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Thrombolytics: many similarities but no ideal agent

Plasminogen activators act through the same biochemical pathways on plasmin production. Fibrin degradation is the desired effect, to produce thrombolysis and thus reperfusion . However, fibrinolysis may also remove other physiological haemostatic plugs and cause haemorrhagic complications. Plasminogen activators can also have a prothrombotic effect resulting from platelet activation, thus causing reocclusion.

Considerations for reperfusion and reacclusion The efficacy of thrombolytic agents in

reperfusion depends on the delay between symptom onset and treatment. The superior efficacy of alteplase over streptokinase and urokinase is much less noticeable if the treatment delay exceeds 4 hours. Reocclusion is promoted by several factors, such as platelet reactions to a re-exposed atherosclerotic plaque, an incompletely dissolved thrombus causing altered blood flow, or platelet disintegration and embolisation causing vasoconstriction. Heparin may activate platelets and promote occlusion, and a high reocclusion rate has been noted when heparin was used alone after alteplase.

Measures to reduce reocclusion include longer­acting thrombolytics, anticoagulants that do not activate platelets, use of agents such as aspirin to reduce blood viscosity, and neutralisation of clot­promoting effects of fissured plaques. Monoclonal antibodies have been used against platelet fibrinogen receptors to reduce reocclusion.

Effects on mortality Mortality after acute myocardial infarction is

reduced by 25% with streptokinase and alteplase, and by about 50% when aspirin is used in conjunction, or by anistreplase alone. The effect of anistreplase and aspirin in combination has yet to be determined.

Fibrinolytic bleeding is probably caused by disintegration of haemostatic plugs due to degradation of adhesion proteins and platelet receptors, resulting in a hypocoagulable state. Plasminogen activators induce abrupt reductions in fibrinogen, plasminogen and euglobin lysis times, followed by a nadir of 4 hours and then gradual regeneration. Plasminogen activators thus have an active phase when in circulation, which is dependent on their half-life: anistreplase has the longest half-life, of 90 mins, streptokinase is intermediate with 20 min, and alteplase is relatively short, with 9 min. Hence anistreplase can be given by bolus injection whereas alteplase is given by prolonged infusion. The recovery phase is similar for all agents, at about 2 days.

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Haemorrhagic events Bleeding complications are probably due to

vascular injury rather than blood coagulation changes, because bleeding events seem to be independent of fibrinogen levels, and usually occur at the site of invasive procedures. Post-thrombotic surgical intervention or invasive procedures can be performed after thrombolytic therapy, but result in increased bleeding and transfusion requirements. Replacement of cryoprecipitate is needed to recover fibrinogen levels during such procedures, and prophylactic antifibrinolytic therapy may be needed if activator is still present in the blood.

Conclusion. Plasminogen activators have generally similar

effects on thrombus dissolution, vascular reperfusion and mortality after myocardial infarction, though their half-lives are different. Residual fissured plaques and undissolved thrombi contribute to reocclusion. Bleeding can be controlled by normalising fibrinogen levels and using antifibrinolytic treatment. The ideal

thrombolytic would dissolve thrombi but not haemostatic plugs, and avoid vascular reocclusion . Marder VJ Comparison of thrombolytIC agents selected hematologIC. vascular and clinical IM!flts. American Journal 01 Cardiology 64 (Symp ) 2A·7A. Jul 1989 [35 references I am

INPHAR",A ' 19 Aug 1989 17