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.

Agostoni, A; Gardinali, M; Frangi, D; Cafaro, Cristina; Conciato, Luisa; Sponzilli, Carlo; Salvioni, Alessandro; Cugno, Massimo; Cicardi, Marco

doi:10.1161/01.cir.90.6.2666

Cited by 59 publications

(38 citation statements)

References 19 publications

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“…It may also be that the late rise in CRP is partly an indirect consequence of reperfusion or revascularisation therapy. 38) Our results, together with the evidence of an inflammatory component documented in previous studies, [7][8][9][10][11][12][13][14][15]17) have important pathophysiologic implications regarding acute-phase response and C-reactive protein levels in patients with acute coronary syndromes. However, it is not known whether the elevated levels of acute-phase proteins are related to the type of inflammatory stimuli or to the intensity of the individual response.…”

Section: Discussionsupporting

confidence: 71%

<b>C-reactive Protein and Coronary Artery Disease</b>

et al. 2002

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SUMMARYEvidence suggests that inflammation plays a key role in the pathogenesis of atherosclerosis. The chronic inflammatory process can develop to an acute clinical event by the induction of plaque rupture and therefore cause acute coronary syndromes.The aim of this study was to determine the serum levels of the circulating acute-phase reactant C-reactive protein (CRP), which is a sensitive indicator of inflammation, in patients with chronic stable coronary artery disease (CAD) and acute coronary syndromes (ACS).We studied 56 subjects: 1) 25 consecutive patients (18 men, 7 women; mean age, 68.5±14.3 years, range, 40-86) with unstable angina (UA) or acute myocardial infarction (AMI); 2) 31 consecutive patients (25 men, 6 women; mean age 64±12.7; range, 47-83, years) with signs and symptoms of clinically stable CAD. High-sensitivity-C-reactive protein (hs-CRP) levels were determined with a commercially available enzyme-linked immunoassay method.In patients with unstable angina and AMI before reperfusion therapy, CRP levels were not significantly different to those in patients with stable CAD (5.96±2.26 versus 4.35±2.6 mg/L; P=0.12), but tended to be higher in patients with unstable angina and AMI. Baseline CRP levels in the subgroup of patients with AMI (6.49±2.28 mg/L) were significantly higher than levels in patients with stable CAD (4.35±2.6 mg/L; P=0.02).CRP levels in patients with unstable angina and AMI were measured four times during a 72-hour period (0, 12, 24, and 72 hours). The lowest value was observed at baseline and differed significantly from values measured at any other time of the observation period (P<0. 001; 5.96±2.26; 9.5±9.04, 18.25±11.02; 20.25±10.61). CRP levels after 12, 24, and 72 hours were also significantly different to the initial values for patients with stable CAD (P<0.01). There was no correlation between CRP and creatine kinase (CK), CK-MB isoenzyme, or troponin I positivity as markers for the extent of the myocardial injury during the observation period.Baseline levels of serum CRP tended to be higher in patients with unstable angina or AMI but were not significantly different from levels in patients with chronic stable CAD. In the subgroup of patients with AMI, baseline CRP levels were significantly higher than the levels in patients with stable CAD. CRP as a marker of inflammation is significantly increased in patients with AMI and unstable angina shortly after the onset of symptoms (after a period of 12 hours), supporting the hypothesis of an activation of inflammatory From

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Section: Discussionsupporting

confidence: 71%

<b>C-reactive Protein and Coronary Artery Disease</b>

et al. 2002

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“…The complement system is crucially involved in the inflammatory response to renal I/R (26,32) and can be activated by tPA (33). Indeed, C3Ϫ/Ϫ mice show reduced neutrophil influx and as a result are protected from renal I/R injury (32).…”

Section: Discussionmentioning

confidence: 99%

Tissue-Type Plasminogen Activator Modulates Inflammatory Responses and Renal Function in Ischemia Reperfusion Injury

Roelofs¹,

Rouschop²,

Leemans³

et al. 2006

Journal of the American Society of Nephrology

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Acute renal failure is often the result of ischemia-reperfusion (I/R) injury. Neutrophil influx is an important damaging event in I/R. Tissue-type plasminogen activator (tPA) not only is a major fibrinolytic agent but also is involved in inflammatory processes. A distinct upregulation of tPA after I/R, with de novo tPA production by proximal renal tubules, was found. For investigating the role of tPA in I/R, renal ischemia was induced in tPA؊/؊ and wild-type (WT) mice by clamping both renal arteries for 35 min followed by reperfusion. Mice were killed 1, 5, and 10 d after reperfusion. After 1 d, tPA؊/؊ mice displayed significantly less neutrophil influx into the interstitial area compared with WT mice. In addition, tPA؊/؊ mice showed quicker recovery of renal function than WT mice. The protocol was repeated after injection of tPA-antisense oligonucleotides into WT mice, leading to even more explicit results: Antisense-treated mice showed less histologic damage, better renal function, and less neutrophil influx than control mice. Surprising, complement C3 concentration, levels of proinflammatory cytokines and chemokines, intercellular adhesion molecule-1 expression, and matrix metalloproteinase activity were similar in WT and tPA؊/؊ mice. Plasmin activity levels in WT and tPA؊/؊ kidneys were also comparable, indicating that tPA influences neutrophil influx into ischemic renal tissue independent from plasmin generation. This study shows that targeting tPA could be of therapeutic importance in treating I/R injury by diminishing neutrophil influx and preserving renal function.

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“…However, staining was not detected when the cells were incubated with plasmin in the presence of heat-inactivated normal human serum (20), thereby suggesting that plasmin-dependent lytic agents may contribute to the extension of tissue injury associated with reperfusion. The plasmin-dependent thrombolytic agents possess the potential to augment tissue demolition through activation of the classical complement pathway and facilitation of a local inflammatory response within the area at risk (1,16,33).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its proteolytic effects, plasmin is known to activate the complement system (1,12,16,33), which in turn can lead to an extension of reperfusion injury (18,19). In addition, plasmin increases the synthesis of leukotriene B4 (41), cytokines (IL-1␣, IL-1␤, TNF-␣), and tissue factor (TF) expression (35); and directly influences platelet reactivity (31,32), neutrophils (30), and endothelial cells (9).…”

Section: Discussionmentioning

confidence: 99%

Effect of thrombolysis on myocardial injury: recombinant tissue plasminogen activator vs. alfimeprase

Hong

Huang

Lucchesi

2006

American Journal of Physiology-Heart and Circulatory Physiology

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dependent thrombolytic agents are potentially prothrombotic and proinflammatory. Alfimeprase, a zinc-containing metalloproteinase, degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This study examines the hypothesis that thrombolysis in the absence of plasmin generation results in improved myocardial salvage on reperfusion. The thrombolytic effects of recombinant tissue plasminogen activator [rt-PA; 0.022 mg/kg, 1/10 of which was administered as a loading dose; the rest (9/10) was infused over 60 min by intracoronary (ic) administration] or alfimeprase (0.5 mg/kg over 1 min ic) were evaluated in a canine model of arterial thrombosis involving electrolytic injury of the left circumflex (LCX) coronary artery. Both agents induced thrombolysis, with onset of reperfusion being more rapid after alfimeprase compared with rt-PA (1.5 Ϯ 0.6 vs. 10.1 Ϯ 2.1 min). In the absence of adjunctive therapy, time to reocclusion after alfimeprase was 3.2 Ϯ 0.5 min compared with 77.5 Ϯ 31.9 min with rt-PA. The glycoprotein IIb/IIIa platelet receptor antagonist CRL-42796 prolonged reperfusion time after thrombolysis with alfimeprase or rt-PA. The effect of each lytic agent on myocardial infarct size was examined in a separate group of dogs subjected to 60 min of LCX coronary artery ligation and 4 h of reperfusion. Myocardial infarct size, expressed as percentage of the risk region, was larger (32.16 Ϯ 3.95%) after rt-PA compared with alfimeprase (19.85 Ϯ 3.61%) or that of the saline control group (18.46 Ϯ 3.34%). rt-PA in contrast to alfimeprase, a direct-acting fibrinolytic agent, is associated with an increase in myocyte reperfusion injury. myocardium; reperfusion injury; thrombolytic agents THROMBOLYTIC AGENTS in current use activate the fibrinolytic system and achieve thrombolysis through the conversion of plasminogen to plasmin. In addition to its well-characterized mechanism of action on clot lysis, plasmin directly activates other enzymatic systems that contribute to proinflammatory events that may compromise the overall benefits of lytic therapy.Previous studies document the induction of platelet activation by plasmin and plasmin-dependent thrombolytic agents (4, 26), while others have shown both activation as well as inhibitory effects (6, 27). Therapeutic reperfusion, achieved by intravenous administration of recombinant tissue plasminogen activator (rt-PA), is effective in salvaging tissue at risk of irreversible ischemic injury. The benefit of lytic therapy, however, may be limited because of failed reperfusion in 25-40% of the patients (40, 42) and the high incidence (30%) of reocclusion (43). Furthermore, because of the activation of the plasminogen-plasmin system, the mechanism for the cardioprotective effect of thrombolytic therapy remains unresolved (20).Myocardial ischemia of sufficient duration, followed by reperfusion, is associated with an extension of irreversible tissue injury. The ensuing myocyte cell death is attributed to both the ischemic episode as well as to undefined cov...

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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.

Cited by 59 publications

References 19 publications

<b>C-reactive Protein and Coronary Artery Disease</b>

<b>C-reactive Protein and Coronary Artery Disease</b>

Tissue-Type Plasminogen Activator Modulates Inflammatory Responses and Renal Function in Ischemia Reperfusion Injury

Effect of thrombolysis on myocardial injury: recombinant tissue plasminogen activator vs. alfimeprase

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