Apart from effects on vascular permeability, surfactant dysfunction, or acute inflammation, evidence of a causal relationship between impaired alveolar fibrin clearance and accelerated pulmonary fibrosis has been reported. This relationship is best supported by selective manipulation of the fibrinolytic system in transgenic animals. For example, in bleomycin-treated mice overexpressing PAI-1, fibrinolysis is relatively impaired and accelerated pulmonary fibrosis is increased. In mice deficient in PAI-1, fibrinolysis is conversely potentiated and pulmonary fibrosis relatively attenuated (51). These observations provide compelling evidence that the protracted fibrinolytic defect in ARDS contributes to the development of accelerated pulmonary fibrosis.
Limited preclinical evidence supports the feasibility of using profibrinolytic activities to protect the lung against acute injury. In a porcine model of ARDS, intravenous administration of plasminogen activators increased arterial oxygenation and provided a survival advantage (52). Tissue plasminogen activator (tPA)and uPA were effective and provided histologic as well as physiologic protection against acute lung injury. An alternative strategy involving administration of plasminogen or plasmin to increase systemic fibrinolysis, has been used to protect against acute lung injury. In one study, circulating levels of plasminogen were shown to be decreased in experimental animals with acute lung injury, premature infants at risk for respiratory distress syndrome, and patients with ARDS (53). Administration of plasminogen decrease d the incidence of respiratory distress syndrome in treated infants. The mortality rate of infants with established respiratory distress syndrome was also decreased by administration of plasmin.
Other anticoagulants have been used to reverse the coagulopathic and lethal effects of sepsis. These agents have been used with varying degrees of success. For example, an inactive form of factor X reversed the coagulopathy of sepsis, but not the hemodynamic effects or tissue injury (64). Other agents have been used to block the extrinsic activation complex, tissue factor associated with factor VII. An inhibitor of the extrinsic activation complex; site-inactivated factor VII, was found to exert antiinflammatory as well as anticoagulant properties in a model of systemic sepsis (65). Another inhibitor of extrinsic coagulation, tissue factor pathway inhibitor (TFPI), was found to reduce the mortality associated with sepsis (66). Early Phase II trials of TFPI have been performed in relatively small numbers of patients with sepsis. The results have yet to be published but preliminary reports presented at national meetings suggest that patients with ARDS could benefit in terms of a survival advantage. Full assessment of the safety and efficacy of this approach must await scrutiny of the full publications derived from this interventional approach.
As described above, preliminary studies have been performed in which fibrinolysins improve d hemodynamics and oxygenation in patients with severe ARDS. The rationale for these interventions was to improve pulmonary vascular perfusion by lysis of pulmonary thrombi. The more recent anticoagulant interventions in sepsis and ARDS suggest that fibrinolytic interventions could likewise be useful to prevent pulmonary fibrin deposition and protect the lungs.
Fibrinolysins are now commonly used in clinical practice and clinicians are now more familiar with their use. As reviewed recently, several plasminogen activators are currently available (68). Urokinase, streptokinase, and the modified complex anistreplase are relatively less fibrin specific than recombinant tPA and its derivatives. Urokinase in its low molecular weight form is not generally available now owing to manufacturing issues that have yet to be fully resolved.
Plasminogen activators occupy a special niche in specific clinical scenarios in which fibrinolysis has been found to be of clinical benefit. In particular, plasminogen activators are now commonly used in the acute therapy of myocardial infarction (69). Thrombolytic therapy has more recently been advocated for therapy of acute ischemic stroke, within a 3-hour therapeutic window in patients with a clinically meaningful neurologic deficit, no evidence of intracranial bleeding by CT scan, and otherwise meeting rigorous exclusion criteria (70). Thrombolytic therapy can also be of advantage for patients with massive pulmonary embolism and hemodynamic instability. The use of thrombolytic agents for deep venous thrombosis is not routine (71), although this approach may be of value for highly selected patients with limb threatening thrombosis or extensive ileofemoral deep venous thrombosis who are therefore at risk for postphlebitic syndrome. Additionally, plasminogen activators are currently used in cases of organizing pleuritis, such as those associated with complicated parapneumonic pleural effusions. In this situation, the agents are locally instilled in order to promote degradation of pleural loculations in an effort to avoid surgical decortication (72–74). The intrapleural exudate is typically fibrinous early after injury. In a model of fibrosing pleuritis induced by tetracycline (75), either repeated intrapleural instillation of urokinase or heparin can attenuate pleural fibrosis (76).
Modifications of several plasminogen activators have been introduced into clinical use within the past few years. These modifications influence plasma half-life and fibrin specificity. For example, TNK-tPA or tenecteplase is modified at three separate sites and exhibits slightly greater fibrin specificity and a longer plasma half-life versus human recombinant tPA (68). Interestingly, the efficacy of several of these agents, used in the context of acute myocardial infarction, is actually rather similar despite profound differences in cost. For example, single-chain recombinant tPA and streptokinase both yield coronary patency rates of approximately 60%, comparable reocclusion rates of up to 20%, and improvement in survival with comparable rates of bleeding complications, including intracranial bleeding in up to 0.5% of cases (69). The cost of a course of streptokinase, which is associated with allergic reactions, is approximately $500 wholesale, whereas that of recombinant single-chain tPA (Alteplase), which does not elicit allergic reactions, is generally in excess of five times as much (69). Rather than tPA or its congeners, uPA or streptokinase was used in most of the small interventional studies of severely ill ARDS patients noted above. Because the data are preliminary and derive from the analysis of small numbers of patients, it is currently unclear whether there might be any difference in the efficacy or safety of any of the available fibrinolysins when used in the setting of ARDS. Although the available interventional studies suggest the possibility of benefit in cases of severe ARDS, the use of any available agent in this context is not routine and the benefits and risks of this approach in these seriously ill patients are yet to be established. In most of the available reports, the fibrinolysins have been administered intravenously in ARDS patients and it is currently unclear as to whether inhalational administration would be more effective or safer.
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