Prothrombin G20210A mutation and oral contraceptive use increase upper-extremity deep vein thrombotic risk

Summary

The role played by a hypercoagulable state, either inherited or acquired, in the pathogenesis of upper-extremity deep vein thrombosis (UEDVT) remains a question of debate. We performed a case-control study including 79 patients with a first objectively confirmed episode of UEDVT, 31 secondary and 48 primary, and 165 healthy controls. Nine patients (11.4%) with UEDVT were carriers of the prothrombin G20210A mutation vs. six (3.7%) in controls; P = 0.025, OR: 3.39 (95% CI 1.16 to 9.88). No statistical difference was observed between cases and controls for the factor V Leiden mutation, AT, protein C or protein S deficiency and anticardiolipin antibodies (ACAs). Thirteen (35.1%) UEDVT patients were oral contraceptive (OC) users vs. 12 (16%) controls; P = 0.020, OR: 2.89 (95% CI 1.16-7.21). When secondary UEDVT patients were compared with controls, no differences were observed in any of the risk factors analysed. On the other hand, when primary UEDVT was considered, six (12.5%) patients were carriers of the prothrombin G20210A mutation vs. six (3.7%) controls; P = 0.031, OR: 3.76 (95% CI 1.15-12.26). Regarding ACAs, a borderline statistical significance was observed when primary UEDVT was compared with controls, P = 0.048; OR: 4.88 (95% CI 1.05-22.61). In primary UEDVT, 52% of the fertile women were OC users vs. 16% of controls; P = 0.001, OR:5.78 (95% CI 2.13-15.67). When the interaction of both factors, i.e. prothrombin G20210A mutation and OC intake, were considered, the risk increased markedly, indicating a synergistic effect as observed with other thrombotic locations. In patients with primary UEDVT screening for antithrombin, protein C and protein S deficiency and APC resistance would not be justified, although it might be reasonable to determine the carrier status of the prothrombin G20210A mutation only in OC users.

Keywords

Prothrombin G20210A mutation - contraceptives - upper-extremity deep vein thrombosis - inherited thrombophilic risk factors - acquired thrombophilic risk factors

• References

• 1 Horattas MC, Wright DJ, Fenton AH, Evans DM, Oddi MA, Kamiensk RW, Suhields EF. Changing concepts of deep venous thrombosis of the upper extremity: report of a series and review of the literature. Surgery 1988; 104: 561-7.
• 2 Bolgiano EB, Foxwell MM, Browne BJ, Barish RA. Deep venous thrombosis of the upper extremity: diagnosis and treatment. J Emergency Med 1990; 8: 85-91.
• 3 Elliot G. Upper-extremity deep vein thrombosis. Lancet 1997; 349: 1188-9.
• 4 Martinelli I, Cattaneo M, Panzeri D, Taioli E, Mannucci PM. Risk factors for deep venous thrombosis of the upper extremities. Ann Intern Med 1997; 126: 707-11.
• 5 Ruggeri M, Castaman G, Tosseto A, Rodeghiero F. Low prevalence of thrombophilic coagulation defects in patients with deep vein thrombosis of the upper limbs. Blood Coagul Fibrinolysis 1997; 8: 191-4.
• 6 Prandoni P, Polistena P, Bernardi E, Cogo A, Casara D, Verlato F, Angelini F, Simioni P, Signorini GP, Benedetti L, Girolami A. Upper extremity deep vein thrombosis. Arch Intern Med 1997; 157: 57-62.
• 7 Héron E, Lozinguez O, Alhenc-Gelas M, Emmerich J, Fiessinger JN. Hypercoagulable states in primary upper-extremity deep vein thrombosis. Arch Intern Med 2000; 160: 382-6.
• 8 Ellis MH, Manor Y, Witz M. Risk factors and management of patients with upper limb deep vein thrombosis. Chest 2000; 117: 43-6.
• 9 Leebeek FWG, Stadhouders NAM, van Stein D, Gómez-García EB, Kappers-Klunne MC. Hypercoagulability states in upper-extremity deep venous thrombosis. Am J Hematol 2001; 67: 15-9.
• 10 Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998; 338: 1793-7.
• 11 Chamouard P, Pencreach E, Maloisel F, Grunebaum L, Ardizzone JF, Meyer A, Gaub MP, Goetz J, Baumann R, Uring-Lambert B, Levy S, Dufour P, Hauptmann G, Oudet P. Frequent Factor II G20210A mutation in idiopathic portal vein thrombosis. Gastroentero-logy 1999; 116: 144-8.
• 12 Vandenbroucke JP, Rosing J, Bloemenkamp KWM, Middeldorp S, Helmerhost FM, Bouma BN, Rosendaal FR. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527-34.
• 13 Herings RMC, Urquhart J, Leufkens HGM. Venous thromboembolism among new users of different oral contraceptives. Lancet 1999; 354: 127-8.
• 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 Gandrille S, Alhenc-Gelas M, Aiach M. A rapid screening method for the factor V Arg 506 Gln mutation. Blood Coagul Fibrinolysis 1995; 6: 245-7.
• 16 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variant in the 3’ untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 17 Rosendaal FR, Doggen JM, 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.
• 18 Alhenc-Gelas M, Le Cam-Duchez V, Emmerich J, Frebourg T, Fiessinger JN, Borg JY, Aiach M. The A20210 allele of the prothrombin gene is not frequently associated with the factor V Arg 506 to Gln mutation in thrombophilic families. Blood 1997; 90: 1711
• 19 Souto JC, Coll I, Llobet D, del Río E, Oliver A, Mateo J, Borrel M, Fontcuberta J. The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 1998; 80: 366-9.
• 20 Aznar J, Vayá A, Estellés A, Mira Y, Seguí R, Villa P, Ferrando F, Falcó C, Corella D, España F. Risk of venous thrombosis in carriers of the prothrombin G21210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000; 85: 1271-6.
• 21 Silver RM, Porter TF, van Leeuween I, Jeng G, Scott JR, Branch W. Anticardiolipin antibodies: clinical consequences of “low titers”. Obstet Gynecol 1996; 87: 494-500.
• 22 Onida P, Tresoldi M, Rugarli C. Anti-phospho-lipid antibody syndrome associated with peripheral T-cell lymphoma. Am J Hematol 1997; 55: 167-8.
• 23 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci PM. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol 1999; 19: 700-3.
• 24 Emmerich J, Rosendaal FR, Cattaneo M, Margaglione M, De Stefano V, Cumming T, Arruda V, Hillarp A, Reny JL. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thrombo-embolism. Thromb Haemost 2001; 86: 809-16.
• 25 Mira Y, Aznar J, Estellés A, Vayá A, Villa P, Ferrando F. Congenital and acquired thrombotic risk factor in women using oral contraceptives: Clinical Aspects. Clin Appl Thromb Hemost 2000; 6: 162-8.
• 26 Vayá A, García M, Mira Y, Ferrando F, Villa P, Estellés A, Aznar J. Homozygous 20210G/A prothrombin gene mutation associated with bilateral iliac vein thrombosis: a case report. Thromb Res 2001; 104: 293-6.
• 27 Santamaría A, Mateo J, Oliver A, Menéndez B, Souto JC, Borrell M, Soria JM, Tirado I, Fontcubera J. Risk of thrombosis associated with oral contraceptives of women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene. Haematologica 2001; 86: 965-71.