Lack of degradation of antithrombin III by tissue-type plasminogen activator or plasmin.
BACKGROUND
Coronary thrombolysis is an established initial approach in the treatment of acute transmural myocardial infarction. However, conjunctive anticoagulation regimens are often suboptimal. Heparin is the only intravenously administered anticoagulant approved by the USA Food and Drug Administration commonly used for this purpose. Unfortunately, it exhibits potential limitations that may either predispose arteries to reocclusion or result in failure of initial recanalization. This study was designed to determine whether consumption of heparin cofactor, antithrombin-III (AT-III), compromises the efficacy of heparin in the setting of pharmacologic fibrinolysis and, if so, whether this degradation or inactivation is directly attributable to the effects of tissue-type plasminogen activator (t-PA) or plasmin in the blood stream.


METHODS
AT-III was assayed by Western blotting and with a microlatex particle immunoassay in buffer, plasma, or in vivo after exposure to plasmin or t-PA.


RESULTS
Neither t-PA (1-10 micrograms/ml) nor plasmin (2 microM) appeared directly to degrade AT-III in purified systems or in plasma. However, levels fell in some patients treated with t-PA, albeit a minority, in association with intense thrombosis, as reflected by failure of recanalization.


CONCLUSIONS
Our results demonstrate that AT-III is not degraded directly by t-PA or plasmin. They suggest that intense, ongoing thrombosis is responsible for consumption of AT-III in some patients and support the hypothesis that diminution of AT-III is a manifestation rather than a cause of inadequate anticoagulation.
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
S R
SR
Torr-Brown
D
D
Nachowiak
S
S
Fujii
B E
BE
Sobel
D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage*; D000990:Antithrombin III / Q000032:analysis / Q000378:metabolism*; D001241:Aspirin / Q000008:administration & dosage; D015153:Blotting, Western; D005341:Fibrinolysin / Q000378:metabolism*; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D007118:Immunoassay; D007262:Infusions, Intravenous; D009203:Myocardial Infarction / Q000188:drug therapy; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D000925:Anticoagulants; D000990:Antithrombin III; D006493:Heparin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D001241:Aspirin