Factor V Leiden (G1691A) and Prothrombin Gene G20210A Mutations as Potential Risk Factors for Venous Thromboembolism after Total Hip or Total Knee Replacement Surgery

K. Wåhlander; G. Larson; T. L. Lindahl; C. Andersson; L. Frison; D. Gustafsson; A. Bylock; B. I. Eriksson

doi:10.1055/s-0037-1613052

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 87(04): 580-585
DOI: 10.1055/s-0037-1613052

Review Article

Schattauer GmbH

Factor V Leiden (G1691A) and Prothrombin Gene G20210A Mutations as Potential Risk Factors for Venous Thromboembolism after Total Hip or Total Knee Replacement Surgery

K. Wåhlander

¹Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden

²AstraZeneca R&D Mölndal, Mölndal, Sweden

,

G. Larson

¹Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden

,

T. L. Lindahl

³Department of Clinical Chemistry, University Hospital, Linköping, Sweden

,

C. Andersson

⁴Department of Orthopaedic Surgery, University Hospital, Linköping, Sweden

,

L. Frison

²AstraZeneca R&D Mölndal, Mölndal, Sweden

,

D. Gustafsson

²AstraZeneca R&D Mölndal, Mölndal, Sweden

,

A. Bylock

²AstraZeneca R&D Mölndal, Mölndal, Sweden

,

B. I. Eriksson

⁵Department of Orthopaedic Surgery, Sahlgrenska University Hospital/Ostra, Göteborg, Sweden

› Author Affiliations

Abstract

Summary

Patients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with the Factor V Leiden mutation (p = 0.09). PE were few, but significantly over-represented in both the Factor V Leiden and prothrombin gene G20210A mutated patients (p = 0.03 and p = 0.05, respectively). However, since 90% of the patients with these genetic risk factors will not suffer a VTE event, a general pre-operative genotyping is, in our opinion, of questionable value.

Keywords

Factor V Leiden mutation - prothrombin gene mutation - pulmonary embolism - deep vein thrombosis - anticoagulation

Full Text

References

References
1 Turpie AG, Levine MN, Hirsh J, Carter CJ, Jay RM, Powers PJ, Andrew M, Hull RD, Gent M. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 1986; 315: 925-9.
2 Clagett GP, Anderson Jr FA, Geerts W, Heit JA, Knudson M, Lieberman JR, Merli GJ, Wheeler HB. Prevention of venous thromboembolism. Chest 1998; 114 Suppl 531S-60S.
3 Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med 1988; 318: 1162-73.
4 Hull RD, Pineo GF. Prophylaxis of deep venous thrombosis and pulmonary embolism. Current recommendations. Med Clin North Am 1998; 82: 477-93.
5 Eriksson BI, Wille-Jørgensen P, Kälebo P, Mouret P, Rosencher N, Bosch P, Baur M, Ekman S, Bach D, Lindbratt S, Close P. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329-35.
6 Eriksson BI, Lindbratt S, Kälebo P, Bylock A, Frison L, Welin L, Dahl O, Gustafsson D. METHRO II: Dose-response study of the novel oral, direct thrombin inhibitor, H 376/95 and its subcutaneous formulation melagatran, compared with dalteparin as thromboembolic prophylaxis after total hip or total knee replacement. Haemostasis 2000; 30 (Suppl. 01) 20-1.
7 Heit JA, Colwell CW, Francis CW, Ginsberg JS, Berkowitz SD, Whipple J, Peters G. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement. Arch Intern Med 2001; 161: 2215-21.
8 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
9 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
10 Zöller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343: 1536-8.
11 Voorberg J, Roelse J, Koopman R, Buller H, Berends F, ten Cate JW, Mertens K, van Mourik JA. Association of idiopathic thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-6.
12 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: 2521-4.
13 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: 3698-703.
14 Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78: 990-2.
15 Rosendaal FR, Doggen CJM, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH. Geographic distribution of the 20210G to A prothrombin variant. Thromb Haemost 1998; 79: 706-8.
16 Svensson PJ, Benoni G, Fredin H, Björgell O, Nilsson P, Hedlund U, Nylander G, Bergqvist D, Dahlbäck B. Female gender and resistance to activated protein C (FV:Q506) as potential risk factors for thrombosis after elective hip arthroplasty. Thromb Haemost 1997; 78: 993-6.
17 Lindahl TL, Lundahl TH, Nilsson L, Andersson CA. APC-resistance is a risk factor for postoperative thromboembolism in elective replacement of the hip or knee – a prospective study. Thromb Haemost 1999; 81: 18-21.
18 Ryan DH, Crowther MA, Ginsberg JS, Francis CW. Relation of Factor V Leiden genotype to risk for acute deep venous thrombosis after joint replacement surgery. Ann Intern Med 1998; 128: 270-6.
19 Philipp CS, Diley A, Saidi P, Evatt B, Austin H, Zawadsky J, Harwood D, Ellingsen D, Barnhart E, Phillips DJ, Hooper WC. Deletion polymorphism in angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty. Thromb Haemost 1998; 80: 869-73.
20 Campos M, Morais S, Cabeda JM, Justiça B. Absence of venous thromboembolism during orthopedic surgery in patients with FV Leiden mutation or 20210 A allele of prothrombin gene. Haemostasis 2000; 30 (Suppl. 01) 35.
21 Kälebo P, Anthmyr BA, Eriksson BI, Zachrisson BE. Optimization of ascending phlebography of the leg for screening of deep vein thrombosis in thromboprophylactic trials. Acta Radiol 1997; 38: 320-6.
22 Biello DR, Mattar AG, McKnight RC, Siegal BA. Ventilation-perfusion studies in suspected pulmonary embolism. Am J Roentgenol 1979; 133: 1033-7.
23 Holm J, Zöller B, Berntorp E, Erhardt L, Dahlbäck B. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Intern Med 1996; 239: 221-6.
24 Heit JA, Elliott CG, Towbridge AA, Morrey BF, Gent M, Hirsh J. Ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement. A randomised, double-blind, placebo-controlled trial. Ann Intern Med 2000; 132: 853-61.
25 Kakkar VV, Howe CT, Flanc C, Clarke MB. Natural history of postoperative deep-vein thrombosis. Lancet 1969; 02: 230-2.
26 Haas SB, Tribus CB, Insall JN, Becker MW, Windsor RE. The significance of calf thrombi after total knee arthroplasty. J Bone Joint Surg Br 1992; 74: 799-802.
27 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briët E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-8.
28 Simmonds RE, Ireland H, Lande DA, Zöller B, García de Frutos P, Dahlbäck B. Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect. Ann Intern Med 1998; 128: 8-14.
29 Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency. Incidence and clinical features. Am J Med 1989; 87 Suppl 34-8.