Development of appropriate clinical dose regimens of individual plasminogen activators such as tissue-type plasminogen activator (t-PA) has generally relied primarily on nonpharmacological endpoints such as angiographically documented clot lysis. The recent availability of monoclonal antibodies that differentiate products of plasmin lysis of fibrin from those of lysis of fibrinogen should permit delineation of the relative fibrin specificity of different plasminogen activators or of different doses of the same activator in vivo. Thus, their use should accelerate and facilitate development of implementation of optimal dose regimens for diverse activators and combinations of activators. The present study was designed to determine whether assay of such markers effectively differentiates effects of two doses of t-PA, each of which are comparably effective in opening infarct-related arteries, in patients studied at the Washington University Clinical Unit of the National Institutes of Health - sponsored Thrombolysis in Myocardial Infarction Trial. The extent of lysis of fibrin and of lysis of fibrinogen by plasmin resulting from administration of t-PA was evaluated in 19 patients given 150 mg t-PA over 6 hours and 17 given 100 mg over the same interval by assay of serially obtained plasma samples for croslinked fibrin degradation products (XL-FDP) and Bβ1-42, a peptide released when fibrinogen is degraded to fragment X by plasmin. XL-FDP were markedly elevated after 6-hour infusions of both doses of t-PA. However, elevations were not more with the higher dose [peak value, 4,321 ± 986 ng/ml (± SEM)] compared with the lower dose (3,397 ± 1,096 ng/ml) (p = NS). Thus, the extent of lysis of fibrin appeared to be comparable. In contrast, lysis of fibrinogen reflected by elevated concentrations in plasma of Bβ1-42 2-4 hours after the onset of infusion of t-PA was significantly more after administration of 150 mg (423 ± 100 pmol/ml) compared with 100 mg (166 ± 37 pmol/ml) (p < 0.05), which is indicative of more intense fibrinogenolysis with the higher dose. Thus, serial assay of XL-FDP and Bβ1-42 differentiated the fibrin specificity of the two doses of t-PA tested and should prove useful in developing dose regimens for individual activators and combinations of activators of plasminogen with distinctive pharmacological properties.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)