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