FV HR2 Haplotype as Additional Inherited Risk Factor for Deep Vein Thrombosis in Individuals with a High-Risk Profile

Maurizio Margaglione; Anna Bossone; Donatella Coalizzo; Giovanna D’Andrea; Vincenzo Brancaccio; Antonio Ciampa; Elvira Grandone; Giovanni Di Minno

doi:10.1055/s-0037-1612939

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 87(01): 32-36
DOI: 10.1055/s-0037-1612939

Review Article

Schattauer GmbH

FV HR2 Haplotype as Additional Inherited Risk Factor for Deep Vein Thrombosis in Individuals with a High-Risk Profile

Authors

Maurizio Margaglione

¹Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
Anna Bossone

¹Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
Donatella Coalizzo

¹Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
Giovanna D’Andrea

¹Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
Vincenzo Brancaccio

²Divisione di Ematologia, Unità di Coagulazione, Ospedale “A. Cardarelli”, Napoli
Antonio Ciampa

³Divisione di Ematologia, Ospedale “G. Moscati”, Avellino
Elvira Grandone

¹Unita’ di Aterosclerosi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo
Giovanni Di Minno

⁴Istituto di Medicina Interna e Geriatria, Università di Palermo, Italy

Abstract

Summary

A number of strongly linked polymorphisms within the Factor V gene (FV HR2 haplotype) has been identified as a cause of resistance to activated protein C, and has suggested a modest risk factor for vein thrombosis. We investigated the frequency of the HR2 haplotype in 433 consecutive patients with confirmed deep vein thrombosis and 326 controls. The HR2 haplotype was more frequent in patients (15.2%) than in controls (10.1%). The risk of thrombosis among carriers of this haplotype was significantly increased (odds ratio: 1.6 [95% CI: 1.0-2.5]). The estimated risk associated with the HR2 haplotype was 1.8 (95% CI: 1.1-2.9) in subjects with (n = 255), and 1.4 (95% CI: 0.8-2.4) in those without (n = 178) acquired risk factors for vein thrombosis. After adjustment for sex, FV Leiden and FII A²⁰²¹⁰ mutations, the estimated risk of vein thrombosis among carriers of the HR2 haplotype was 1.8 (95% CI: 1.1-2.8). Present data indicate that the HR2 haplotype is independently associated with vein thrombosis among individuals with a highrisk profile.

Keywords

HR2 haplotype - FV gene - inherited risk factors - vein thrombosis

Full Text

References

References
1 Kniffin WD, Baron JA, Barret J, Birkmeyer JD, Anderson Jr FA. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154: 861-6.
2 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia. Pathogenesis, clinical syndromes and management. Blood 1996; 87: 3531-44.
3 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia. Part 1. Thromb Haemost 1996; 76: 651-62.
4 Poort SR, Rosendal 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.
5 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol 1997; 98: 353-5.
6 Margaglione M, Brancaccio V, Giuliani N, D’Andrea G, Cappucci G, Iannaccone L, Vecchione G, Grandone E, Di Minno G. Increased risk of venous thrombosis in carriers of the prothrombin A²⁰²¹⁰ gene variant. Ann Intern Med 1998; 129: 89-93.
7 Bernardi F, Faioni EM, Castoldi E, Lunghi B, Castaman G, Sacchi E, Mannucci PM. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997; 90: 1552-7.
8 Castoldi E, Rosing J, Girelli D, Hoekma L, Lunghi B, Mingozzi F, Ferraresi P, Friso F, Corrocher R, Tans G, Bernardi F. Mutations in the R2 FV gene affect the ratio between the two FV isoforms in plasma. Thromb Haemost 2000; 83: 362-5.
9 Hoekma L, Castoldi E, Tans G, Girelli D, Gemmati D, Bernardi F, Rosing J. Functional properties of Factor V and Factor Va envoded by the R2-gene. Thromb Haemost 2001; 85: 75-81.
10 Alhenc-Gelas M, Nicaud V, Gandrille S, van Dreded P, Amiral J, Aubry ML, Fiessinger JN, Emmerich J, Aiach M. The factor V gene A4070G mutation and the risk of venous thrombosis. Thromb Haemost 1999; 81: 193-7.
11 Faioni EM, Franchi F, Bucciarelli P, Margaglione M, De Stefano V, Castaman G, Finazzi G, Mannucci PM. Co-inheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thrombosis to carriers of factor V R506Q (factor V Leiden). Blood 1999; 94: 3062-4.
12 Luddington R, Jackson A, Pannerselvam S, Brown K, Baglin T. The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost 2000; 83: 204-8.
13 De Visser MCH, Guash JF, Kamphuisen PW, Vos HL, Rosendaal FR, Bertina RM. The HR2 haplotype of factor V: effects on factor V levels, normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost 2000; 83: 577-82.
14 Frezzato M, Tosetto A, Rodeghiero F. Validated questionnaire for the identification of previous personal or familial venous thromboembolism. Am J Epidemiol 1996; 143: 1257-65.
15 Margaglione M, D’Andrea G, D’Addedda M, Giuliani N, Cappucci G, Iannaccone L, Vecchione G, Grandone E, Brancaccio V, Di Minno G. The Methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A²⁰²¹⁰ mutations. Thromb Haemost 1998; 79: 907-11.
16 Koeleman BPC, Reitsma PH, Allart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-5.
17 Heijboer H, Brandjes D, Büller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deepvein thrombosis. N Engl J Med 1990; 323: 1512-6.
18 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell 1993; 72: 477-80.
19 Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999; 130: 643-50.
20 De Visser MCH, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-6.
21 Váradi K, Rosing J, Tans G, Pabinger I, Keil B, Schawarz HP. Factor V enhances the cofactor function of protein S in the APC-mediated inactivation of factor VIII. Influence of the Factor V R506Q mutation. Thromb Haemost 1996; 76: 208-14.
22 Koeleman BPC, van Rumpt D, Halmulyàk K, Reitsma PH, Bertina RM. Factor V leiden. An additional risk factor for thrombosis in protein S deficient families? Thromb Haemost 1995; 74: 580-3.
23 Gandrille S, Greengard JS, Alhenc-Gelas M, Juhan-Vague I, Abgrall JF, Jude B, Griffin JH, Aiach M. and the French Network on behalf of INSERM. Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein Cdeficient patients. Blood 1995; 86: 219-24.
24 van Boven HH, Reitsma PH, Rosendaal FR, Bayston TA, Chowdhury V, Bauer KA, Scharrer I, Conard J, Lane DA. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75: 417-21.
25 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-9.
26 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
27 Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999; 82: 610-9.