Factor V Leiden Mutation and Thrombin Activatable Fibrinolysis
Transcription
Factor V Leiden Mutation and Thrombin Activatable Fibrinolysis
Factor V Leiden Mutation and Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Polymorphisms are Mild Genetic Modifiers of Hemorrhagic Phenotype in Haemophilia H. Chambost1,2,3, P. Morange1, C. Rothschild4, A. Doncarli8, N. Saut1, J. Goudemand5, C. Guérois6, C. Gerdil7, D. Costagliola2, I. Juhan-Vague1 and T. Calvez2 for the FranceCoag Network9 Inserm U626 Mediterranean University Marseille1; Inserm U720 Paris2; Hemophilia Treatment Centers of Marseille3, Paris-Necker4, Lille5 & Tours6; EFS Annemasse7; Institut de Veille Sanitaire (InVS) St-Maurice8; http://www.francecoag.org9 - France FranceCoag Cohort : Background for the Study design Between 1994 and 2002, 1400 hemophiliacs from 40 centers entered the French survey “SNH” that was originally designed for main objectives of pharmacosurveillance. This project included a database with items related to the patients’ hemorrhagic profile and a centralized blood sample bank. Since 2003, the ongoing multicenter prospective cohort FranceCoag Network extends the SNH cohort, providing helpful tools for research projects, following approval of the steering committee, physicians’ agreement and patients’ informed consent. Results Rationale The hemorrhagic phenotype, that is related to the titer of deficit factor in hemophilia, may be more heterogeneous than expected : some severe hemophiliacs demonstrating moderate phenotype. The role of prothrombotic factors as genetic modifiers of the hemorrhagic phenotype has been suspected, but results of previous studies in which Factor V Leiden (FVL) appears as the most relevant candidate remain to be strengthened. Our study aimed to verify or to demonstrate (?) if FVL or other markers in the field of thrombosis and fibrinolysis are related to the phenotype in severe and moderate hemophilia. hemophilia Pourquoi ne pas parler aussi du TAFI? "Prevalence des génotypes FII Leiden (2.6%) du FV Leiden (4.9%) et des génotypes du TAFI sont comparables à la population générale" Significantly reduced numbers of bleedings and/or CED were observed observed in patients with FVL (p 0.008; p 0.005) and TAFI polymorphisms Ala147Thr (NS; p 0.044) & T+1583A (p 0.048; p 0.001) (1713 person-year multivariate analysis with 1833 follow-up periods) Conclusion Even if the phenotype of hemophilia is chiefly predicted by the AHF titer, that is clearly verified in our multivariate analysis, our study confirms that FVL and also polymorphisms of TAFI may be mild genetic modifiers of the bleeding pattern. Further studies including plasmatic dosages of TAFI might be of interest to strengthen these findings. However, such genetic modifiers of the phenotype do not appear strong enough to bear relevant therapeutic concerns, for instance by modifying the indication of prophylaxis regimen. Criteria of bleeding phenotype according to polymorphisms and cofactors Number of hematomas/hemartroses / year (weighted mean and CI 95%) 390 Patients Severe or moderate hemophilia A or B Year of birth [1980; 1999] 23 French hemophilia centers at least 1 PBMC sample available for research Methods PCR assays / 9 Genetic Markers Number of CED / year (weighted mean and CI 95%) (Age at first treatment (months) : mean and CI 95% FVL & Prothrombin G20210A (FIIL) genotypes Polymorphisms of : Tissue Factor (TF) -1208(Ins/Del?), Tissue Factor Pathway Inhibitor (TFPI) -33(T->C) Thrombin activatable fibrinolysis inhibitor (TAFI) C-2599G, Ala147Thr, Thr325Ile, C+1542G & T+1583A End points - Cofactors - Statistics Data from 1833 followfollow-up visits : Hematomas / hemarthrosis (yearly number) Age at first treatment Cumulative exposure days (CED)* Amount of product (yearly consumption)* *periods without prophylaxis, nor surgery, nor inhibitor Type of hemophilia - AHF titer - Age - Calendar period Multivariate robust linear regression analyses with cluster option for intrapatient correlation S means a significant association (p<0,050) Participants to the study : Hemophilia care centers (physicians) : Hôpital Necker, Paris (C Rothschild, MF Torchet, N Pertuiset); CHU de Bicêtre, Kremlin Bicêtre (T Lambert, Y Laurian, R d’Oiron, A Rafowicz); Hôpital Trousseau, Tours (C Guérois, Y. Gruel); CHRU la Timone, Marseille (H Chambost, K Pouymayou); Hôpital de Purpan, Toulouse (S Claeyssens, P Sié); Hôpital Cardiologique, Lille (J Goudemand, P Renom, N Trillot, B Wibaut); Centre Médical Rey-Leroux, La Bouexière (B Coatmelec); Hôpital de Brabois, Vandœuvre-lès-Nancy (ME Briquel); CHRU de Nantes, Nantes (E Fressinaud, M Fiks-Sigaud, M Trossaërt, S Voisin); CHU Hautepierre, Strasbourg (A Faradji, P Lutz); Hôpital Pellegrin Tripode, Bordeaux (AM Ferrer, V Guérin, M Micheau, A Ryman); Hôpital Debrousse, Lyon (A Durin-Assollant); EFS du Chesnay, Le Chesnay (J Peynet, B Bastenaire); CHR Brest - Hôpital Morvan, Brest (B Pan-Petesch); CHRU Hôpital Nord, Saint-Étienne (C Berger, J Reynaud); CHU Dupuytren, Limoges (L De Lumley, S Gaillard, S Giraud, A Julia); Hôpital Jean Minjoz, Besançon (MA Bertrand); CHRU de Caen, Caen (A Borel-Derlon, P Gautier); Hôpital Charles Nicolle, Rouen (JY Borg, V Le Cam-Duchez, P Schneider, JP Vannier); CHR Hôpital Nord, Amiens (J Diéval, A Voyer, JJ Lefrere); Centre Hospitalier de Bastia, Bastia (O Pincemaille, J Nguyen); CHR Bocage Sud, Dijon (F Dutrillaux, JL Lorenzini, F Volot); Centre Hospitalier Général, Chambéry (V Gay) Coordinating Center InVS, Saint-Maurice : J Donadieu, A Doncarli, V Demiguel Héritier, A Doussin International Cell Bank, EFS Anemasse : C Gerdil, C Morel. Inserm U626 Marseille : P Morange, N Saut, MF Aillaud, MC Alessi, I Juhan Vague Inserm U720, Paris : T Calvez, D Costagliola • Lee DH et al (2000) Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 83:387-91 • Escuriola Ettingshausen C et al (2001) Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. Thromb Haemost 85:218-20 • Calvez T et al (2001) The French haemophilia cohort: rationale and organization of a long-term national pharmacosurveillance system. Haemophilia 7:82-88