Recent prospective and retrospective family studies support the view that deficiencies of the naturally occurring anticoagulants (antithrombin, protein C and protein S) are of greater clinical significance than heterozygous carriage of factor V Leiden or the prothrombin gene mutation.59,76
Recent studies have been consistent with a higher risk of pregnancy-related VTE in women who are antithrombin deficient or who are homozygous for factor V Leiden, the prothrombin gene mutation or are compound heterozygotes for factor V Leiden and the prothrombin gene mutation.61,62,77,78
Women should be stratified according to both the level of risk associated with their thrombophilia (see Table below) and the presence or absence of a family history or other risk factors.79
59. Lijfering WM, Brouwer JL, Veeger NJ, Bank I, Coppens M, Middeldorp S, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives.
61. Bramham K, Retter A, Robinson SE, Mitchell M, Moore GW, Hunt BJ. How I treat heterozygous hereditary antithrombin deficiency in pregnancy. Thromb Haemost 2013;110:550–9.
62. Rogenhofer N, Bohlmann MK, Beuter-Winkler P, Würfel W, Rank A, Thaler CJ, et al. Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency. Ann Hematol 2014;93:385–92.
76. Mahmoodi BK, Brouwer JL, ten Kate MK, Lijfering WM, Veeger NJ, Mulder AB, et al. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin.
J Thromb Haemost 2010;8:1193–200.
77. Jacobsen AF, Dahm A, Bergrem A, Jacobsen EM, Sandset PM. Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms. J Thromb Haemost 2010;8:2443–9.
78. van Vlijmen EF, Veeger NJ, Middeldorp S, Hamulyák K, Prins MH, Büller HR, et al. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. Blood 2011;118:2055–61.
79. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost 2009;101:428–38.
82. Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients? Br J Haematol 2008;143:321–35.
83. Pabinger I, Schneider B; Gesellschaft fur ThromboseundHamostaseforschung (GTH) Study Group on Natural Inhibitors. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Arterioscler Thromb Vasc Biol 1996;16:742–8.
84. Bucciarelli P, Rosendaal FR, Tripodi A, Mannucci PM, De Stefano V, Palareti G, et al.; GIRTE (Italian Research Group on Inherited Thrombophilia). Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study. Arterioscler Thromb Vasc Biol 1999;19:1026–33.
85. van Boven HH, Vandenbroucke JP, Briët E, Rosendaal FR. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood 1999;94:2590–4.
86. Conard J, Horellou MH, van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb
87. McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997;78:1183–8.
88. Martinelli I, Battaglioli T, De Stefano V, Tormene D, Valdrè L, Grandone E, et al.; the GIT (Gruppo Italiano Trombofilia). The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A. J Thromb Haemost 2008;6:494–8.
89. Martinelli I, Legnani C, Bucciarelli P, Grandone E, De Stefano V, Mannucci PM. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 2001;86:800–3.