In this issue of Blood, Yau and colleagues provide evidence that guide catheter thrombosis in patients undergoing percutaneous coronary intervention (PCI) is initiated by contact system activation, and that unfractionated heparin is more effective than fondaparinux at limiting catheter occlusions because heparin-antithrombin complexes are able to target multiple points along the coagulation cascade, as opposed to the smaller fractionated heparins and heparinoids that provide higher selectivity for factor Xa.