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Thromb Haemost 2014; 111(02): 226-232
DOI: 10.1160/TH13-06-0489
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Factor IX-Padua enhances the fibrinolytic resistance of plasma clots

Concetta T. Ammollo
1   Department of Cardiologic, Thoracic and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy
,
Fabrizio Semeraro
1   Department of Cardiologic, Thoracic and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy
,
Mario Colucci
2   Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University, Bari, Italy
,
Paolo Simioni
1   Department of Cardiologic, Thoracic and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy
› Author Affiliations Financial support: This work was supported in part by a grant from the University of Bari to Mario Colucci and by a grant from the University of Padua, DCTVS (Dept. of Cardiologic, Thoracic and Vascular Sciences) and MIUR (Ministero dell’ Università e Ricerca) grant n. 60A07–3718/10 to Paolo Simioni.
Further Information

Publication History

Received: 16 June 2013

Accepted after major revision: 14 September 2013

Publication Date:
27 November 2017 (online)

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Summary

Hypercoagulable conditions may determine a hypofibrinolytic state by increasing the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Factor (F)IX-Padua is a mutated FIX with an eight-fold increased clotting activity and associates with a higher venous thrombotic risk. We evaluated the influence of FIX-Padua on TAFI-mediated regulation of fibrinolysis. A subject hemizygous for FIX-Padua, two family members (heterozygous and normal) and six healthy controls were studied. Clot lysis, TAFI activation and thrombin generation were evaluated in contact-inhibited plasma challenged with low concentrations of tissue factor. Fibrinolysis times were significantly longer in FIX-Padua carriers than controls. The difference disappeared when activated TAFI (TAFIa) was inhibited, when TAFI activation was avoided or when clotting was made independent of FIX. TAFIa generation was markedly enhanced in FIX-Padua carriers as compared to controls, and this could be explained by a greater thrombin generation in the former. Hyperactive FIX, but not wild-type FIX, enhanced fibrinolytic resistance also when the FXI-dependent positive feedback was blocked by a neutralising anti-FXI antibody. This thrombin-mediated, TAFI-dependent down-regulation of fibrinolysis provides new clues for explaining the heightened thrombotic risk in subjects carrying the FIXPadua mutation.

Keywords

Factor IX - fibrinolysis - thrombin activatable fibrinolysis inhibitor - thrombin generation - thrombosis
 

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