Recent studies have demonstrated that concentrations of soluble fibrin are elevated in patients with acute myocardial infarction (AMI). However, the molecular nature of soluble fibrin fragments in plasma in this setting is unknown. In this study, we characterized the species of soluble fibrin elaborated in 81 patients with AMI by determining the concentration of soluble fibrin, fibrin II, and cross-linked fibrin using specific monoclonal antibodies. Soluble fibrin was isolated from patient plasma with a capture antibody to a neoepitope exposed when fibrinopeptide A is cleaved from fibrin. The concentration of fibrin(ogen) (4D2, Agen), fibrin II (T2G1, B. Kudryk), and D-dimer regions (3B6, Agen) present in the patient plasma were determined by ELISA using a tag antibody specific for each. Soluble fibrin (32.55 ng/ml) and fibrin II (0.699 ng/ml) were increased in AMI compared with normal controls (6.64 |ig/ml and 0.20 ng/ml, respectively); however, the increases in fibrin II did not correlate with those of total soluble fibrin (r=0.009). In addition, 19.8% of AMI patients soluble fibrin contained D-dimer regions in plasma either noncovalently bound to fibrin or as part of a larger fibrin fragment. Increases in fibrin II levels correlated with Ddimer in patient plasma (r=0.411), whereas increases in total soluble fibrin did not (r=0.018). In a subset of patients with AMI treated with 100 mg rt-PA, fibrin II concentrations, but not total soluble fibrin, increased in serial samples obtained following treatment with from 0.21 ng/ml to a peak of 1.54 Hg/ml at 6 hours. Thus increases in soluble fibrin observed in patients with AMI are attributable to elaboration of multiple species of fibrin, including fibrin II and fibrin associated with cross-linked fragments. Measurement of fibrin II concentrations may be a specific marker of clot lysis.