Venous thromboembolism during pregnancy is not associated with persistent elevated activated protein C (APC) sensitivity ratio based on the endogenous thrombin potential

Summary

Women who are using oral contraceptives can acquire APC resistance, measured by the effect of APC on the endogenous thrombin potential (ETP). The objective of our study was to examine whether persistentAPC resistance determined with an ETP-based normalized APC sensitivity ratio (nAPCsr) is a risk marker for venous thromboembolism in women with pregnancy-associated thromboembolism. We determined the activities of antithrombin, protein C, protein S, and performed a genetic analysis of factor V Leiden G1691A, prothrombin mutation G20210A, and methylenetetrahydrofolate reductase mutation (MTHFR C677T) in 65 women with venous thromboembolism during pregnancy or the puerperium and in 114 normal women. A significantly (p<0.05) higher nAPCsr was present in normal women using hormones, in younger women (≤ 45 yrs), and in women with carrier status of factorV Leiden. In normal women without factor V Leiden a significant (p< 0.05) negative correlation of nAPCsr with age (r= –0.39),antithrombin activity (r= –0.38),protein S activity (r= –0,26),and a significant positive correlation with hormone intake (r= 0.36) was present. nAPCsr is influenced by several coagulation parameters, which are modified by the use of oral contraceptives. Consequently, a multivariate analysis of our data did not show a significant association of nAPCsr to venous thromboembolism, neither as a continuous variable (odds ratio 0.8, 95% CI 0.6–1.1, p=0.10) nor using a cutoff value (nAPCsr cut-off 3.1: odds ratio 1.2, 95% CI 0.3–5.3, p=0.77). Our study demonstrates that nAPCsr is not a risk marker for pregnancy-associated venous thromboembolism.

Keywords

Endogenous thrombin potential (ETP) - APC sensitivity ratio (nAPCsr) - venous thromboembolism - pregnancy

• References

• 1 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by a poor anticoagulant response to activated protein C.. Proc Natl Acad Sci USA 1993; 94: 1004-8.
• 2 Bertina RM, Koeleman PC, Koster T. et al Mutation in blood coagulation factor V associated with resistance to activated protein C.. Nature 1994; 369: 64-6.
• 3 Hellgren M, Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives.. Am J Obstet Gynecol 1995; 173: 210-3.
• 4 Hallak M, Senderowicz J, Cassel A. et al Activated protein R resistence (factor V Leiden) associated with thrombosis in pregnancy.. Am J Obstet Gynecol 1997; 176: 889-93.
• 5 Bokarewa MI, Bremme K, Blombäck M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy.. Br J Haematol 1996; 92: 473-8.
• 6 Rosing J, Hemker HC, Tans G. Molecular biology and pathophysiology of APC resistance. Sem Thromb Hemost 1998; 24: 329-35.
• 7 Kluft C, de Maat MPM, Heinemann LAJ. et al Importance of levonorgestrel dose in oral contraceptives for effects on coagulation.. Lancet 1999; 354: 832-3.
• 8 Curvers J, Thomassen MC, Nicolaes GA. et al Acquired APC resistance and oral contraceptives: differences between two functional tests.. Br J Haematol 1999; 105: 88-94.
• 9 Rosing J, Middeldorp S, Curvers J. et al Low-dose oral contraceptives and acquired resistance to activated protein C: a randomized cross-over study.. Lancet 1999; 354: 2036-40.
• 10 Ridker PM, Hennekens CH, Lindpaintner K. et al Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men.. N Engl J Med 1995; 332: 912-7.
• 11 Poort SR, Rosendaal FR, Reitsma PH. et al A common genetic variation 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.
• 12 Frosst P, Blom HJ, Milos R. et al A candidate genetic risk factor for vascular disease in methylenetetrahydrofolate- reductase.. Nat Genet 1995; 10: 111-3.
• 13 Kluft C, Meijer P, Gram J. et al Acquired activated protein-C resistance.. Lancet 1999; 353: 1882
• 14 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.
• 15 Tans G, Rosendaal FR, Curvers J. et al APC resistance determined with the endogenous thrombin generation potential is associated with venous thrombosis: a blinded evaluation.. Thromb Haemost 1999; 82 (suppl) abstract (640) 202-3.
• 16 Grand'Maison A, Douketis J, Bates SM. et al Endogenous thrombin potential and the risk of venous thromboembolism.. Blood 2000; 96: 95b
• 17 Kluft C. Renewed interest in haemostasis changes induced by oral contraceptives.. Thomb Haemost 2000; 84 (01) 1-3.
• 18 Heinemann LAJ, Kluft C, Spannagl M. et al The association between extrinsic activated protein C resistance and venous thromboembolism in women.. Contraception 2002; 66: 297-304.
• 19 Hoibraaten E, Mowinckel MC, de Ronde H. et al Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, doubleblind, placebo-controlled trial.. Br J Haematol 2001; 115: 415-20.