Rationale: Although acute pulmonary embolism is epidemiologically associated with chronic thromboembolic pulmonary hypertension, the factors responsible for resistance to thrombolysis and a shift toward vascular remodeling within the pulmonary arteries of patients with chronic thromboembolic pulmonary hypertension are unknown. Objective: Determine whether fibrin from patients is more resistant to plasmin-mediated lysis than fibrin from healthy controls. Methods: Fibrinogen purified from patients and controls was used to prepare fibrin clots, which were subsequently digested with plasmin for various periods of time. The degradation of the -, -, and -chains of fibrin and the appearance of peptide fragments over time were assessed by polyacrylamide gel electrophoresis and western blotting. Measurements and Main Results: Densitometry of Coomassie-stained gels revealed significantly slower cleavage of all three polypeptide chains of fibrin from patients compared to controls (P<0.05). In particular, release of N- terminal fragments from the -chain of fibrin, which promote cell signaling, cell migration and angiogenesis, was retarded in patients compared to controls (P<0.01). Conclusions: The relative resistance of patient fibrin to plasmin-mediated lysis may be due to alterations in fibrin(ogen) structure affecting accessibility to plasmin cleavage sites. The persistence of structural motifs of fibrin, such as the -chain N-terminus, within the pulmonary vasculature could promote the transition from acute thromboemboli into chronic, obstructive vascular scars.