Background and Purpose: Thrombin-activatable fibrinolysis inhibitor (TAFI) activation following thrombolysis may affect thrombolysis effectiveness in acute ischemic stroke (AIS). To support this hypothesis, we propose to study the relationship between TAFI consumption, activated/inactivated TAFI (TAFIa/ai) and stroke severity and outcome in 2 groups of AIS patients, one treated and one untreated with intravenous recombinant tissue type plasminogen activator (rt-PA). Methods: In this prospective, longitudinal, multicenter, observational study, we aimed to study the association between TAFIa/ai and stroke outcome. TAFI levels were sequentially measured in patients treated with intravenous rt-PA thrombolysis (T), and in patients not given any thrombolytic therapy (NT). Baseline reference values were established in healthy subjects matched for age and gender. The National Institutes of Health Stroke Scale (NIHSS) score assessed at baseline and on day 2 was dichotomized into 2 severity groups (0-7 vs. >7). The modified Rankin Scale (mRS) score at day 90 was dichotomized for favorable (0-1) and unfavorable (2-6) outcomes. Results: A total of 109 patients were included, with 41 receiving rt-PA. At admission, patients had higher TAFIa/ai levels than reference. A significant increase in TAFIa/ai levels was observed at the end of thrombolysis (mean change from baseline of 963%) and lasted up to 4 h (191%). Higher TAFIa/ai levels were associated with a more severe day 2 NIHSS score (p = 0.0098 at T2h post thrombolysis) and an unfavorable mRS score from T48h (p = 0.0417) to day 90 (p = 0.0046). In NT patients, higher TAFIa/ai levels at admission were associated with a more severe stroke, as assessed by day 2 NIHSS score (p = 0.0026) and mRS score (p = 0.0003). Conclusion: These data demonstrate a consistent relationship between TAFI levels and early clinical severity during rt-PA treatment.

Tissue plasminogen activator for acute ischemic stroke. The national institute of neurological disorders and stroke rt-PA stroke study group. N Engl J Med 1995;333:1581-1587.
Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al: Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329.
Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al: Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695-1703.
Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr: Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American heart association/American stroke association. Stroke 2009;40:2945-2948.
Paul CL, Levi CR, D'Este CA, Parsons MW, Bladin CF, Lindley RI, et al: Thrombolysis implementation in stroke (TIPS): evaluating the effectiveness of a strategy to increase the adoption of best evidence practice - protocol for a cluster randomised controlled trial in acute stroke care. Implement Sci 2014;9:38.
Christou I, Felberg RA, Demchuk AM, Burgin WS, Malkoff M, Grotta JC, et al: Intravenous tissue plasminogen activator and flow improvement in acute ischemic stroke patients with internal carotid artery occlusion. J Neuroimaging 2002;12:119-123.
Bhatia R, Hill MD, Shobha N, Menon B, Bal S, Kochar P, et al: Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke 2010;41:2254-2258.
Zangerle A, Kiechl S, Spiegel M, Furtner M, Knoflach M, Werner P, et al: Recanalization after thrombolysis in stroke patients: predictors and prognostic implications. Neurology 2007;68:39-44.
Fonarow GC, Zhao X, Smith EE, Saver JL, Reeves MJ, Bhatt DL, et al: Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. JAMA 2014;311:1632-1640.
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al; ESCAPE Trial Investigators: Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019-1030.
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al; EXTEND-IA Investigators: Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009-1018.
Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al; MR CLEAN Investigators: A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20.
Lin JH, Garand M, Zagorac B, Schadinger SL, Scipione C, Koschinsky ML, Boffa MB: Identification of human thrombin-activatable fibrinolysis inhibitor in vascular and inflammatory cells. Thromb Haemost 2011;105:999-1009.
Mosnier LO, Buijtenhuijs P, Marx PF, Meijers JC, Bouma BN: Identification of thrombin activatable fibrinolysis inhibitor (TAFI) in human platelets. Blood 2003;101:4844-4846.
Schadinger SL, Lin JH, Garand M, Boffa MB: Secretion and antifibrinolytic function of thrombin-activatable fibrinolysis inhibitor from human platelets. J Thromb Haemost 2010;8:2523-2529.
Foley JH, Kim PY, Mutch NJ, Gils A: Insights into thrombin activatable fibrinolysis inhibitor function and regulation. J Thromb Haemost 2013;11(suppl 1):306-315.
Mao SS, Cooper CM, Wood T, Shafer JA, Gardell SJ: Characterization of plasmin-mediated activation of plasma procarboxypeptidase B. Modulation by glycosaminoglycans. J Biol Chem 1999;274:35046-35052.
Marx PF, Dawson PE, Bouma BN, Meijers JC: Plasmin-mediated activation and inactivation of thrombin-activatable fibrinolysis inhibitor. Biochemistry 2002;41:6688-6696.
Mishra N, Vercauteren E, Develter J, Bammens R, Declerck PJ, Gils A: Identification and characterisation of monoclonal antibodies that impair the activation of human thrombin activatable fibrinolysis inhibitor through different mechanisms. Thromb Haemost 2011;106:90-101.
Vercauteren E, Mutch NJ, Declerck PJ, Gils A: Plasmin and the thrombin-thrombomodulin complex both contribute to thrombin-activatable fibrinolysis inhibitor activation in whole blood model thrombi. J Thromb Haemost 2013;11:190-192.
Vercauteren E, Emmerechts J, Peeters M, Hoylaerts MF, Declerck PJ, Gils A: Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model. Blood 2011;117:4615-4622.
Wang W, Hendriks DF, Scharpé SS: Carboxypeptidase U, a plasma carboxypeptidase with high affinity for plasminogen. J Biol Chem 1994;269:15937-15944.
Bajzar L, Manuel R, Nesheim ME: Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem 1995;270:14477-14484.
Redlitz A, Nicolini FA, Malycky JL, Topol EJ, Plow EF: Inducible carboxypeptidase activity. A role in clot lysis in vivo. Circulation 1996;93:1328-1330.
Ceresa E, Brouwers E, Peeters M, Jern C, Declerck PJ, Gils A: Development of ELISAs measuring the extent of TAFI activation. Arterioscler Thromb Vasc Biol 2006;26:423-428.
Tregouet DA, Schnabel R, Alessi MC, Godefroy T, Declerck PJ, Nicaud V, Munzel T, Bickel C, Rupprecht HJ, Lubos E, Zeller T, Juhan-Vague I, Blankenberg S, Tiret L, Morange PE; AtheroGene Investigators: Activated thrombin activatable fibrinolysis inhibitor levels are associated with the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2009;7:49-57.
Meltzer ME, Lisman T, de Groot PG, Meijers JC, le Cessie S, Doggen CJ, Rosendaal FR: Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010;116:113-121.
Leenaerts D, Bosmans JM, van der Veken P, Sim Y, Lambeir AM, Hendriks D: Plasma levels of carboxypeptidase U (CPU, CPB2 or TAFIa) are elevated in patients with acute myocardial infarction. J Thromb Haemost 2015;13:2227-2232.
Wang W, Ma H, Lu L, Sun G, Liu D, Zhou Y, Tong Y, Lu Z: Association between thrombin-activatable fibrinolysis inhibitor gene polymorphisms and venous thrombosis risk: a meta-analysis. Blood Coagul Fibrinolysis 2016;27:419-430.
Shi J, Zhi P, Chen J, Wu P, Tan S: Genetic variations in the thrombin-activatable fibrinolysis inhibitor gene and risk of cardiovascular disease: a systematic review and meta-analysis. Thromb Res 2014;134:610-616.
Kozian DH, Lorenz M, März W, Cousin E, Mace S, Deleuze JF: Association between the Thr325Ile polymorphism of the thrombin-activatable fibrinolysis inhibitor and stroke in the Ludwigshafen risk and cardiovascular health study. Thromb Haemost 2010;103:976-983.
Fernandez-Cadenas I, Alvarez-Sabin J, Ribo M, Rubiera M, Mendioroz M, Molina CA, Rosell A, Montaner J: Influence of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 gene polymorphisms on tissue-type plasminogen activator-induced recanalization in ischemic stroke patients. J Thromb Haemost 2007;5:1862-1868.
Kim SH, Han SW, Kim EH, Kim DJ, Lee KY, Kim DI, et al: Plasma fibrinolysis inhibitor levels in acute stroke patients with thrombolysis failure. J Clin Neurol 2005;1:142-147.
Santamaría A, Oliver A, Borrell M, Mateo J, Belvis R, Martí-Fábregas J, et al: Risk of ischemic stroke associated with functional thrombin-activatable fibrinolysis inhibitor plasma levels. Stroke 2003;34:2387-2391.
Montaner J, Ribó M, Monasterio J, Molina CA, Alvarez-Sabín J: Thrombin-activable fibrinolysis inhibitor levels in the acute phase of ischemic stroke. Stroke 2003;34:1038-1040.
Biswas A, Tiwari AK, Ranjan R, Meena A, Akhter MS, Yadav BK, et al: Thrombin activatable fibrinolysis inhibitor gene polymorphisms are associated with antigenic levels in the Asian-Indian population but may not be a risk for stroke. Br J Haematol 2008;143:581-588.
Leebeek FW, Goor MP, Guimaraes AH, Brouwers GJ, Maat MP, Dippel DW, Rijken DC: High functional levels of thrombin-activatable fibrinolysis inhibitor are associated with an increased risk of first ischemic stroke. J Thromb Haemost 2005;3:2211-2218.
de Bruijne EL, Gils A, Guimarães AH, Dippel DW, Deckers JW, van den Meiracker AH, et al: The role of thrombin activatable fibrinolysis inhibitor in arterial thrombosis at a young age: the ATTAC study. J Thromb Haemost 2009;7:919-927.
Brouns R, Heylen E, Sheorajpanday R, Willemse JL, Kunnen J, De Surgeloose D, et al: Carboxypeptidase U (TAFIa) decreases the efficacy of thrombolytic therapy in ischemic stroke patients. Clin Neurol Neurosurg 2009;111:165-170.
Brouns R, Heylen E, Willemse JL, Sheorajpanday R, De Surgeloose D, Verkerk R, et al: The decrease in procarboxypeptidase U (TAFI) concentration in acute ischemic stroke correlates with stroke severity, evolution and outcome. J Thromb Haemost 2010;8:75-80.
Ladenvall C, Gils A, Jood K, Blomstrand C, Declerck PJ, Jern C: Thrombin activatable fibrinolysis inhibitor activation peptide shows association with all major subtypes of ischemic stroke and with TAFI gene variation. Arterioscler Thromb Vasc Biol 2007;27:955-962.
Jood K, Redfors P, Gils A, Blomstrand C, Declerck PJ, Jern C: Convalescent plasma levels of TAFI activation peptide predict death and recurrent vascular events in ischemic stroke survivors. J Thromb Haemost 2012;10:725-727.
Martí-Fàbregas J, Borrell M, Cocho D, Martínez-Ramírez S, Martínez-Corral M, Fontcuberta J, et al: Change in hemostatic markers after recombinant tissue-type plasminogen activator is not associated with the chance of recanalization. Stroke 2008;39:234-236.
Ribo M, Montaner J, Molina CA, Arenillas JF, Santamarina E, Quintana M, Alvarez-Sabín J: Admission fibrinolytic profile is associated with symptomatic hemorrhagic transformation in stroke patients treated with tissue plasminogen activator. Stroke 2004;35:2123-2127.
DeGraba TJ, Hallenbeck JM, Pettigrew KD, Dutka AJ, Kelly BJ: Progression in acute stroke: value of the initial NIH stroke scale score on patient stratification in future trials. Stroke 1999;30:1208-1212.
Hacke W, Bluhmki E, Steiner T, Tatlisumak T, Mahagne Mh, Sacchetti Ml, Meier D: Dichotomized efficacy end points and global end-point analysis applied to the ecass Intention-to-treat data set: post hoc analysis of ECASS I. Stroke 1998;29:2073-2075.
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke 1993;24:35-41.
Higashida RT, Furlan AJ, Roberts H, Tomsick T, Connors B, Barr J, et al; Technology Assessment Committee of the American Society of Interventional and Therapeutic Neuroradiology; Technology Assessment Committee of the Society of Interventional Radiology: Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke 2003;34:e109-e137.
Willemse JL, Brouns R, Heylen E, De Deyn PP, Hendriks DF: Carboxypeptidase U (TAFIa) activity is induced in vivo in ischemic stroke patients receiving thrombolytic therapy. J Thromb Haemost 2008;6:200-202.
Kraft P, Schwarz T, Meijers JC, Stoll G, Kleinschnitz C: Thrombin-activatable fibrinolysis inhibitor (TAFI) deficient mice are susceptible to intracerebral thrombosis and ischemic stroke. PLoS One 2010;5:e11658.
Orbe J, Alexandru N, Roncal C, Belzunce M, Bibiot P, Rodriguez JA, Meijers JC, Georgescu A, Paramo JA: Lack of TAFI increases brain damage and microparticle generation after thrombolytic therapy in ischemic stroke. Thromb Res 2015;136:445-450.
Durand A, Chauveau F, Cho TH, Kallus C, Wagner M, Boutitie F, Maucort-Boulch D, Berthezène Y, Wiart M, Nighoghossian N: Effects of a TAFI-inhibitor combined with a suboptimal dose of rtPA in a murine thromboembolic model of stroke. Cerebrovasc Dis 2014;38:268-275.
Quagraine MO, Tan F, Tamei H, Erdös EG, Skidgel RA: Plasmin alters the activity and quaternary structure of human plasma carboxypeptidase N. Biochem J 2005;388(pt 1):81-91.
Redlitz A, Tan AK, Eaton DL, Plow EF: Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest 1995;96:2534-2538.
Morser J, Gabazza EC, Myles T, Leung LL: What has been learnt from the thrombin-activatable fibrinolysis inhibitor-deficient mouse? J Thromb Haemost 2010;8:868-876.
Klement P, Liao P, Bajzar L: A novel approach to arterial thrombolysis. Blood 1999;94:2735-2743.
Wyseure T, Rubio M, Denorme F, Martinez de Lizarrondo S, Peeters M, Gils A, et al: Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke. Blood 2015;125:1325-1332.
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