LETTER TO THE EDITOR Clinical variability of haemophilia A and B in Mexican families by factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T/A1298C J. J. LO ´ PEZ-JIME ´ NEZ,*  C. P. BELTRA ´ N-MIRANDA, à J. M. MANTILLA-CAPACHO,   M. A. ESPARZA-FLORES,§ L. C. LO ´ PEZ GONZA ´ LEZ – and A. R. JALOMA-CRUZ* *Divisio ´n de Gene ´tica, Centro de Investigacio ´ n Biome ´dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Me ´xico;  Doctorado en Gene ´ tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Me ´xico; àDepartamento de Salud y Bienestar, Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzma ´ n, Jalisco, Me ´xico; §Servicio de Hematologı ´a, Hospital de Pediatrı ´a, Centro Me ´dico de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Me ´xico; and –Servicio de Hematologı ´a, Hospital General de Zona No. 46, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Me ´xico Different reports [1–4] and meta-analysis studies [5] have demonstrated that clinical variability in hae- mophilia may be explained by natural anticoagulants [1] and the concomitant presence of mutations related to thrombotic risk (TR), such as FV G1691A (FV Leiden) [2,4] or FII G20210A [3,4]. The co-expression of thrombophilic mutations theo- retically may influence the general nature and the phenotype of the bleeding symptoms in individuals with haemophilia, including the severity of bleeding, the inclination to bleed spontaneously, the response of bleeds to various treatment strategies and the sites and/or number of haemarthroses. However, the attenuation of haemophilia phenotype has not been evident uniformly in previously reported cases [5]. Alternatively, haemophilic carriers of the TR muta- tions may experience reduced haemorrhagic tenden- cies after major surgeries, or could be prone to increased venous thromboembolism (VTE) risks and could be candidates for more aggressive VTE pro- phylaxis protocols [6]. In those patients with mild or moderate severity haemophilia, the screening for TR mutations prior to major orthopaedic or other surgeries may be particularly important since their endogenous FVIII/FIX levels are higher and the physiological potential for concurrent TR mutations to trigger a thrombotic event is greater, especially after the administration of large amounts of clotting factor replacement therapies with resultant high levels of clotting factor activity [6]. To determine the frequency of TR mutations in a Mexican haemophilia population and to evaluate their clinical effects, we screened 257 Mexican haemophilia patients from 196 independent families. Three HA and two HB families were positive for FV Leiden or FII G20210A. To evaluate an additional TR effect in the positive families, we tested the MTHFR polymorphisms C677T/A1298C in 18 affected individuals. We evaluated their clinical symptoms and analyzed the attenuation of haemor- rhagic symptoms according to the presence of TR markers among family members. Genotyping of FV Leiden and FII G20210A was done using a duplex PCR assay [7]. For MTHFR (C677T) [8] and MTHFR (A1298C) [9], the methods were carried out according to the conditions described by the reported authors. Amplified alleles were observed by electrophoresis in silver nitrate- stained polyacrylamide gel. All patients gave written consent to participate in the study. All research procedures and management of the participants received official institutional approval by the Research and Ethics committees (registration #CLIS 1305-IMSS 2003249014). Clin- ical diagnosis of HA and HB was verified by clotting times and quantification of FVIII and FIX by the one- stage clotting assay. Clinical severity and haemo- philia symptoms in patients were assessed by a questionnaire (verified by patients’ haematologists) Correspondence: A. R. Jaloma Cruz, PhD, Centro de Investigacio ´n Biome ´dica de Occidente, IMSS, Sierra Mojada 800, Col. Independencia, C.P. 44340, A.P. 1-3838, Guadalajara, Jalisco, Me ´xico. Tel.: +52 33 36189410; fax: +52 33 36181756; e-mail: arjaloma@gmail.com; jesuslopezqfb@yahoo.com.mx Accepted after revision 26 May 2009 Haemophilia (2009), 1–4 DOI: 10.1111/j.1365-2516.2009.02069.x Ó 2009 Blackwell Publishing Ltd 1