traps, also called NETs, that trigger the blood to clot in patients with APS."

Now, Knight and team are building upon that prior work in a new study, published in Nature Communications, that investigated two drugs and their effects on NETs in mice with APS.

"We explored a new strategy for inhibiting those neutrophils, using experimental drug CGS21680 and an approved drug called dipyridamole," says Knight, senior author of the study.

Testing potential treatments

Using mouse models with APS, the research team first administered CGS21680 and found that it reduced the levels of NETs in their blood.

"The drug works by activating adenosine receptors on the neutrophil surface," says Ramadan Ali, Ph.D., a member of Knight's lab and lead author of the study. "Adenosine is best known for its role in energy metabolism, but also has anti-inflammatory effects when released outside of cells. This appears to be a natural pathway for turning off inflammation."

The research team observed that the drug also dramatically reduced the tendency of the mice to form blood clots in large veins.

"Testing this specific drug allowed us to show that activation of adenosine receptors is an effective strategy for preventing NET release in APS, and potentially other contexts as well," Ali says. "We also found that the adenosine-receptor pathway can be exploited to prevent the formation of blood clots."

Because CGS21680 is not approved for use in humans, the research team also decided to test the stroke drug dipyridamole, which has been shown previously to activate adenosine receptors.

"It was very gratifying to see that dipyridamole copied the results of the experimental drug that we began the study with," Ali says. "It reduced both NET release and the tendency of the mice with APS to form clots."

Translating from bench to bedside

While all of the work was preclinical, the research team believes it could be translated to patients with APS.

"This is what's exciting," Knight says. "We have identified a pathway here that is already influenced by a number of drugs approved for use in humans. Beyond dipyridamole, drugs like apremilast, used in patients with psoriasis and psoriatic arthritis, and methotrexate, used to treat rheumatoid arthritis and certain types of cancer, can also modulate adenosine-receptor signaling."

He adds, "Translating these findings to a clinical trial in patients could therefore be very straightforward."

Based on their findings, the research team plans to move forward with a pilot clinical trial in patients with APS.

"We're very motivated to provide safer, more effective and more individualized treatments for patients with APS we see in our clinic," Knight says. "The hope is that by continuing to pursue anti-neutrophil therapeutics, we will be treating APS closer to its source and thereby neutralize all aspects of the condition."
-end-
This study was a multiple-year collaboration across the following authors and their departments at the University of Michigan including: Yogendra Kanthi, M.D. (vascular medicine); David Pinsky, M.D. (cardiology); Paula Bockenstedt, M.D. (hematology); Jose Diaz, M.D. (vascular surgery); and Joan Greve, Ph.D., and Olivia Palmer, Ph.D. (biomedical engineering). Additional authors of the study from Knight's lab include: Alex Gandhi, Srilakshmi Yalavarthi, M.S., Andrew Vreede, M.D., He Meng, M.D., Ph.D., and Shanea Estes, MLI.

The study was funded by NIH-NHLBI (R01HL134846 to Knight) and the lead author (Ali) was supported by NIH-NIAMS through the Michigan Rheumatology training grant (T32AR007080).


Michigan Medicine - University of Michigan

Related Blood Clots Articles:

New study provides insight into the mechanisms of blood clots in cancer patients
Researchers have identified a potential new signaling pathway that may help further the understanding of blood clot formation in cancer patients and ultimately help prevent this complication from occurring.
Cellular senescence is associated with age-related blood clots
Cells that become senescent irrevocably stop dividing under stress, spewing out a mix of inflammatory proteins that lead to chronic inflammation as more and more of the cells accumulate over time.
New guidance on potentially fatal blood clots published today
The European Society of Cardiology (ESC) Guidelines on acute pulmonary embolism are published online today in European Heart Journal, and on the ESC website.
One in five haematological cancer patients suffer blood clots or bleeding
In the years following haematological cancer, one in five survivors suffer a blood clot or bleeding which requires hospital treatment.
Targeting inflammation to better understand dangerous blood clots
Forty percent of people who develop venous thromboembolism don't know what caused it.
Impeding white blood cells in antiphospholipid syndrome reduced blood clots
A new study examined APS at the cellular level and found that two drugs reduced development of blood clots in mice affected with the condition.
Research unlocks biomechanical mystery behind deadly blood clots
Researchers at the University of Sydney have used biomechanical engineering techniques to unlock the mystery surrounding the mechanical forces that influence blood clotting.
HRT tablets associated with increased risk of blood clots
Hormone replacement therapy (HRT) tablets are associated with a higher risk of rare but serious blood clots (known as venous thromboembolism or VTE), finds a large study in The BMJ today.
HRT tablets increase risk of blood clots in women
Women who use certain types of hormone replacement therapy (HRT) are at a higher risk of developing potentially life-threatening blood clots, new research has confirmed.
How and why blood clots shrink
In an article published in Nature Communications, researchers at the University of California, Riverside and the University of Pennsylvania School of Medicine used high-powered microscopy and rheometry -- the measurement of how materials become deformed in response to applied force -- to view the blood clotting process in real time and at the cellular level.
More Blood Clots News and Blood Clots Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab