Activation of complement and kinin systems after thrombolytic therapy in patients with acute myocardial infarction. A comparison between streptokinase and recombinant tissue-type plasminogen activator.
BACKGROUND
We have previously shown that treatment with streptokinase induces abrupt complement activation and transient neutropenia in patients with acute myocardial infarction (AMI). The purpose of this study was to compare the effects of two different thrombolytic agents--streptokinase (SK) and recombinant tissue-type plasminogen activator (rTPA)--on activation of the complement and kinin systems in plasma of patients with AMI.


RESULTS
Forty-one patients with AMI who were eligible for thrombolytic therapy were studied. Twenty-three patients were treated with streptokinase (1.5 million IU IV over 60 minutes) and 18 were treated with rTPA (8 with bolus of 10 mg IV, followed by 50 mg infused over 60 minutes and then 40 mg infused over 120 minutes; 10 patients were administered rTPA and heparin according to the accelerated infusion protocol indicated by the GUSTO study). C4a and C3a were measured by radioimmunoassay, soluble terminal complement components (SC5b-9) and anti-SK IgG antibodies were measured by ELISA. Cleaved high molecular weight kininogen (HK) was quantitated in plasma by SDS-PAGE and immunoblotting analysis. C4a levels were significantly and similarly increased in both groups, whereas the levels of C3a and SC5b-9 after rTPA infusion were only slightly elevated and were significantly lower than after SK. No differences were observed between patients treated with slow or accelerated rTPA regimens. The titer of antibodies to SK was highly correlated with the levels of C3a and SC5b-9, whereas a lesser correlation was observed with C4a. Treatment with rTPA did not induce the transient neutropenia observed after SK infusion. The cleavage products of HK were significantly greater after SK than after rTPA infusion.


CONCLUSIONS
Our results show that both thrombolytic agents activate the classic complement pathway and that plasmin could be the common trigger for this phenomenon. A significant activation of the complement common pathway (from C3 to terminal components) was observed only with SK infusion and is attributable to the rapid formation of immunocomplexes between SK and anti-SK antibodies present in plasma as a consequence of previous streptococcal infections. The minimal activation of C5 component of the common pathway explains the absence of leukopenia in patients treated with rTPA. Cleavage of HK, larger after SK than after rTPA infusion, represents a condition enhancing the generation of bradykinin by kallikrein. The recent experimental data that indicate a damaging effect of complement activation on the infarcted zone and the contrasting favorable effect consequent to bradykinin formation raise some questions about the clinical importance of the different biological consequences of SK versus rTPA.
Agostoni
A
A
Institute of Internal Medicine, University of Milan, Italy.
Gardinali
M
M
Frangi
D
D
Cafaro
C
C
Conciato
L
L
Sponzilli
C
C
Salvioni
A
A
Cugno
M
M
Cicardi
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003167:Complement Activation / Q000187:drug effects; D015926:Complement C3a / Q000032:analysis; D015934:Complement C4a / Q000032:analysis; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins / Q000032:analysis; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007704:Kininogens / Q000737:chemistry / Q000502:physiology; D007705:Kinins / Q000502:physiology*; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000503:physiopathology* / Q000628:therapy*; D011994:Recombinant Proteins; D013300:Streptokinase / Q000627:therapeutic use*; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D015938:Complement Membrane Attack Complex; D006023:Glycoproteins; D007704:Kininogens; D007705:Kinins; D011994:Recombinant Proteins; C047610:SC5b-9 protein complex; D015926:Complement C3a; D015934:Complement C4a; D003165:Complement System Proteins; D013300:Streptokinase; D010959:Tissue Plasminogen Activator