High functional levels of thrombin-activatable fibrinolysis inhibitor are associated with an increased risk of first ischemic stroke

Abstract

Summary. Background and objective: Several studies have suggested that thrombin-activatable fibrinolysis inhibitor (TAFI) levels are associated with the risk of arterial thrombosis, but results have been contradictory. We studied functional TAFI levels and TAFI gene polymorphisms in 124 patients with a recent ischemic stroke and 125 age-and sex-matched controls to establish the role of TAFI in ischemic stroke. Methods and results: Functional TAFI levels, defined as TAFI-related retardation (RT), the difference in clot lysis time (LT) in the absence or presence of a specific activated TAFI inhibitor (potato carboxypeptidase inhibitor [PCI]), were higher in patients than controls (19.5 ± 4.2 vs. 17.7 ± 3.7 min, P < 0.005). Clot LTs in the presence of PCI, which were independent of TAFI, were also increased in ischemic stroke patients. This indicates that in these patients fibrinolysis is impaired not only by high TAFI levels, but also by other mechanisms. Individuals with functional TAFI levels in the highest quartile had an increased risk of ischemic stroke compared with the lowest quartile [odds ratio (OR) 4.0, 95% confidence interval (CI): 1.6-9.8]. In an unselected group of 36 of the 125 stroke patients functional TAFI levels were also measured at 3 months, and were persistently high. This indicates that increased functional TAFI levels after stroke are not caused by an acute phase reaction. No difference was found between patients and controls with respect to TAFI genotype distribution. Conclusions: Increased functional TAFI levels, resulting in decreased fibrinolysis, are associated with an increased risk of ischemic stroke.

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

“…view of this, it is of interest that there is a recent study reporting increased plasma levels of functional TAFI in acute ischemic stroke. 22 However, ischemic stroke is a highly heterogeneous disorder, and as this study included only approximately 120 patients, it was not possible to study the association between TAFI and ischemic stroke subtypes.Here we aimed to perform a comprehensive investigation of the possible association between ischemic stroke and TAFI among participants in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), in which ischemic stroke subtype has been determined by Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. 23 To this end, TAFI was analyzed at the protein level by 2 newly developed immunologic assays with distinct reactivities, recognizing either intact TAFI or the released AP, 24 and, at the genetic level, by a selection of tagging SNPs over the TAFI locus.…”

“…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.…”

Meta-analysis of TAFI polymorphisms and risk of cardiovascular and cerebrovascular diseases

“…Additionally, TAFI may also help the growth and spread of tumor cells owing to the accumulation of intra-tumor fibrin and activation of the blood coagulation system (Fidan et al, 2012). TAFI is important in CCVDs, such as coronary heart disease, angina pectoris, ischemic stroke, myocardial infarction, and venous thrombosis, mainly owing to its role in thrombosis treatment (Zorio et al, 2003;Leebeek et al, 2005;Tokgoz et al, 2013). Polymorphisms of the CPB2 gene result in changes in the amino acid sequence and function of TAFI, especially in the molecular stability of TAFIa and its anti-fibrinolytic activity in arterial thrombosis.…”

“…An additional study was removed owing to a lack of data integrity. Ultimately, we obtained nine case-control research papers published between 2003 and 2013 that were of moderate-to-high quality (Zorio et al, 2003;Leebeek et al, 2005;Xu et al, 2008;Biswas et al, 2009;Si, 2010;Kamal et al, 2011;Shi et al, 2011;Sun et al, 2011;Tokgoz et al, 2013). The demographic information, baseline characteristics, and other features, and the methodological quality of the extracted studies are presented in Tables 1 and 2.…”

“…Obviously, any disturbance in the level of TAFI or its activity may lead to elevated rates of thrombotic complication in human cancer patients (Fidan et al, 2012). After an investigation of several publications on the relationship between genetic variations in CPB2 and the occurrence of and susceptibility to human diseases and cancers, it was suggested that an increase in the level of TAFI may affect the formation of an arterial or venous thrombus, and may further contribute to the development of several CCVDs (Leebeek et al, 2005;Meltzer et al, 2009). Moreover, a different study has revealed that CPB2 gene variation is an independent variable in the development of ischemia stroke (Ladenvall et al, 2007).…”