Molecule prevents blood clots without increasing risk of bleeding

Study discovers mechanism behind blood clots that could help prevent heart attacks and strokes

It may be possible to disrupt harmful blood clots in people at risk for heart attack or stroke without increasing their risk of bleeding, according to a new study published in Nature Communications. The research out of Case Western Reserve School of Medicine, University Hospitals (UH) Cleveland Medical Center and Cleveland Clinic reveals a previously unknown cell receptor interaction that, when manipulated with therapeutic molecules, safely prevents blood clots. Approximately 100,000 Americans die annually from blood clots, or thrombosis, according to the Centers for Disease Control and Prevention. “We have found a new thrombosis target that does not increase bleeding risk,” said Professor of Medicine Daniel I. Simon, the study’s senior author. “Our discovery indicates that you can identify a new pathway and target that mediates blood clotting, but does not affect our body’s natural processes to stop bleeding, called hemostasis.” The new pathway centers around a pair of protein receptors that help certain cells interact in inflammation and thrombosis. One receptor—Mac-1—is found on the surfaces of white blood cells recruited to sites of blood vessel injury, and the other—GPIbα—resides on the surfaces of platelets that form clots. When the receptors interact, they trigger cascades of signals that amplify both inflammation and clotting. Mac-1 binding to GPIbα also broadly regulates inflammation in laboratory models of kidney disease, vasculitis and multiple sclerosis. Simon, the Herman K. Hellerstein, MD, Chair in Cardiovascular Research, and his colleagues found that the interaction causes large and small artery clots in mice, but can be blocked by an antibody or a new, therapeutic small molecule that binds to the Mac-1 receptor. The researchers showed that genetically engineered mice had delayed blood clot formation in response to artery injury. Mice exposed to the interfering antibody or small molecule were also unable to form the kinds of blood clots that can lead to stroke or heart attack. While the results showed the Mac-1-GPIbα receptor duo is required for harmful clots, the researchers discovered blocking their interaction with the small molecule had no effect on bleeding risk. Mice exposed to the molecule were still able to successfully stop minor bleeding, like tail cuts, and maintain normal blood coagulation and platelet function. The findings could lead to new medications that stave off heart attacks and strokes without harmful side effects, like excessive bleeding. “Current anti-clotting drugs (anticoagulants, such as warfarin, Xarelto/rivaroxaban, Eliquis/apixaban) and antiplatelet agents (aspirin, Plavix/clopdigorel, Brilinta/ticagrelor) are effective in reducing heart attack and stroke, but are associated with increased bleeding and transfusion,” said Simon, also the president of UH Cleveland Medical Center. “We have learned that bleeding and transfusion complications are equally as bad from a prognosis standpoint as heart attack or stroke.” The research team is now pursuing pre-clinical studies using antibodies to test the new technology, developed jointly by Simon; co-senior author Edward Plow, chair of molecular cardiology and the Robert C. Tarazi, MD, Endowed Chair in Heart and Hypertension Research at Cleveland Clinic Lerner Research Institute; and Yunmei Wang, first author and assistant professor of cardiovascular medicine at Case Western Reserve. In 2015, the trio founded Sujana Biotech, a BioMotiv company. This work was supported by National Institutes of Health grants to E.P. (P01HL073311 and R01 HL096062) and D.I.S. (R37 HL57506 and R01 HL126645) and a Harrington Discovery Institute Consortium Scholar Award to Simon.