A central (ascending aorta-to-pulmonary artery) shunt is a standard palliative operation for infants with cyanotic congenital heart disease. Thrombosis of these shunts can be life-threatening. We report our experience with catheter-directed thrombolysis using recombinant tissue plasminogen activator to locally treat totally occluded central shunts as an alternative to surgery. Ten patients (median age 47 days) successfully underwent the procedure. Following thrombolysis, shunt patency was verified by angiography. The arterial oxygen (O 2 ) saturations in 100% O 2 increased from a median value of 55% to 90%. Major bleeding did not occur in any patients. Computational fluid dynamics was used to identify a relationship between shunt hemodynamics and thrombosis. We retrospectively analyzed blood flow through simulations of these shunts as they would have appeared prior to obstruction. The calculations revealed that flow negotiating "angulated" portions of these central shunts produced wall shear stresses of 157-168 Pa (or N/m 2 ), with shear rates reaching 31,400-33,600/s. These values are easily high enough to initiate platelet activation/aggregation, leading to thrombus formation. We conclude that: 1) catheter-directed thrombolysis can be used to rapidly, effectively, and safely resolve total central shunt occlusion in critically ill neonates and 2) central shunts containing prominent angulation are at risk for developing shear stress-induced, plateletmediated thrombosis. This finding is clinically important as this flow-directed process is not affected by prophylactic aspirin against shunt thrombosis.