Characterization InVivooftheFibrin Specificity ofActivators ofthe Fibrinolytic System

Development ofappropriate clinical doseregimens ofindividual plasminogen activators suchas tissue-type plasminogen activator (t-PA) hasgenerally relied primarily onnonpharmacological endpoints suchasangiographically documented clot lysis. Therecent availability ofmonoclonal antibodies that differentiate products ofplasmin lysis offibrin fromthose oflysis offibrinogen should permit delineation oftherelative fibrin specificity ofdifferent plasminogen activators or ofdifferent doses ofthesameactivator invivo. Thus, their useshould accelerate andfacilitate development ofimplementation ofoptimal doseregimens fordiverse activators andcombinations ofactivators. Thepresent study wasdesigned todetermine whether assay ofsuchmarkers effectively differentiates effects oftwodoses oft-PA, eachofwhicharecomparably effective in opening infarct-related arteries, inpatients studied attheWashington University Clinical Unit oftheNational Institutes ofHealth-sponsored Thrombolysis inMyocardial Infarction Trial. Theextent oflysis offibrin andoflysis offibrinogen byplasmin resulting fromadministration oft-PAwasevaluated in19patients given 150mgt-PAover6hoursand17given 100mgover thesameinterval byassay ofserially obtained plasma samples forcrosslinked fibrin degradation products (XL-FDP) andBp1-42, apeptide released whenfibrinogen isdegraded tofragment X byplasmin. XL-FDPweremarkedly elevated after 6-hour infusions ofbothdoses oft-PA. However, elevations werenotmorewiththehigher dose[peak value, 4,321 ±986ng/ml (±+ SEM)]compared withthelower dose(3,397 ±1,096 ng/ml) (p=NS).Thus, theextent oflysis offibrin appeared tobecomparable. Incontrast, lysis offibrinogen reflected byelevated concentrations inplasma ofB,B1-42 2-4hours after onset ofinfusion oft-PAwassignificantly moreafter administration of150mg (423 ±100pmollml) compared with100mg (166 ±37 pmol/ml) (p<0.05), whichisindicative ofmoreintense fibrinogenolysis withthehigher dose. Thus,serial assay ofXL-FDPandB131-42 differentiated thefibrin specificity ofthetwodoses oft-PAtested andshould prove useful indeveloping doseregimens forindividual activators and combinations ofactivators ofplasminogen withdistinctive pharmacological properties. (Circulation 1988;78:592-597)