Influence of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 gene polymorphisms on tissue-type plasminogen activator-induced recanalization in ischemic stroke patients.
OBJECTIVE
Endogenous resistance to tissue-type plasminogen activator (t-PA) might decrease the benefit of thrombolysis-induced recanalization. Thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are fibrinolysis inhibitors. TAFI removes residues from partially degraded fibrin that in turn eliminates plasminogen binding sites; PAI-1 directly inhibits the activity of t-PA. We aimed to study whether the presence of two common functional polymorphisms of the TAFI and PAI-1 genes influence rates of recanalization of the middle cerebral artery (MCA) among t-PA-treated stroke patients.


RESULTS
TAFI and PAI-1 polymorphism determinations were performed by restriction fragment length polymorphism mapping and conventional sequencing in 139 patients with strokes involving the MCA and who received t-PA within 3 h. Recanalization was diagnosed by means of transcranial Doppler. No association was found between PAI-1 4 G/5 G polymorphism and recanalization rate. Dyslipidemia and TAFI Thr325Ile polymorphism were the main variables associated with recanalization resistance by the end of t-PA infusion: odds ratio (OR) 4.1 [95% confidence interval (95% CI) 1.6-10.8, P = 0.003] and OR 5.6 (95% CI 1.2-20, P = 0.031), respectively. The combination of the two polymorphisms doubled the risk of absence of recanalization: OR 11.1 (95% CI 1.4-89.8, P = 0.025).


CONCLUSIONS
Polymorphic fibrinolysis inhibitor genes influence t-PA-induced recanalization resistance in ischemic stroke patients, especially when coexisting in the same patient. Efforts to individualize thrombolytic treatments are required.
Fernandez-Cadenas
I
I
Neurovascular Research Laboratory, Neurovascular Unit, Department of Neurology of Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Vall d'Hebron University Hospital, Barcelona, Spain.
Alvarez-Sabin
J
J
Ribo
M
M
Rubiera
M
M
Mendioroz
M
M
Molina
C A
CA
Rosell
A
A
Montaner
J
J
D000368:Aged; D002545:Brain Ischemia / Q000235:genetics*; D025901:Carboxypeptidase B2 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D011446:Prospective Studies
D017395:Plasminogen Activator Inhibitor 1; D025901:Carboxypeptidase B2