A comprehensive analysis involving 14 different groups of inflammatory bowel disease (IBD) patients and 1,800 intestinal biopsies has pinpointed a key genetic component linked to more aggressive cases of the condition. The study's findings identify a protein that could be potentially targeted to reduce the severity of symptoms and offer much-needed insights into the biology underlying IBD. Autoimmune diseases such as IBD - one of the most common intestinal disorders - often involve highly complex interactions between genetic and environmental variables, which can affect disease severity and how patients respond to treatment. This complexity has made it difficult for researchers to zero in on the molecular culprits responsible for inflammation and disease, especially in patients with moderate or severe IBD. Here, Gerard Kaiko and colleagues showed that patients with more severe IBD displayed excessive activity in genes associated with blood coagulation. These patients also harbored elevated levels of a protein called PAI-1, which the researchers observed exacerbated colon inflammation. Further experiments showed PAI-1 promoted inflammation by targeting another protein named tPA, which was produced by the cells that line the intestine and protected against colon injury in mice. Interestingly, inhibiting PAI-1 with a small molecule drug restored tPA levels and decreased inflammation and mucosal damage (a hallmark of IBD) in the rodents. The authors say the findings identify PAI-1 as a promising therapeutic target, and could help explain why IBD patients also have an increased risk of harmful side effects related to blood coagulation such as dangerous blood clot formation.