In vitro clot lysis as a potential indicator of thrombus resistance to fibrinolysis--study in healthy subjects and correlation with blood fibrinolytic parameters.
Using an in vitro model of clot lysis, the individual response to a pharmacological concentration of recombinant tissue plasminogen activator (rt-PA) and the influence on this response of the physiological variations of blood parameters known to interfere with the fibrinolytic/thrombolytic process were investigated in 103 healthy donors. 125I-fibrin labelled blood clots were submersed in autologous plasma, supplemented with 500 ng/ml of rt-PA or solvent, and the degree of lysis was determined after 3 h of incubation at 37 degrees C. Baseline plasma levels of t-PA, plasminogen activator inhibitor 1 (PAI-1), plasminogen, alpha 2-antiplasmin, fibrinogen, lipoprotein (a), thrombomodulin and von Willebrand factor as well as platelet and leukocyte count and clot retraction were also determined in each donor. rt-PA-induced clot lysis varied over a wide range (28-75%) and was significantly related to endogenous t-PA, PAI-1, plasminogen (p < 0.001) and age (p < 0.01). Multivariate analysis indicated that both PAI-1 antigen and plasminogen independently predicted low response to rt-PA. Surprisingly, however, not only PAI-1 but also plasminogen was negatively correlated with rt-PA-induced clot lysis. The observation that neutralization of PAI-1 by specific antibodies, both in plasma and within the clot, did not potentiate clot lysis indicates that the inhibitor, including the platelet-derived form, is insufficient to attenuate the thrombolytic activity of a pharmacological concentration of rt-PA and that its elevation, similarly to the elevation of plasminogen, is not the cause of clot resistance but rather a coincident finding. It is concluded that the in vitro response of blood clots to rt-PA is poorly influenced by the physiological variations of the examined parameters and that factors other than those evaluated in this study interfere with clot dissolution by rt-PA. In vitro clot lysis test might help to identify patients who may be resistant to thrombolytic therapy.
Colucci
M
M
Department of Biomedical Sciences, University of Bari, Italy.
Scopece
S
S
Gelato
A V
AV
Dimonte
D
D
Semeraro
N
N
D000328:Adult; D000368:Aged; D004341:Drug Evaluation; D004351:Drug Resistance; D005260:Female; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D010960:Plasminogen Activators / Q000627:therapeutic use*; D011379:Prognosis; D011994:Recombinant Proteins / Q000627:therapeutic use; D012016:Reference Values; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator