The alpha-2-antiplasmin Arg407Lys polymorphism is associated with Abdominal Aortic Aneurysm

• Published in: Thrombosis research Vol. 134; no. 3; pp. 723 - 728
• Main Authors: Bridge, Katherine I., Macrae, Fraser, Bailey, Marc A., Johnson, Anne, Philippou, Helen, Scott, D. Julian A., Ariёns, Robert A.S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.09.2014
• Subjects: Abdominal Aortic Aneurysm; Aged; Alpha-2-antiplasmin; alpha-2-Antiplasmin - genetics; Aneurysm; Aortic Aneurysm, Abdominal - blood; Aortic Aneurysm, Abdominal - diagnosis; Aortic Aneurysm, Abdominal - ethnology; Aortic Aneurysm, Abdominal - genetics; Case-Control Studies; Chi-Square Distribution; England; Female; Fibrin - metabolism; Fibrinolysis; Fibrinolysis - genetics; Gene Frequency; Genetic Association Studies; Genetic Polymorphism; Genetic Predisposition to Disease; Hematology, Oncology and Palliative Medicine; Humans; Linkage Disequilibrium; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Prevalence; Prospective Studies; Real-Time Polymerase Chain Reaction; Risk Factors; White People - genetics; England; ILT; Alpha-2-antiplasmin; AAA; tPA; DNA; TAFI; Aneurysm; LEADS; Abdominal Aortic Aneurysm; Genetic Polymorphism; Fibrinolysis; α2AP; Intra-luminal thrombus; tissue plasminogen activator; alpha 2 antiplasmin; deoxyribonucleic acid; Leeds Aneurysm Development Study; Thrombin activatable fibrinolysis inhibitor
• ISSN: 0049-3848; 1879-2472; 1879-2472
• DOI: 10.1016/j.thromres.2014.06.019

Abdominal Aortic Aneurysm (AAA) involves dilatation of the abdominal aorta, with a natural history of expansion and eventual rupture. We have previously shown that AAA patients form denser clots with smaller pores, which are more resistant to fibrinolysis. The aim of this study was to use functional polymorphisms of the fibrinolytic system to identify how changes to proteins involved in fibrinolysis may play a role in the development of AAA. Caucasian subjects ≥55years (602 AAA patients and 490 matched controls) were genotyped for four polymorphisms (α-2-antiplasmin α2AP Arg6Trp and Arg407Lys, Thrombin-activatable fibrinolysis inhibitor TAFI Thr325Ile and tissue plasminogen activator tPA 7351C→T). DNA was extracted from blood, and genotype identified using real time PCR. Fibrin clot structure was analysed by permeation and turbidity in a subset of patients and controls. Genotypes across the study population were in Hardy-Weinberg Equilibrium. The two α2AP polymorphisms, Arg6Trp and Arg407Lys were in linkage disequilibrium (P<0.0001), and possession of a 407Lys allele negatively associated with AAA (odds ratio 0.833, CI95 0.7-0.991, P=0.040). The TAFI Thr325Ile and the tPA 7351C→T polymorphisms were not associated with AAA. The α2AP 407Lys allele was not associated with in-vitro fibrinolysis times in plasma from patients with AAA. Possession of the α2AP 407Lys allele was negatively associated with AAA, and thus changes in α2AP may affect aneurysm growth and development. These data indicate that the regulation of plasmin activity (through binding to α2AP), rather than plasmin generation (TAFI, tPA), may play a role in AAA. •Patients with Abdominal Aortic Aneurysm (AAA) develop denser clots that are more resistant to lysis.•Fibrinolytic proteins have been shown to contribute to the degradation of the arterial wall in AAA.•We used functional polymorphisms as markers of which fibrinolytic proteins may be implicated in the changes seen in lysis in patients with AAA.•α2AP Arg407Lys is negatively associated with AAA, but does not have an effect on the ex-vivo fibrin clot structure or lysis in this group of patients.