In an academic-industrial collaboration, researchers have developed an antibody that blocks the formation of blood clots without triggering bleeding, a serious risk associated with current blood thinners. The study was conducted in multiple animal models. Paving the way for safe use in humans one day, the authors also developed a second antibody that can rapidly reverse the drug's effects, offering an additional safety check. Blood clots can cause heart attack, stroke, and other heart and vascular diseases. Patients with these conditions are commonly treated with drugs that prevent blood from clotting, but carry a high risk for causing uncontrolled bleeding. Coagulation factor XIa (FXIa), a protein that plays a key role in blood clot formation, has emerged as a major drug target, but achieving FXIa-specific inhibition remains challenging. Here, Tovo David and colleagues designed an antibody that specifically binds FXIa and blocks its enzymatic activity. The antibody staved off clotting in human blood as well as in mice and rabbits. The drug appeared safe in monkeys, which showed no signs of spontaneous bleeding even when given doses far higher than those required to prevent clotting. Even though increased bleeding was not detected in these animal studies, because deficiency of FXI in humans can be associated with bleeding, the researchers also developed a second antibody as an antidote to rapidly reverse the anti-FXIa antibody's activity. With further development, the reversible FXIa-specific antibody may offer a new and potentially safer class of anticoagulant drug.