Regulation of tissue-type plasminogen activator-mediated fibrinolysis by plasminogen activator inhibitor type-1 in patients with ischaemic heart disease: possible unfavourable effect of diuretics.
BACKGROUND
Impaired endogenous tissue-type plasminogen activator (t-PA)-mediated fibrinolysis may be involved in the evolution of myocardial infarction. t-PA-mediated fibrinolysis is believed to depend on the amount of active t-PA present in the circulation. Accordingly, we investigated the possible mechanisms responsible for impaired t-PA-mediated fibrinolysis in patients with ischaemic heart disease.


METHODS
Forty-five survivors of acute myocardial infarction were examined 8 weeks after discharge from hospital. Intravenous infusion of 1-desamino-8-D-arginine vasopressin (DDAVP; 0.4 micrograms/kg bodyweight) was used to stimulate the endogenous fibrinolytic system, and blood samples were collected before and after infusion. We compared the response of the t-PA-plasminogen activator inhibitor type-1 (PAI-1) fibrinolytic system in patients with preinfusion levels of active t-PA below or at the detection limit of the assay with that in patients with higher preinfusion levels of active t-PA.


RESULTS
All patients responded to DDAVP infusion with an increase in plasma concentration of t-PA antigen. This response did not differ between the two groups. In contrast, the preinfusion levels of PAI activity were significantly higher in patients with undetectable plasma levels of active t-PA compared with patients with higher levels of active t-PA (22.3 versus 12.8 IU/ml; P < 0.01). Subgroup analyses demonstrated that patients treated with diuretics had significantly higher plasma concentrations of PAI-1 antigen (28.5 versus 17.9 ng/ml; P < 0.03) and a trend towards higher PAI activity (24.0 versus 14.6 IU/ml; P = 0.07) compared with patients not receiving diuretics.


CONCLUSIONS
Our study strongly suggests that a high plasma level of PAI-1, the main inhibitor of t-PA, is responsible for impaired t-PA-mediated fibrinolysis in patients with ischaemic heart disease, and that treatment with diuretics may be associated with an unfavourable effect on the fibrinolytic system.
Departments of Clinical Chemistry, Ribe County Hospital, Esbjerg, Denmark.
O D
OD
Pedersen
J
J
Gram
H
H
Bagger
N
N
Keller
J
J
Jespersen
D000368:Aged; D003894:Deamino Arginine Vasopressin; D004232:Diuretics / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005342:Fibrinolysis; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood; D017202:Myocardial Ischemia / Q000097:blood* / Q000188:drug therapy; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D010959:Tissue Plasminogen Activator / Q000097:blood*
D004232:Diuretics; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator; D003894:Deamino Arginine Vasopressin