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One of the key functions of blood coagulation is to produce a fibrin clot to stem bleeding after injury. The protease responsible for fibrin production is thrombin, which has many other functions including the activation of platelets but also the activation of anticoagulant systems (protein C) and inhibition of fibrinolysis (via the thrombin activatable fibrinolysis inhibitor). 1 Fibrin is produced in a matter of minutes by thrombin-mediated cleavage of fibrinogen, a protein with a very high concentration in the blood, second only to albumin and the immunoglobulins. Once converted from highly soluble fibrinogen to fibrin, the protein rapidly generates a network that contains

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ObjectiveThrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition on AAA formation in adult ApoE-/- mice is unknown. The aim of this paper was to investigate the effects of TAFI inhibition on AAA development and progression.MethodsUsing the Angiotensin II model of AAA, male ApoE-/- mice were infused with Angiotensin II 750ng/kg/min with or without a monoclonal antibody inhibitor of plasmin-mediated activation of TAFI, MA-TCK26D6, or a competitive small molecule inhibitor of TAFI, UK-396082.ResultsInhibition of TAFI in the Angiotensin II model resulted in a decrease in the mortality associated with AAA rupture (from 40.0% to 16.6% with MA-TCK26D6 (log-rank Mantel Cox test p = 0.16), and 8.3% with UK-396082 (log-rank Mantel Cox test p = 0.05)). Inhibition of plasmin-mediated TAFI activation reduced the incidence of AAA from 52.4% to 30.0%. However, late treatment with MA-TCK26D6 once AAA were already established had no effect on the progression of AAA in this model.ConclusionsThe formation of intra-mural thrombus is responsible for the dissection and early rupture in the angiotensin II model of AAA, and this process can be prevented through inhibition of TAFI. Late treatment with a TAFI inhibitor does not prevent AAA progression. These data may indicate a role for inhibition of plasmin-mediated TAFI activation in the early stages of AAA development, but not in its progression.

Patients with abdominal aortic aneurysms (AAA) develop dense clots that are resistant to lysis. This study explores the role of thrombin‐activatable fibrinolysis inhibitor (TAFI) in human AAA. There is evidence of chronically increased TAFI activation in patients with AAA. TAFI may represent a pharmacological target for cardiovascular risk reduction in AAA. Summary BackgroundIntra‐luminal thrombosis is a key factor in growth of abdominal aortic aneurysms (AAAs). Patients with AAA form dense clots that are resistant to fibrinolysis. Thrombin‐activatable fibrinolysis inhibitor (TAFI) has been shown to influence AAA development in murine models. ObjectiveThe aim of this study is to characterize the role of TAFI in human AAA. MethodsPlasma levels of TAFI, TAFI activation peptide (TAFI‐AP), activated/inactivated TAFI (TAFIa/ai) and plasmin‐α2‐antiplasmin complex were measured by ELISAs in patients with AAA (n = 202) and controls (n = 188). ResultsTAFIa/ai and TAFI‐AP levels were higher in patients than controls (median [IQR], 20.3 [14.6–32.8] ng mL−1 vs. 14.2 [11.2–19.3] ng mL−1 and 355.0 [232.4–528.1] ng mL−1 vs. 248.6 [197.1–328.1] ng mL−1). TAFIa/ai was positively correlated with TAFI‐AP (r = 0.164). Intact TAFI levels were not different between patients and controls (13.4 [11.2–16.1] μg mL−1 vs. 12.8 [10.6–15.4] μg mL−1). Plasmin‐α2‐antiplasmin was higher in AAA patients than controls (690.0 [489.1–924.3] ng mL−1 vs. 480.7 [392.6–555.3] ng mL−1). ConclusionsThe increase in TAFIa/ai and TAFI‐AP suggests an increased TAFI activation in patients with AAA. Prospective studies are required to further elucidate the role of TAFI and fibrinolysis in AAA pathogenesis.