Activation of the contact system and inflammation after thrombolytic therapy in patients with acute myocardial infarction

Merlini, Piera Angelica; Cugno, Massimo; Rossi, Marco; Agricola, Pietro; Repetto, Alessandra; Fetiveau, Raffaella; Diotallevi, P; Canosi, Umberto; Mannucci, Pier Mannuccio; Ardissino, Diego

doi:10.1016/j.amjcard.2003.12.017

Cited by 36 publications

(29 citation statements)

References 21 publications

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“…The data support the concept that plasmin may increase the extent of myocardial tissue injury associated with ischemia and reperfusion. The results of the present study are in agreement with findings by others who express the view that plasmindependent thrombolytic agents activate several enzymatic systems with proinflammatory effects, thus potentially contributing to the pathogenesis of ischemia-reperfusion injury (20,22). Inflammation and activation of the coagulation cascade contribute significantly to the etiology of postthrombolytic complications that include obstruction of the microvasculature and reperfusion injury.…”

Section: Discussionsupporting

confidence: 82%

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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Section: Discussionsupporting

confidence: 82%

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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“…13) Elevation in CRP levels seems to correlate with in-hospital and shortterm adverse prognosis irrespective of the extent of myocardial damage and reflects an important role of a pre-existing inflammation for ischemic-reperfusion damage. 14) In our study, it was found that MA can prevent the CRP increase and inhibit CRP release further as additional treatment during ischemia/reperfusion.…”

Section: Discussionmentioning

confidence: 86%

Madecassoside Reduces Ischemia-Reperfusion Injury on Regional Ischemia Induced Heart Infarction in Rat

Bian¹,

Li²,

Yang³

et al. 2008

Biological & Pharmaceutical Bulletin

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“…Wide use of recombinant t-PA (rt-PA) for thrombolysis in patients with myocardial infarction stimulated intensive studies of structure function relationships of t-PA and development of mutant forms of t-PA with improved pharmacokinetic properties, that is, with prolonged lifetime in circulation and increased resistance to inhibitors and to cleavage by plasmin (46). However, by stimulating the plasmin formation, thrombolytic drugs not only dissolve the clot but also activate factor XII, the complement cascade and the kinin system (20,217). In vitro, rt-PA at a therapeutic concentration generates significant quantities of BK and des-Arg 9 -BK from human plasma, and this kinin-forming activity depends on the activation of plasmin which hydrolyzes HK, independently of the activation of factor XII and PKK (47).…”

Section: Antithrombolytic Treatment and Kininsmentioning

confidence: 99%

“…Factor XII activation is not only a first step in the initiation of the intrinsic clotting cascade and the generation of kinins, but it also leads to the activation of the complement pathway (20).…”

Section: Contact System Activation Of Plasmamentioning

confidence: 99%

The Kallikrein-Kinin System: Current and Future Pharmacological Targets

et al. 2005

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Abstract. The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.

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Activation of the contact system and inflammation after thrombolytic therapy in patients with acute myocardial infarction

Cited by 36 publications

References 21 publications

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

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

Madecassoside Reduces Ischemia-Reperfusion Injury on Regional Ischemia Induced Heart Infarction in Rat

The Kallikrein-Kinin System: Current and Future Pharmacological Targets

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