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DOI: 10.1160/TH13-06-0489
Factor IX-Padua enhances the fibrinolytic resistance of plasma clots
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.
Publication History
Received:
16 June 2013
Accepted after major revision:
14 September 2013
Publication Date:
27 November 2017 (online)
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.
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References
- 1 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231.
- 2 Simioni P, Tormene D, Tognin G. et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009; 361: 1671-1675.
- 3 Chang J, Jin J, Lollar P. et al. Changing residue 338 in human factor IX from ar-ginine to alanine causes an increase in catalytic activity. J Biol Chem 1998; 273: 12089-12094.
- 4 Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA 1977; 74: 5260-5264.
- 5 Cantore A, Nair N, Della Valle P. et al. Hyperfunctional coagulation factor IX improves the efficacy of gene therapy in haemophilic mice. Blood 2012; 120: 4517-4520.
- 6 Lorand L. Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann NY Acad Sci 2001; 936: 291-311.
- 7 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21: 131-142.
- 8 Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol 2000; 20: 2511-2518.
- 9 Mosnier LO, Bouma BN. Regulation of fibrinolysis by thrombin activatable fi-brinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 2006; 26: 2445-2453.
- 10 Semeraro F, Piro D, Rossiello MR. et al. Profibrinolytic activity of the direct thrombin inhibitor melagatran and unfractionated heparin in platelet-poor and platelet-rich clots. Thromb Haemost 2007; 98: 1208-1214.
- 11 Ammollo CT, Semeraro F, Semeraro N. et al. The contribution of anti-Xa and anti-IIa activities to the profibrinolytic activity of low-molecular-weight hepa-rins. Thromb Haemost 2009; 101: 782-785.
- 12 Ammollo CT, Semeraro F, Incampo F. et al. Dabigatran enhances clot susceptibility to fibrinolysis by mechanisms dependent on and independent of throm-bin-activatable fibrinolysis inhibitor. J Thromb Haemost 2010; 8: 790-798.
- 13 Binette TM, Taylor Jr. FB, Peer G. et al. Thrombin-thrombomodulin connects coagulation and fibrinolysis: more than an in vitro phenomenon. Blood 2007; 110: 3168-3175.
- 14 von dem Borne PA, Meijers JC, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86: 3035-3042.
- 15 Asakai R, Chung DW, Davie EW. et al. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991; 325: 153-158.
- 16 Lisman T, de Groot PG, Meijers JC. et al. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 2005; 105: 1102-1105.
- 17 van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-2859.
- 18 Eichinger S, Schönauer V, Weltermann A. et al. Thrombin-activatable fibrinoly-sis inhibitor and the risk for recurrent venous thromboembolism. Blood 2004; 103: 3773-3776.
- 19 Colucci M, Binetti BM, Tripodi A. et al. Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism. Blood 2004; 103: 2157-2161.
- 20 Hemker HC, Al Dieri R, De Smedt E. et al. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost 2006; 96: 553-561.
- 21 Buyue Y, Sheehan JP. Fucosylated chondroitin sulfate inhibits plasma thrombin generation via targeting of the factor IXa heparin-binding exosite. Blood 2009; 114: 3092-3100.
- 22 Davie EW. A brief historical review of the waterfall/cascade of blood coagulation. J Biol Chem 2003; 278: 50819-50832.
- 23 Ratnoff OD, Colopy JE. A familial haemorrhagic trait associated with a deficiency of a clot-promoting fraction of plasma. J Clin Invest 1955; 34: 602-613.
- 24 von dem Borne PAK, Bajzar L, Meijers JCM. et al. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997; 99: 2323-2327.
- 25 Orfeo T, Butenas S, Brummel-Ziedins KE. et al. The tissue factor requirement in blood coagulation. J Biol Chem 2005; 280: 42887-42896.
- 26 Nesheim M. Thrombin and fibrinolysis. Chest 2003; 124: 33S-39S.
- 27 Finn JD, Nichols TC, Svoronos N. et al. The efficacy and the risk of immunoge-nicity of FIX Padua (R338L) in haemophilia B dogs treated by AAV muscle gene therapy. Blood 2012; 120: 4521-4523.
- 28 Schuettrumpf J, Herzog RW, Schlachterman A. et al. Factor IX variants improve gene therapy efficacy for haemophilia B. Blood 2005; 105: 2316-2323.