Risk of Ischemic Stroke Associated With Functional Thrombin-Activatable Fibrinolysis Inhibitor Plasma Levels

Abstract

Background and Purpose-Recently, a novel procarboxypeptidase B-like proenzyme, called thrombin-activatable fibrinolysis inhibitor (TAFI), has been described. It plays an important role in the delicate balance between coagulation and fibrinolysis. TAFI leads to potent inhibition of tissue plasminogen activator-induced fibrinolysis. The relevance of TAFI in thromboembolic disease is unclear. We have investigated the risk of ischemic stroke (IS) in relation to plasma levels of functional TAFI. Methods-In a case-control study, we enrolled 264 individuals; 114 had IS, and 150 were recruited as controls who were age and sex matched and had no history of arterial disease. The individuals supplied information on their personal and family histories of cardiovascular diseases and conventional cardiovascular risk factors. Functional TAFI assays were performed by use of a method based on the activation of TAFI with thrombin-thrombomodulin and the measure of the TAFI activity generated. Other hemostatic parameters assayed were factor VIIIc, anti-phospholipid antibodies, fibrinogen, factor V Leiden, and the prothrombin gene G20210A mutations (PT20210A). Results-Functional TAFI levels were significantly higher in patients with IS (113.7Ϯ25%; range, 57% to 209%) than in controls (102.6Ϯ19%). The odds ratio for IS in patients with functional TAFI levels Ͼ120% was 5.7 (95% confidence interval, 2.3 to 14.1). Conclusions-We found that functional TAFI levels in plasma (Ͼ120%) increased the risk of IS Ϸ6-fold. Further studies should elucidate the physiological role of TAFI in arterial disease and possibly provide clues to therapeutic approaches.

Thrombin Activatable Fibrinolysis Inhibitor Activation Peptide Shows Association With All Major Subtypes of Ischemic Stroke and With TAFI Gene Variation

“…31 Santamaría et al investigated 114 young (mean age 56 years) patients with ischemic stroke or transient ischemic attacks. 30 TAFI levels, as measured within the first month after the event by an activity assay after full activation of TAFI with thrombin-thrombomodulin, were increased in patients compared with controls. Leebeek et al found increased functional TAFI levels, as determined by a clot lysis assay in 124 patients with a recent first episode of ischemic stroke.…”

“…The finding of increased plasma levels of TAFI in overall ischemic stroke is in agreement with 3 previous studies, despite somewhat different study designs. 22,30,31 Montaner et al showed that TAFI Ag levels, measured within 24 hours of onset of the event, were increased in a small sample (nϭ30) of elderly ischemic stroke patients. 31 Santamaría et al investigated 114 young (mean age 56 years) patients with ischemic stroke or transient ischemic attacks.…”

Renal transplant recipients with coronary artery disease exhibit impairment in fibrinolysis and structural changes in carotid arteries

“…In addition, elevated TAFI (above 126%) was associated with an almost fourfold higher risk of CAD [8]. High TAFI in hypercholesterolemic kidney transplant recipients may contribute to hypofibrinolysis and to the progression of atherosclerosis in these patients.…”

“…Recently, we have reported an enhanced thrombin generation and increased thrombin-activatable fibrinolysis inhibitor (TAFI) in kidney transplant recipients with dyslipidemia [7]. Moreover, high TAFI is associated with increased risk of acute coronary artery disease (CAD) [8]. Markers of endothelial cell injury are also predictors of coronary events [9].…”

Plasma Levels of Unactivated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Are Down‐Regulated in Young Adult Women: Analysis of a Normal Japanese Population

“…In previous reports, the risk of acute coronary artery disease was associated with a disturbance in functional thrombin activatable fibrinolysis inhibitor plasma levels (30) as was the risk of deep vein thrombosis (39). Obstructive vascular disease as well as inflammatory states, burns and septic injuries induce profound changes in the coagulation status.…”