Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence

Kristina Sundquist; Xiao Wang; Peter J. Svensson; Jan Sundquist; Anna Hedelius; Sara Larsson Lönn; Bengt Zöller; Ashfaque A. Memon

doi:10.1160/TH15-01-0031

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 114(06): 1156-1164
DOI: 10.1160/TH15-01-0031

Coagulation and Fibrinolysis

Schattauer GmbH

Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence

Kristina Sundquist

¹Center for Primary Care Research, Lund University, Malmo, Sweden

²Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California, USA

,

Xiao Wang

¹Center for Primary Care Research, Lund University, Malmo, Sweden

,

Peter J. Svensson

³Clinical Coagulation Research Unit, Lund University, Malmo, Sweden

,

Jan Sundquist

¹Center for Primary Care Research, Lund University, Malmo, Sweden

²Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California, USA

,

Anna Hedelius

¹Center for Primary Care Research, Lund University, Malmo, Sweden

,

Sara Larsson Lönn

¹Center for Primary Care Research, Lund University, Malmo, Sweden

,

Bengt Zöller

¹Center for Primary Care Research, Lund University, Malmo, Sweden

,

Ashfaque A. Memon

¹Center for Primary Care Research, Lund University, Malmo, Sweden

› Author Affiliations

Abstract

Summary

Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmö Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5–3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3–2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent.

Keywords

Fibrinolysis - plasminogen - PAI-1 polymorphism - recurrence - venous thromboembolism

Full Text

References

References
1 Anderson Jr. FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933-938.
2 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-593.
3 Prandoni P, Lensing AW, Cogo A. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
4 Heit JA, Mohr DN, Silverstein MD. et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000; 160: 761-768.
5 Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet 2005; 365: 1163-1174.
6 Lijfering WM, Rosendaal FR, Cannegieter SC. Risk factors for venous thrombosis – current understanding from an epidemiological point of view. Br J Haematol 2010; 149: 824-833.
7 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107: I4-8.
8 Eichinger S, Heinze G, Jandeck LM. et al. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010; 121: 1630-1636.
9 Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recurrent venous thrombosis. Lancet 2010; 376: 2032-2039.
10 De Stefano V, Simioni P, Rossi E. et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants anti-thrombin, protein C and protein S. Haematologica 2006; 91: 695-698.
11 Ho WK, Hankey GJ, Quinlan DJ. et al. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166: 729-736.
12 Labropoulos N, Spentzouris G, Gasparis AP. et al. Impact and clinical significance of recurrent venous thromboembolism. Br J Surg 2010; 97: 989-999.
13 Ribeiro DD, Lijfering WM, Barreto SM. et al. Epidemiology of recurrent venous thrombosis. Brazil J Med Biol Res 2012; 45: 1-7.
14 Eichinger S, Schonauer V, Weltermann A. et al. Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism. Blood 2004; 103: 3773-3776.
15 Meltzer ME, Bol L, Rosendaal FR. et al. Hypofibrinolysis as a risk factor for recurrent venous thrombosis; results of the LETS follow-up study. J Thromb Hae-most 2010; 08: 605-607.
16 Burzotta F, Di Castelnuovo A, Amore C. et al. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in Italians: a model of gene-environment interaction. Thromb Haemost 1998; 79: 354-358.
17 Segui R, Estelles A, Mira Y. et al. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol 2000; 111: 122-128.
18 Zoller B, Garcia de Frutos P, Dahlback B. A common 4G allele in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene as a risk factor for pulmonary embolism and arterial thrombosis in hereditary protein S deficiency. Thromb Haemost 1998; 79: 802-807.
19 Stegnar M, Uhrin P, Peternel P. et al. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thromboembolism. Thromb Haemost 1998; 79: 975-979.
20 Isma N, Svensson PJ, Gottsater A. et al. Prospective analysis of risk factors and distribution of venous thromboembolism in the population-based Malmo Thrombophilia Study (MATS). Thromb Res 2009; 124: 663-666.
21 Memon AA, Sundquist J, Zoller B. et al. Apolipoprotein M and the risk of un-provoked recurrent venous thromboembolism. Thromb Res 2014; 133: 322-326.
22 Memon AA, Sundquist K, Wang X. et al. Transforming growth factor (TGF)-beta levels and unprovoked recurrent venous thromboembolism. J Thromb Thrombol 2014; 38: 348-354.
23 Margaglione M, Cappucci G, Colaizzo D. et al. The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscl Thromb Vasc Biol 1998; 18: 152-156.
24 Sveinsdottir SV, Saemundsson Y, Isma N. et al. Evaluation of recurrent venous thromboembolism in patients with Factor V Leiden mutation in heterozygous form. Thromb Res 2012; 130: 467-471.
25 Francis Jr RB, Seyfert U. Rapid amidolytic assay of protein C in whole plasma using an activator from the venom of Agkistrodon contortrix. Am J Clin Pathol 1987; 87: 619-625.
26 Giri TK, Hillarp A, Hardig Y. et al. A new direct, fast and quantitative enzyme-linked ligandsorbent assay for measurement of free protein S antigen. Thromb Haemost 1998; 79: 767-772.
27 Odegard OR, Lie M, Abildgaard U. Heparin cofactor activity measured with an amidolytic method. Thromb Res 1975; 06: 287-294.
28 Jeppesen LL, Wilhelmsen K, Nielsen LB. et al. An Insertion/Deletion polymorphism in the promoter region of the plasminogen activator inhibitor-1 gene is associated with plasma levels but not with stroke risk in the elderly. J Stroke Cerebrovasc Dis 1998; 07: 385-390.
29 van Goor ML, Gomez Garcia E, Leebeek F. et al. The plasminogen activator inhibitor (PAI-1) 4G/5G promoter polymorphism and PAI-1 levels in ischemic stroke. A case-control study. Thromb Haemost 2005; 93: 92-96.
30 Roest M, van der Schouw YT, Banga JD. et al. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000; 101: 67-70.
31 de Paula Sabino A, Ribeiro DD, Domingueti CP. et al. Plasminogen activator inhibitor-1 4G/5G promoter polymorphism and PAI-1 plasma levels in young patients with ischemic stroke. Mol Biol Rep 2011; 38: 5355-5360.
32 Wiklund PG, Nilsson L, Ardnor SN. et al. Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke: replicated findings in two nested case-control studies based on independent cohorts. Stroke 2005; 36: 1661-1665.
33 Ringelstein M, Jung A, Berger K. et al. Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults. J Neurol 2012; 259: 2287-2292.
34 Visanji JM, Seargent J, Tahri D. et al. Influence of the –675 4G/5G dimorphism of the plasminogen activator inhibitor 1 promoter on thrombotic risk in patients with factor V Leiden. Br J Haematol 2000; 110: 135-138.
35 Tsantes AE, Nikolopoulos GK, Bagos PG. et al. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost 2007; 97: 907-913.
36 Wang J, Wang C, Chen N. et al. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: a meta-analysis. Thromb Res 2014; 134: 1241-1248.
37 Middeldorp S. Evidence-based approach to thrombophilia testing. J Thromb Thrombol 2011; 31: 275-281.
38 Eriksson P, Kallin B, van ’t Hooft FM. et al. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-1855.
39 Ridker PM, Hennekens CH, Lindpaintner K. et al. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997; 95: 59-62.
40 Sartori MT, Danesin C, Saggiorato G. et al. The PAI-1 gene 4G/5G polymorphism and deep vein thrombosis in patients with inherited thrombophilia. Clin Appl Thromb Hemost 2003; 09: 299-307.
41 Diebold I, Kraicun D, Bonello S. et al. The ’PAI-1 paradox’ in vascular remodeling. Thromb Haemost 2008; 100: 984-991.
42 Meade TW, Ruddock V, Stirling Y. et al. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-1079.
43 Juhan-Vague I, Pyke SD, Alessi MC. et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 1996; 94: 2057-2063.
44 Baglin T, Luddington R, Brown K. et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523-526.
45 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-1457.
46 Levine MN, Hirsh J, Gent M. et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995; 74: 606-611.
47 Schulman S, Rhedin AS, Lindmarker P. et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med 1995; 332: 1661-1665.

Supplementary Material

Online Supplementary Material (PDF)