Prevalence and Association of the Factor V Leiden and Prothrombin G20210A in Healthy Subjects and Patients with Venous Thromboembolism

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1 42(4): ,2001 CLINICAL SCIENCES Prevalence and Association of the Factor V Leiden and Prothrombin G20210A in Healthy Subjects and Patients with Venous Thromboembolism Désirée Coen, Renata Zadro, Lorena Honoviæ 1, Ljiljana Banfiæ 2, Ana Stavljeniæ Rukavina Clinical Institute of Laboratory Diagnostics, Zagreb University Hospital Center, Zagreb; 1 Department of Laboratory Diagnostics, Pula General Hospital, Pula; 2 Department for Cardiovascular Diseases, Zagreb University Hospital Center, Zagreb, Croatia Aim. To determine the prevalences of factor V Leiden and the G20210A mutation in the prothrombin gene (PT20210A) and the frequency of their association in healthy subjects and in patients with venous thromboembolism (VTE). Method. We studied 160 Croatian patients with at least one episode of VTE and 155 healthy subjects as a control group. Genomic DNA was extracted according to standard procedures and the presence of factor V Leiden and PT20210A were determined by polymerase chain reaction-restriction fragment length polymorphism method. Results. The prevalences of factor V Leiden and PT20210A were in VTE patients 21% and 8% respectively, and 4% in controls for both mutations. Additionally, 4 patients were affected by double heterozygous defects, corresponding to a frequency of 3%, whereas none of the controls were double heterozygotes. The coexistence of the PT20210A in heterozygous carriers of factor V Leiden was 15% in VTE group. The results obtained for different subgroups of VTE patients showed that the carriers of analyzed mutations were identified only in subgroups of patients with deep venous thrombosis of lower extremities (in 30 patients with factor V Leiden and in 13 patients with PT20210A) and superficial venous thrombosis (in 3 patients with factor V Leiden). Conclusion. The prevalences of factor V Leiden and PT20210A in analyzed population of VTE patients are higher than in the group of healthy subjects. High frequency of association between both mutations supports the need to perform simultaneous genetic analyses of factor V Leiden and PT20210A in all VTE patients. Key words: blood coagulation factors; factor V; genes; point mutation; prothrombin; thromboembolism; thrombophilia; venous thrombosis Venous thromboembolism is one of the leading causes of mortality and morbidity with the annual incidence increasing from 1:100,000 during childhood to 1:100 in old age (1). During the past few years, two new single point prothrombotic mutations in the genes coding for coagulation factor V (2) and factor II (prothrombin) (3) were identified. They represent the two most common currently known genetic risk factors for venous thromboembolism in Caucasians (2-4). The substitution of adenine for guanine at nucleotide position 1691 (G1691A) in exon 10 of the factor V gene results in the replacement of arginine at position 506 by glutamine (FV:R506Q). The resulting protein is called factor V Leiden (2). The prevalence of factor V Leiden varies between 2% and 15% in healthy Caucasian population, being more frequent in Scandinavian and northern European countries (5) but also, according to recent reports, in the Eastern Mediterranean (6). About 18% of patients with the first occurrence of deep venous thrombosis (4) and about 40% of thrombophilic families carry the mutation (2). Heterozygous carriers have 3-8-fold increased risk of venous thrombosis (4,7), whereas homozygous carriers have an 80-fold increased risk (4). The second prothrombotic mutation involves guanine-to-adenine transition at nucleotide position in the 3 -untranslated region of the prothrombin gene (G20210A). The mutation in the prothrombin gene (PT20210A) is associated with both increased plasma concentration of prothrombin and an increased risk of thrombosis (3). The reported prevalence of the mutation in Caucasian populations varies between 1% and 6%, with an overall prevalence of about 2%, found to be more frequent in southern (3%) than in northern Europe (2%) (8). This mutation was found in high prevalence (18%) in individuals from selected families with thrombosis and in 6% of unselected patients with the first occurrence of thrombosis. Heterozygous carriers of the 20210A allele have a 2.8-fold increased risk of thrombosis (3). Recent studies have shown that there is a strong interaction of factor V Leiden and the prothrombin 488

2 20210A allele (9-10). This association could increase the risk of the first thrombotic event at younger age and of repeated venous thromboembolism episodes when compared with carriers of a single defect (11-14). The fact that there were no published data on the prevalence of these two common prothrombotic genetic polymorphisms in Croatia prompted us to determine their prevalences in healthy subjects and in the population of patients with venous thromboembolism, and to identify the frequency of association of both mutations in with venous thrombolism emblism. Here we present our results. Subjects and Methods Subjects A retrospective analysis included 160 patients (57 men and 103 women) referred to the Zagreb University Hospital Center between December 1995 and May 2001 for evaluation of thrombophilia after experiencing at least 1 objectively confirmed episode of deep venous thrombosis and/or pulmonary embolism. Evidence for venous thromboembolism, site of the thrombotic event, and age at onset had been documented in their medical records. Their median age was 39 years (range, years) at the time of thrombosis and 45 years (range, years) at the time of blood sampling. Patients were divided in 4 subgroups according to the site of the thrombotic event: 138 patients had deep venous thrombosis of the lower extremities, 12 patients had superficial venous thrombosis, 3 patients had a thrombotic event in unusual sites, and 7 patients had isolated pulmonary embolism. Eight patients with deep venous thrombosis also experienced an episode of pulmonary embolism. Additional information regarding the circumstances under which they manifested the first event of venous thromboembolism (recent surgery, immobilization, pregnancy or puerperium, the use of oral contraceptives or hormone replacement therapy), the number of episodes of venous thromboembolism, previous or current use of oral anticoagulants, and a family history of venous thromboembolism was obtained by using a standardized questionnaire. The questionnaire was constructed according to the questionnaire validated for the retrospective diagnosis of venous thromboembolism (15). Trained staff interviewed the patients and recorded all relevant information. The control group consisted of 155 healthy subjects (45 men and 110 women) recruited from our hospital staff and their friends, aged years. The inclusion criterion was the lack of any personal history of a thromboembolic disorder. Methods Whole blood for DNA analysis was collected in sodium citrate (0.129 mol/l) or EDTA. Genomic DNA was prepared according to standard procedures using either phenol/chloroform extraction with ethanol precipitation (16) or the salting out method (17). The presence of factor V Leiden and the PT20210A was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A 287-bp fragment encompassing nucleotide position 1691 of factor V gene was amplified with primers, according to Zöller et al (18). Following the digestion with MnlI (Stratagene, Austin, TX, USA), the wild type allele (1691G allele) resulted in 37-bp, 93-bp, and 157-bp fragments, whereas the mutant allele (1691A allele) resulted in 130-bp and 157-bp fragments. Analysis for PT20210A was performed according to the method described by Poort et al (3). After the digestion of amplified 345-bp fragments with Hind III (Roche Diagnostics, Mannheim, Germany), the mutant A allele was cleaved in two 23-bp and 322-bp fragments, whereas the wild type G allele remained undigested. Digested PCR products were separated by electrophoresis on 1.5% agarose gels (Applied Biosystems, Foster City, CA, USA) for factor V Leiden (Fig. 1) and on Spreadex gels (Guest Elchrom Scientific, Cham, Switzerland) for PT20210A (Fig. 2). Results Among 155 healthy controls, 6 (4%) were carriers of factor V Leiden. In contrast, factor V Leiden was detected in 33 out of 160 patients (21%). Six out of 155 healthy controls (4%), and 13 out of 160 patients (8%) were carriers of PT20210A (Table 1). Among carriers of factor V Leiden, 5 healthy controls (3%) were found to be heterozygous and 1 (1%) homozygous, whereas 27 patients (17%) were heterozygotes and 6 (4%) were homozygotes. All carriers of PT20210A were heterozygotes; no homozygous individual were detected either among patients or healthy controls (Table 1). Similar frequencies for factor V Leiden were observed in men (21%) and women (20%) in the patient Figure 1. Detection of factor V gene mutation (FV: R506Q) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Amplified undigested and MnlI digested fragments were separated by agarose gel electrophoresis and visualized by ethidium bromide staining. The 287-bp PCR undigested products from four separate individuals are shown in lanes 1-4. Corresponding MnlI digests of these products are shown in lanes 6-9, respectively. Lane 5 represents a 100-bp molecular weight marker. Lane 6 represents an individual heterozygous for FV: R506Q with MnlI digest fragments of 157, 130, 93, and 37 bp. Lane 7 represents an individual with normal FV genotype with MnlI digest fragments of 157, 93, and 37 bp. Lane 8 represents an individual homozygous for FV: R506Q with MnlI digest fragments of 157 and 130 bp. Digested fragments from a homozygous positive control are shown in lane 9. Figure 2. Detection of the G/A alleles in the prothrombin gene by HindIII restriction analysis. The normal GG genotype displays a 345-bp fragment, whereas two bands (345 and 322 bp) are distinctive of the GA genotype. Molecular weights (bp) of digested fragments are indicated at the right of the gel photograph. Lanes 1, 2, and 7 represent three patients with normal genotype (345-bp fragment only) whereas lanes 3-6 show digested fragments (345 and 322 bp) from four heterozygous patients. Lane 8 represents a heterozygous positive control. The molecular weight markers used are 20 bp ladder (Guest Elchrom Scientific) in lane 9 and 100 bp ladder (Pharmacia, Uppsala, Sweden) in lane

3 group. In contrast, the frequency was higher in women (5%) than in men (2%) in the control group. The frequency of PT20210A was higher in women (10%) than in men (5%) among the patients, whereas it was higher in men (7%) than in women (3%) among healthy controls (Table 2). Combined defects were identified only in the patient group; four patients (3%) were heterozygous carriers for both mutations (Table 1). The combined defect was observed in one man (2%) and three women (5%) (Table 2). The coexistence of PT20210A and factor V Leiden was identified only in heterozygous carriers of factor V Leiden with a prevalence of 15%, whereas it was not found in factor V Leiden homozygotes. Table 3 shows the results obtained for different subgroups of patients with venous thromboembolism. In the subgroup of patients with deep venous thrombosis of the lower extremities 30 out of 138 patients (22%) were carriers of the factor V Leiden (24 heterozygous and 6 homozygous) and 13 out of 138 patients (9%) were carriers of the PT20210A. All four patients with combined heterozygosity belonged to Table 1. Frequency of 1691 G/A genotypes in factor V gene and of G/A genotypes in the prothrombin gene in patients with venous thromboembolism (n=160) and in healthy control subjects (n=155) No. (%) of subjects Genotype a patients healthy controls Factor V 1691 GG 1691 GA 1691 AA Prothrombin GG GA AA Combined defect 1691 GG and PT GG 1691 GA and PT GA 1691 AA and PT GA 127 (79) 27 (17) 147 (92) 13 (8) 156 (97) 4 (3) a GG wild type; GA heterozygous; AA homozygous. 149 (96) 5 (3) 1 (1) 149 (96) 155 (100) this subgroup of patients with a corresponding prevalence of 3%. In the subgroup of patients with superficial venous thrombosis, the presence of factor V Leiden only was detected in 3 out of 12 patients (25%). All affected individuals were women and heterozygous carriers for factor V Leiden. We found neither factor V Leiden nor the PT20210A in the subgroup of patients with thrombosis in unusual sites or in the subgroup of patients with isolated PE. Discussion Factor V Leiden and PT20210A represent the two most common genetic risk factors for venous thromboembolism in Caucasians. Due to geographic and ethnic distribution of both mutations, their prevalence varies greatly in different countries (2-6,8,26). Factor V Leiden, as the most common inherited risk factor for venous thromboembolism, has been found at an average prevalence of 22%, ranging from 20% to 52% in patients with venous thromboembolism (19-22), whereas the prevalence of PT20210A is reported to be between 5% and 19% (3,23-26). In this study, the prevalences (4%) of factor V Leiden and PT20210A in healthy subjects were the same. The observed prevalence for factor V Leiden corresponded to the reported prevalence (between 2% and 15%) in the healthy Caucasian population (5). The prevalence of PT20210A that we found was higher than the overall prevalence for this mutation reported by Rosendaal et al (26) to be about 2% (8), but similar to previously reported prevalence in southern European countries, particularly around the Mediterranean area. In our study we found an overall prevalence of 21% for the factor V Leiden and 8% for PT20210A in analyzed population of patients with venous thromboembolism, which is close to the reported prevalence for both mutations in the same group of patients. After analyzing the incidence of these two mutations in the subgroups of patients (deep venous thrombosis of lower extremities, superficial venous thrombosis, thrombosis in unusual sites, and isolated Table 2. Prevalence of factor V Leiden, prothrombin gene mutation, and both mutations in patients with venous thromboembolism and healthy control subjects No. of No. (%) of subjects with Subjects subjects factor V Leiden prothrombin gene mutation factor V Leiden and prothrombin gene mutation Patients (total) men women (21) 12 (21) 21 (20) 13 (8) 3 (5) 10 (10) 4 (3) 1 (2) 3 (5) Healthy controls (total) men women (2) 5 (5) 3 (7) 3 (3) Table 3. Prevalence of factor V Leiden, prothrombin gene mutation, and both mutations in different subgroups of patients with venous thromboembolism No. of No. (%) of patients with Subgroup of patients with patients factor V Leiden prothrombin gene mutation factor V Leiden and prothrombin gene mutation Deep venous thrombosis of lower extremities (22) 13 (9) 4 (3) Superficial venous thrombosis 12 3 (25) Thrombosis in unusual sites 3 Isolated pulmonary embolism 7 490

4 pulmonary embolism), we realized that all PT20210A carriers, as well as 30 of 33 identified factor V Leiden carriers were in the subgroup of patients with deep venous thrombosis of lower extremities. Accordingly, the coexistence of both mutations was attributable to this subgroup. The remaining three factor V Leiden carriers were found in the subgroup of patients with superficial venous thrombosis. This finding, together with no mutation detected in other 2 subgroups, suggested that the presence of factor V Leiden, PT20210A, or both, represented the main cause of deep venous thrombosis of lower extremities. Finding no factor V Leiden or PT20210A in cases with isolated pulmonary embolism corroborates the previous reports by Martinelli et al (27) and Ehrenforth et al (13), who found that the prevalence of factor V Leiden and PT20210A is not increased in patients with isolated pulmonary embolism. The limitations of our study is the small number of patients in the subgroups. To obtain more informative results, a larger study is needed. We observed the difference in the prevalence of PT20210A between sexes in both groups studied. We can only speculate that women who were carriers of the mutation in our patient group (10%) were more prone to develop deep venous thrombosis, whereas men with PT20210A in the group of healthy subjects (7%) seemed to be more protected. The combination of the most frequent genetic risk factors, factor V Leiden and PT20210A, has been frequently found in patients with venous thromboembolism (10-12,14). Ridker et al (28) found a prevalence of 0.4% of both mutations in individuals included in the physicians health study, of whom 1.5% had experienced venous thromboembolism and 0.3% had not. We demonstrated a high frequency of the association between both mutations (3%) among patients with deep venous thrombosis. There are numerous reports (case/control studies) of unrelated individuals showing the additional inheritance of PT20210A with factor V Leiden (11-14). Our study results, showing that these two mutations tend to coexist in a heterozygous form (15%), are similar to those reported by Ehrenforth et al (11%)(13), Zöller et al (10%)(10), and Ferraresi et al (14%)(29). In conclusion, the data presented here indicate that 29% of investigated patients with venous thromboembolism were carriers of these prothrombotic defects in contrast to 8% in controls. Additionally, our findings of frequently combined heterozygosity for these two gene defects support the need to perform simultaneous genetic analyses of factor V Leiden and PT20210A in all patients with venous thromboembolism, especially in those with deep venous thrombosis of lower extremities. References 1 Rosendaal FR. Thrombosis in the young: epidemiology and risk factors: a focus on venous thrombosis. Thromb Haemost 1997;78: Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369: Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3 -untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88: Rosendaal FR, Koster T, Vanderbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85: Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346: Irani-Hakime N, Tamim H, Kreidy R, Almawi WY. The prevalence of factor V R506Q mutation-leiden among apparently healthy Lebanese. Am J Hematol 2000;65: Ridker PM, Hennekens CH, Lindpainter K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke and venous thrombosis in apparently healthy men. N Engl J Med 1995;332: Rosendaal FR, Doggen C, Zivelin A, Arruda V, Aiach M, Siscovick D, et al. Geographic distribution of the G to A prothrombin variant. Thromb Haemost 1998;79: Bertina RM. The prothrombin 20210G to A variation and thrombosis. Curr Op Haematol 1998;5: Zöller B, Svensson PJ, Dahlbäck B, Hillarp A. The A20210 allele of the prothrombin gene is frequently associated with the factor V Arg 506 to Gln mutation but not with protein S deficiency in thrombophilic families. Blood 1998;91: Makris M, Preston FE, Beuchamp NJ, Cooper PC, Daly ME, Hampton KK, et al. Co-inheritance of the allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997;78: Ehrenforth S, Ludwig G, Klinke S, Krause M, Scharrer I, Nowak-Göttl U, et al. The prothrombin 20210A allele is frequently coinherited in young carriers of the factor V Arg 506 to Gln mutation with venous thrombophilia. Blood 1998;91: Ehrenforth S, von Depka Prondsinski M, Aygören-Pürsün E, Nowak-Göttl U, Scharrer I, Ganser A. Study of the prothrombin gene GA variant in F V:Q 506 carriers in relationship to the presence or absence of juvenile venous thromboembolism. Arterioscler Thromb Vasc Biol 1999;19: Tosetto A, Rodeghiero F, Martinelli I, de Stefano V, Missiaglia E, Chiusolo P, et al. Additional genetic risk factors for venous thromboembolism in carriers of the factor V Leiden mutation. Br J Haematol 1998;103: Frezzato M, Tosetto A, Rodeghiero F. Validated questionnaire for the identification of previous personal or familial venous thromboembolism. Am J Epidemiol 1996;143: Poncz M, Solowiejczyk D, Harpel B, Mory Y, Schwartz E, Surry S. Construction of human gene libraries from small amounts of peripheral blood: analysis of ß-like globin genes. 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5 18 Zöller B, Svensson PJ, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994;94: de Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes and management. Blood 1996;87: Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993;82: Koster T, Rosendaal FR, de Ronde H, Briet E, Vanderbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993;342: Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330: Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position in the 3 -untranslated region of the prothrombin gene. Br J Haematol 1997;98: Margaglione M, Brancaccio V, Giuliani N, D Andrea G, Capucci G, Iannacone L, et al. Increased risk for venous thrombosis in carriers of the prothrombin G A gene variant. Ann Intern Med 1998;129: Leroyer C, Mercier B, Oger E, Chenu E, Abgrall JF, Férec C, et al. Prevalence of 20210A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 1998;80: Nguyen A. Prothrombin G20210A polymorphism and thrombophilia. Mayo Clin Proc 2000;75: Martinelli I, Cattaneo M, Panzeri D, Mannucci PM. Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism. Thromb Haemost 1997;77: Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation 1999;99: Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F, et al. The heterozygous 20210G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease. Arterioscler Thromb Vasc Biol 1997;17: Received: June 15, 2001 Accepted: July 16, 2001 Correspondence to: Renata Zadro Clinical Institute of Laboratory Diagnostics Zagreb University Hospital Center Kišpatiæeva Zagreb, Croatia renata_zadro@hotmail.com 492

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