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      Does plasmin have anticoagulant activity?

      review-article
      Vascular Health and Risk Management
      Dove Medical Press
      thrombosis, anticoagulant, cardiovascular disease, plasminogen, protease, blood

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          Abstract

          The coagulation and fibrinolytic pathways regulate hemostasis and thrombosis, and an imbalance in these pathways may result in pathologic hemophilia or thrombosis. The plasminogen system is the primary proteolytic pathway for fibrinolysis, but also has important proteolytic functions in cell migration, extracellular matrix degradation, metalloproteinase activation, and hormone processing. Several studies have demonstrated plasmin cleavage and inactivation of several coagulation factors, suggesting plasmin may be not only be the primary fibrinolytic enzyme, but may have anticoagulant properties as well. The objective of this review is to examine both in vitro and in vivo evidence for plasmin inactivation of coagulation, and to consider whether plasmin may act as a physiological regulator of coagulation. While several studies have demonstrated strong evidence for plasmin cleavage and inactivation of coagulation factors FV, FVIII, FIX, and FX in vitro, in vivo evidence is lacking for a physiologic role for plasmin as an anticoagulant. However, inactivation of coagulation factors by plasmin may be useful as a localized anticoagulant therapy or as a combined thrombolytic and anticoagulant therapy.

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          Most cited references64

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          Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A.

          Haemophilia A is a classic X-linked disease which affects 1 in 5-10,000 males in all populations and is caused by defects in coagulation factor VIII. Roughly 60% of patients have severe disease with factor VIII activity < 1% of normal; they have frequent spontaneous bleeding into joints, soft tissues, muscles and internal organs. These patients usually require regular injections of plasma-derived or recombinant human factor VIII. Because this is expensive and can potentially lead to life-threatening complications, other forms of therapy, including gene therapy, have been proposed. Natural canine models of factor VIII and factor IX deficiency have been available for many years, and gene therapy attempts on these dogs have met with partial success. However, a small animal model of the disease is desirable for studies of factor VIII function and gene therapy. Using gene targeting, we have made a mouse with severe factor VIII deficiency.
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            Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice.

            Inflammation plays a critical role in the development of cardiovascular diseases. Infiltration of leukocytes to sites of injury requires their exit from the blood and migration across basement membrane; this process has been postulated to require remodeling of the ECM. Plasminogen (Plg) is a protease that binds to the ECM and, upon conversion to plasmin, degrades multiple ECM proteins. In addition, plasmin directly activates MMPs. Here, we used Plg(-/-) mice to investigate the role of Plg in inflammatory leukocyte migration. After induction of peritonitis by thioglycollate injection, we found that Plg(-/-) mice displayed diminished macrophage trans-ECM migration and decreased MMP-9 activation. Furthermore, injection of the active form of MMP-9 in Plg(-/-) mice rescued macrophage migration in this model. We used periaortic application of CaCl2 to induce abdominal aortic aneurysm (AAA) and found that Plg(-/-) mice displayed reduced macrophage infiltration and were protected from aneurysm formation. Administration of active MMP-9 to Plg(-/-) mice promoted macrophage infiltration and the development of AAA. These data suggest that Plg regulates macrophage migration in inflammation via activation of MMP-9, which, in turn, regulates the ability of the cells to migrate across ECM. Thus, targeting the Plg/MMP-9 pathway may be an attractive approach to regulate inflammatory responses and AAA development.
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              Thrombolysis during resuscitation for out-of-hospital cardiac arrest.

              Approximately 70% of persons who have an out-of-hospital cardiac arrest have underlying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis during cardiopulmonary resuscitation may improve survival. In a double-blind, multicenter trial, we randomly assigned adult patients with witnessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardiopulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary end point was 30-day survival; the secondary end points were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome. After blinded review of data from the first 443 patients, the data and safety monitoring board recommended discontinuation of enrollment of asystolic patients because of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenecteplase was administered to 525 patients and placebo to 525 patients; the two treatment groups had similar clinical profiles. We did not detect any significant differences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs. 33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neurologic outcome (P=0.69). There were more intracranial hemorrhages in the tenecteplase group. When tenecteplase was used without adjunctive antithrombotic therapy during advanced life support for out-of-hospital cardiac arrest, we did not detect an improvement in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.) 2008 Massachusetts Medical Society
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                Author and article information

                Journal
                Vasc Health Risk Manag
                Vascular Health and Risk Management
                Vascular Health and Risk Management
                Dove Medical Press
                1176-6344
                1178-2048
                2010
                2010
                15 April 2010
                : 6
                : 199-205
                Affiliations
                Joseph J Jacobs Center for Thrombosis and Vascular Biology, Departments of Cardiovascular Medicine and Molecular Cardiology, Lerner Research Institute Cleveland Clinic, Ohio, USA
                Author notes
                Correspondence: Jane Hoover-Plow, Department of Molecular Cardiology, NB50, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA, Tel +1 216 445 8207, Fax +1 216 445 8024, Email hooverj@ 123456ccf.org
                Article
                vhrm-6-199
                10.2147/VHRM.S9358
                2856575
                20407627
                f4f8abd5-54a2-4698-b4ec-29443dec32b0
                © 2010 Hoover-Plow, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                : 30 March 2010
                Categories
                Review

                Cardiovascular Medicine
                thrombosis,anticoagulant,cardiovascular disease,plasminogen,protease,blood
                Cardiovascular Medicine
                thrombosis, anticoagulant, cardiovascular disease, plasminogen, protease, blood

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