Research Uncovers Why IBD Causes Blood Clots鈥攁nd How to Prevent Them
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Sophia Friesen
Manager, Research Communications, 麻豆学生精品版
Email: sophia.friesen@hsc.utah.edu
Inflammatory bowel disease, in which the immune system attacks the gut, is a painful chronic condition that affects three million Americans. Rates of IBD are rising, and there鈥檚 currently no cure. IBD can also be deadly: up to 8% of people with the disease develop blood clots, which can lead to heart attack and stroke.
New research has uncovered why blood clotting malfunctions in IBD鈥攁nd identified drugs that normalize blood clotting in human cells and animal models of IBD.
鈥淲e think we can leverage these findings to reduce inflammation and the risk of blood clots,鈥 says assistant professor of microbiology and immunology at 麻豆学生精品版, associate director of the U鈥檚 Molecular Medicine Program, and senior author on the paper. 鈥淭his could be lifesaving.鈥
Key points:
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Inflammatory bowel disease increases the risk of blood clots that can lead to heart attack and stroke.
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Lack of a key protein leaves IBD blood cells constantly on the verge of clotting.
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A drug currently in clinical trials for another condition prevents excess clotting in mice and IBD patient cells.
IMPACT: If effective in humans, the drug could save lives and reduce day-to-day symptoms for the 3 million Americans with IBD.
Clotting with the brakes off
Most research into IBD has focused on immune cells. But blood cells called platelets are another key contributor to IBD symptoms. In healthy people, platelets clump together into clots in response to injuries to stop bleeding, and don鈥檛 form clots otherwise. But in patients with IBD, platelets are on a hair trigger, ready to form clots at the slightest provocation.
Surprisingly, platelets from IBD patients weren鈥檛 clotting via the normal pathways that trigger clotting, says postdoctoral researcher in pathology and the first author on the paper. 鈥淚t鈥檚 completely independent of what we would expect.鈥
鈥淭here鈥檚 an innate mechanism by blood vessels to tell platelets to stay quiet and not form a clot yet,鈥 Petrey explains. 鈥淥nce there鈥檚 injury or inflammation, that signal can switch over and tell them to form a clot. That鈥檚 the process that鈥檚 broken in IBD patients.鈥
IBD platelets appear to clot more often because they don鈥檛 have enough of a key protein called layilin, the researchers found. In healthy people, layilin acts as a molecular brake for clotting: it senses the difference between healthy and injured blood vessels and prevents platelets from clotting as long as blood vessels are intact.
But when the researchers deleted the layilin gene in mice, the brakes came off. Without layilin, platelets were extra sticky, forming clots when they shouldn鈥檛.
The researchers also found that platelets from IBD patients only had about 60% of the layilin protein that they should, leaving them constantly on the verge of clotting.
A promising drug target
Layilin prevents unwanted clotting by tamping down the activity of a clot-triggering molecule called Rac1. In mice without the layilin gene鈥攁nd in people with IBD鈥擱ac1 is always a little bit too active, which means platelets are too prone to forming clots.
But there鈥檚 good news. Drugs that prevent Rac1 activity are already in clinical trials for other conditions, and the researchers鈥 results suggest that these Rac1 inhibitors could be powerful therapeutics for IBD.
One Rac1 inhibitor reduced excessive clotting in human platelets in a dish. The inhibitor also decreased the level of tissue damage in the gut in a mouse model of IBD.
Promisingly, the drug decreased clotting in platelets from IBD patients even more strongly than it affected healthy cells. 鈥淲e have shown a hyperactivation pathway in resting IBD patient platelets, but they鈥檙e also incredibly sensitive to treatment, moreso than those from a healthy person,鈥 Mellema says.
Normalizing Rac1 activity might not only reduce the risk of heart attack and stroke鈥攊t could also help alleviate day-to-day IBD symptoms, the researchers say. Excessive clotting can block blood flow in the gut and make inflammation worse, which means that preventing clotting could reduce inflammation.
Unlike established anti-clotting drugs, the researchers say, Rac1 inhibitors shouldn鈥檛 lead to an increased risk of dangerous bleeding, which is a serious concern for IBD patients with chronic inflammation. Blocking Rac1 won鈥檛 interfere with other, independent pathways that can trigger platelet clotting, so the cells should still be able to form needed clots in response to injury.
鈥淲e鈥檙e targeting a pathway that is not pre-activated in healthy people,鈥 Petrey says. 鈥淪o we can address that step of the pathway, and if there鈥檚 a significant injury, the platelets can overcome that inhibition.鈥
Other groups had been looking into the potential of Rac1 inhibitors to reduce inflammation in IBD. The new work emphasizes the potential of these drugs to address multiple symptoms. 鈥淧aying more attention to what we can do to address these blood clotting risks could significantly improve patient lives,鈥 Petrey says.
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The results are published in Blood as
This work was supported by the National Institutes of Health (grant numbers R00HL135265, R01HL167919, K24 HL155856, R35HL145237, and F31HL-164091) and the Programs of Excellence in Glycosciences from the National Heart, Lung, and Blood Institute (grant number HL107147). Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.