Mutations at the activated protein c cleavage sites a ~ ~ 3 3 6 and a ~ ~ 5 6 2 of factor viii in thai patients with venous thrombosis

Venous thrombosis is a mult~causal disease, more than one genetic risk factor may cooperate to effect thrombotic risk. Factor V Leiden is found to be an important hereditary risk factor for venous thromboembolism. Analogous to factor V Leiden, a point mutation at amino acid positions Arg336 and Arg562 i n factor VlII may predispose patients to thrombosis. Eightyone Thai patients with venous thrombosis and 100 Thai healthy volunteers have been studied. Neither heterozygous nor homozygous mutations were detected both thrombosis patients or normal volunteers. However, further studies with larger samples of venous thrombosis patients are recommended. INTRODUCTION methylene tetrahydrofolate reductase (MTHFR) C677T and recently, the two mutations involvThromboembolic diseases remain a major ing Arg306 at the APC cleavage site of factor cause of morbidity and mortality in most V (Poort et a[ . 1996; Arruda et al, 1997; Chan countries. Factor V Leiden (FVL) has been et al, 1998; Williamson et al, 1998; Bertina, known to be an important hereditary risk factor 1999). for venous thromboembolism (Rosendaal, 1999). FVL is a point mutation in the factor V gene (guanine to adenine replacement at nucleotide position 1691), causing the substitution of arginine 506 by glutamine at the cleavage site of activated protein C (APC) (Bertina et al, 1994). FVL is found predominantly in Caucasian populations, varying from 4 to 15%, depending on geographic location, but i t is rare in Asia (Rees et al, 1995). The discovery of FVL was a major stimulus for laboratories around the world to search for other genetic polymorphisrns and mutations predisposing individuals to thromboembolic events, such as prothrombin G20210A, Correspondence: Dr Wichai Prayoonwiwat, Division of Hematology, Department of Medicine, Phramongkutklao College of Medicine, Rajvithi Road, Bangkok 10400, Thailand. Tel: +66 (0) 26446997; Fax: +66(0) 26446997 E-mail: wchaipyw@med.pmk.ac.th We have investigated the FVL, Arg306 and Arg679 of the factor V gene and the G20210A of the prothrombin gene in Thai thrombotic patients and in the Thai population. We found that FVL and factor V Hong Kong (Arg306Gly) were detected 1 1 1470 and 4.3% in Thai patients with venous thrombosis (Amutti et al, 1998; Hiyoshi er al. 1999; Prayoonwiwat et a[ , 2000). Factor V is cleaved by APC at residues Arg306 and Arg506 that are homologous to residues Arg336 and Arg562 in factor VIII (Roelse et al, 1996). Analogous to FVL, a mutation at amino acid position Arg336 and Arg562 of factor VIII may predispose patients to thrombosis. Because the function of factor VIII in the coagulation system is very homologous to factor V, it is possible that any mutation on these cleavage sites can potentially affect the APC inactivation process and the APC resistant (APC-R) factor VIII may lead to hereditary thrombophilia due to its APC-R phenotype. Vol 32 No. 4 December 2001 FACTOR VIII MUTATIONS I N VENOUS THROMBOSIS In this study, we have further investigated the mutation of factor VIII. The Arg336 and Arg562 cleavage sites in factor VIII for APC inactivation were studied to ascertain whether mutations at these sites occur or have any association with patients suffering from venous