Antifibrinolytic therapy: new data and new concepts
2010; Elsevier BV; Volume: 376; Issue: 9734 Linguagem: Inglês
10.1016/s0140-6736(10)60939-7
ISSN1474-547X
Autores Tópico(s)Blood properties and coagulation
ResumoActivation of the fibrinolytic system is an integral part of vascular haemostatic mechanisms to maintain vascular patency. The basis of fibrinolysis is the conversion of the inactive substrate plasminogen to plasmin, an enzyme that cleaves fibrin but also has pleiotropic effects.1Cesarman-Maus G Hajjar KA Molecular mechanisms of fibrinolysis.Br J Haematol. 2005; 129: 307-321Crossref PubMed Scopus (517) Google Scholar, 2Chandler WL The human fibrinolytic system.Crit Rev Oncol Hematol. 1996; 24: 27-45Summary Full Text PDF PubMed Scopus (23) Google Scholar Multiple mechanisms are responsible for generating plasmin, including endothelial activation and release of tissue plasminogen activator, and contact activation and kallikrein-mediated plasmin activation.1Cesarman-Maus G Hajjar KA Molecular mechanisms of fibrinolysis.Br J Haematol. 2005; 129: 307-321Crossref PubMed Scopus (517) Google Scholar, 2Chandler WL The human fibrinolytic system.Crit Rev Oncol Hematol. 1996; 24: 27-45Summary Full Text PDF PubMed Scopus (23) Google Scholar, 3Medcalf RL Fibrinolysis, inflammation, and regulation of the plasminogen activating system.J Thromb Haemost. 2007; 5: 132-142Crossref PubMed Scopus (93) Google Scholar Tissue-type and urokinase-type are the two major plasminogen activators expressed in many cell types and tissues.3Medcalf RL Fibrinolysis, inflammation, and regulation of the plasminogen activating system.J Thromb Haemost. 2007; 5: 132-142Crossref PubMed Scopus (93) Google Scholar As part of the haemostatic balance, plasmin generation and activity are also modulated by multiple inhibitors that include plasminogen activator inhibitor 1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin.1Cesarman-Maus G Hajjar KA Molecular mechanisms of fibrinolysis.Br J Haematol. 2005; 129: 307-321Crossref PubMed Scopus (517) Google Scholar, 2Chandler WL The human fibrinolytic system.Crit Rev Oncol Hematol. 1996; 24: 27-45Summary Full Text PDF PubMed Scopus (23) Google Scholar, 3Medcalf RL Fibrinolysis, inflammation, and regulation of the plasminogen activating system.J Thromb Haemost. 2007; 5: 132-142Crossref PubMed Scopus (93) Google Scholar Thus fibrinolysis involves several regulatory mechanisms under physiological conditions. However, after the extensive tissue injury that occurs with trauma or surgery, the equilibrium is shifted and fibrinolysis that occurs is considered to be an important contributor to bleeding and coagulopathy.4Levy JH Dutton RP Hemphill 3rd, JC et al.Multidisciplinary approach to the challenge of hemostasis.Anesth Analg. 2010; 110: 354-364Crossref PubMed Scopus (127) Google Scholar In surgical patients, many studies reported the use of antifibrinolytic agents to decrease bleeding and need for allogeneic transfusions.5Zufferey P Merquiol F Laporte S et al.Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery?.Anesthesiology. 2006; 105: 1034-1046Crossref PubMed Scopus (280) Google Scholar, 6Brown JR Birkmeyer NJ O'Connor GT Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery.Circulation. 2007; 115: 2801-2813Crossref PubMed Scopus (251) Google Scholar The agents most commonly used are the lysine analogues, ɛ-aminocaproic acid and tranexamic acid, and aprotinin. Lysine analogues interfere with the binding of plasminogen to fibrin, necessary for activating plasmin, whereas aprotinin is a direct plasmin inhibitor. Thus inhibition of fibrinolysis with antifibrinolytics reduces bleeding after tissue injury, as has been extensively studied in surgical patients. In The Lancet today, the CRASH-2 investigators7CRASH-2 trial collaboratorsEffects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.Lancet. 2010; (published online June 15.)https://doi.org/10.1016/S0140-6736(10)60835-5Summary Full Text Full Text PDF Scopus (2231) Google Scholar report the use of tranexamic acid in trauma patients with or at risk for substantial bleeding.7CRASH-2 trial collaboratorsEffects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.Lancet. 2010; (published online June 15.)https://doi.org/10.1016/S0140-6736(10)60835-5Summary Full Text Full Text PDF Scopus (2231) Google Scholar CRASH-2 evaluated an impressive 20 211 trauma patients randomised and treated within 8 h of injury with either 2 g tranexamic acid (1 g load, then 1 g over 8 h) or placebo. In-hospital mortality within 4 weeks of injury was the primary outcome, while vascular occlusive events, transfusions, or surgical interventions were secondary outcomes. All-cause mortality was 14·5% in the tranexamic acid group (1463/10 060) compared with 16·0% with placebo (1613/10 067; relative risk 0·91, 95% CI 0·85–0·97; p=0·0035). Bleeding-related mortality was also reduced (4·9% vs 5·7%, respectively), without an increase in fatal or non-fatal vascular occlusive events. Despite the reduction in mortality, there were no statistically significant differences in transfusion requirements in patients receiving tranexamic acid or placebo. A crucial aspect of the original idea for the study was to reduce bleeding, an important cause of mortality after trauma, by use of an antifibrinolytic agent. Because tissue injury in trauma and surgery are similar, the investigators hypothesised that tranexamic acid could reduce mortality. Although there were no statistical differences in transfusion between the groups, how inhibition of fibrinolysis might have reduced mortality is important. The study did not show an antifibrinolytic effect on the basis of laboratory values; however, the tranexamic acid dose of 2 g administered over 8 h is sufficient to inhibit fibrinolytic activity.8Dowd NP Karski JM Cheng DC et al.Pharmacokinetics of tranexamic acid during cardiopulmonary bypass.Anesthesiology. 2002; 97: 390-399Crossref PubMed Scopus (177) Google Scholar However, there might be additional beneficial effects to inhibiting plasmin beyond clot lysis. Plasmin can induce many other responses that contribute to coagulopathy and bleeding, including further activation of thrombin from prothrombin, cleavage of fibrinogen and fibrin to create fibrin(ogeno)lysis, and cleavage of receptors on platelets (including glycoprotein Ib and IIb/IIIa receptors).1Cesarman-Maus G Hajjar KA Molecular mechanisms of fibrinolysis.Br J Haematol. 2005; 129: 307-321Crossref PubMed Scopus (517) Google Scholar, 2Chandler WL The human fibrinolytic system.Crit Rev Oncol Hematol. 1996; 24: 27-45Summary Full Text PDF PubMed Scopus (23) Google Scholar, 9Pasche B Ouimet H Francis S Loscalzo J Structural changes in platelet glycoprotein IIb/IIIa by plasmin: determinants and functional consequences.Blood. 1994; 83: 404-414Crossref PubMed Google Scholar In CRASH-2, there were 93 fewer patients receiving blood transfusions in the tranexamic acid group than in the placebo group. Plasmin also produces proinflammatory effects by binding and activating monocytes, neutrophils, platelets, and endothelial cells, and complement-releasing lipid mediators and cytokines, and by inducing proinflammatory genes.3Medcalf RL Fibrinolysis, inflammation, and regulation of the plasminogen activating system.J Thromb Haemost. 2007; 5: 132-142Crossref PubMed Scopus (93) Google Scholar, 10Syrovets T Simmet T Novel aspects and new roles for the serine protease plasmin.Cell Mol Life Sci. 2004; 61: 873-885Crossref PubMed Scopus (135) Google Scholar Thus plasmin exhibits a broad spectrum of proinflammatory responses that could influence pathophysiological responses and multiorgan system-failure that might be attenuated with antifibrinolytic agents. A recent report supports this concept, by reporting that antifibrinolytic therapy can improve mortality in high-risk patients undergoing cardiac surgery.11Karkouti K Wijeysundera DN Yau TM McCluskey SA Tait G Beattie WS The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery.Anesth Analg. 2010; 110: 21-29Crossref PubMed Scopus (81) Google Scholar A note of caution is warranted about tranexamic acid. After cardiac surgery, more cases of postoperative convulsive seizures are being reported, a finding temporally coincident with tranexamic acid doses that are 2–10 fold higher than those used in CRASH-2.12Martin K Wiesner G Breuer T Lange R Tassani P The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients.Anesth Analg. 2008; 107: 1783-1790Crossref PubMed Scopus (156) Google Scholar A proposed mechanism for seizures is the structural similarity of tranexamic acid to γ-aminobutyric acid as a potential cause of neurotoxicity. CRASH-2 is an important example of the complex relations between coagulation, fibrinolysis, inflammation, and outcomes after tissue injury.4Levy JH Dutton RP Hemphill 3rd, JC et al.Multidisciplinary approach to the challenge of hemostasis.Anesth Analg. 2010; 110: 354-364Crossref PubMed Scopus (127) Google Scholar Today's study shows that inhibition of fibrinolysis with tranexamic acid after major trauma is an important mechanism to reduce mortality. The similarities of tissue injury after trauma and surgery create a novel model for antifibrinolytic therapy with tranexamic acid. However, caution is needed before extrapolation of the results of CRASH-2 to other antifibrinolytic agents until they have been studied in a similarly robust manner. I have received research support from Novo Nordisk, and serve on their steering committee for recombinant factor XIII evaluation in cardiac surgery. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trialTranexamic acid safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients. Full-Text PDF
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