Admission fibrinolytic profile predicts clot lysis resistance in stroke patients treated with tissue plasminogen activator

Summary

Endogenous fibrinolysis inhibitors may be involved in t-PA resistance, decreasing stroke thrombolysis beneficts. We aim to determine the impact of pretreatment levels of plasminogen activator inhibitor (PAI-1), lipoprotein(a), thrombin-activatable fibrinolysis inhibitor (TAFI) and homocysteine on arterial recanalization and outcome. Forty-four consecutive patients with acute proximal middle cerebral artery occlusion were studied, including assessment of transcraneal Doppler artery patency. The neurological status was determined by NIH Stroke Scale (NIHSS) and long-term outcome with modified Rankin Scale (mRS). Patients who recanalized after t-PA infusion had lower PAI-1 levels than those who remained occluded. Similarly, patients who achieved dramatic clinical recovery at 12 hours exhibited significantly lower PAI-1 levels as those independent (mRS≤2) at third month. We observed a trend towards lower lipoprotein p(a) in patients who achieved recanalization at 1 hour, whereas no relation was found between TAFI or homocysteine levels and recanalization. After a regression model was applied the only independent predictor of thrombolysis resistance was baseline PAI-1≤34 ng/ml, such that high PAI-1 levels interfere with tPA-induced recanalization in stroke, predicting a higher susceptibility towards clot-lysis resistance and poor outcome.

Keywords

Cerebrovascular disease - clinical trials - fibrinolytic therapy - fibrinolysis inhibitors - thrombin activatable fibrinolysis inhibitor / carboxypeptidases - ultrasound / diagnosis

• References

• 1 Ringelstein EB, Biniek R, Weiller C. et al. Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization. Neurology 1992; 42: 289-98.
• 2 Molina CA, Montaner J, Abilleira S. et al. Time course of tissue plasminogen activatorinduced recanalization in acute cardioembolic stroke: a case-control study. Stroke 2001; 32: 2821-7.
• 3 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: 1581-7.
• 4 Demchuk AM, Felburg RA, Alexandrov AV. Clinical recovery from acute ischemic stroke after early reperfusion of the brain with intravenous thrombolysis. N Engl J Med 1999; 340: 894-5.
• 5 Collet JP, Montalescot G, Vicaut E. et al. Acute release of plasminogen activator inhibitor-1 in ST-segment elevation myocardial infarction predicts mortality. Circulation 2003; 108: 391-4.
• 6 Wagner A, Herkner H, Schreiber W. et al. Ramipril prior to thrombolysis attenuates the early increase of PAI-1 in patients with acute myocardial infarction. Thromb Haemost 2002; 88: 180-5.
• 7 Adams Jr HP, Bendixen BH, Kappelle LJ. 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.
• 8 Brott TG, Haley Jr EC, Levy DE. et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992; 23: 632-40.
• 9 The Dutch TIA trial: protective effects of lowdose aspirin and atenolol in patients with transient ischemic attacks or nondisabling stroke. The Dutch TIA Study Group. Stroke 1988; 19: 512-7.
• 10 Demchuk AM, Tanne D, Hill MD. et al. Predictors of good outcome after intravenous tPA for acute ischemic stroke. Neurology 2001; 57: 474-80.
• 11 Burgin WS, Malkoff M, Felberg RA. et al. Transcranial doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke. Stroke 2000; 31: 1128-32.
• 12 Zunker P, Schick A, Padro T. et al. Tissue plasminogen activator and plasminogen activator inhibitor in patients with acute ischemic stroke: relation to stroke etiology. Neurol Res 1999; 21: 727-32.
• 13 Juhan-Vague I, Pyke SD, Alessi MC. et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 1996; 94: 2057-63.
• 14 Vaughan DE, Rouleau JL, Ridker PM. et al. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. Circulation 1997; 96: 442-7.
• 15 Ariyo AA, Thach C, Tracy R. Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med 2003; 349: 2108-15.
• 16 Angles-Cano E, de la Pena ADiaz, Loyau S. Inhibition of fibrinolysis by lipoprotein(a). Ann N Y Acad Sci 2001; 936: 261-75.
• 17 Montaner J, Ribo M, Molina C. et al. Thrombin-Activable Fibrinolysis Inhibitor (TAFI) Level Is Related to T-PA-Induced Recanalization Resistance after Human Ischemic Stroke. Stroke 2003; 34: 240.
• 18 Stringer HA, van Swieten P, Heijnen HF. et al. Plasminogen activator inhibitor-1 released from activated platelets plays a key role in thrombolysis resistance. Studies with thrombi generated in the Chandler loop. Arterioscler Thromb 1994; 14: 1452-8.
• 19 Yamamoto J, Yamashita T, Ikarugi H. et al. Gorog Thrombosis Test: a global in-vitro test of platelet function and thrombolysis. Blood Coagul Fibrinolysis 2003; 14: 31-9.