Elevated coagulation factor VIII and the risk for recurrent early pregnancy loss

Summary

Inherited and acquired thrombophilia are associated with recurrent pregnancy loss. Recently, an increased risk for thromboembolic disease was described for patients with elevated coagulation factor VIII, but it is unknown whether there is also an association to early pregnancy loss. We therefore evaluated the relation between recurrent early pregnancy loss and levels of coagulation factor VIII. We enrolled 49 unrelated Caucasian women with a history of 2 6 early pregnancy losses and 48 healthy controls, who had delivered at least one term infant and had never experienced pregnancy loss. We determined factor V Leiden-, G20210A prothrombin-, MTHFR C677Tand A1298Cgene mutations, levels of antithrombin, protein C, protein S, factor VIII, C-reactive protein and antiphospholipid antibodies. There was a significantly higher rate of pregnancy losses in women with Antiphospholipid Syndrome (p = 0.043). Furthermore, plasma levels of coagulation factor VIII were significantly higher in cases than in controls (130.5 IU/dl ± 25.4 vs 119.5 IU/dl ± 24.1; p = 0.032) and appeared independent of Creactive protein (R = 0.146, p = 0.323 in cases; R = 0.028, p = 0.850 in controls). The relative risk for recurrent pregnancy loss in women with factor VIII levels above 151 IU/dl (90^th percentile of controls) was 2.5 (0.7 – 8.9, 95 percent confidence interval), for levels above 156 IU/dl (95^th percentile of controls) 3.9 (0.8 – 20.0, 95 percent confidence interval). Elevated maternal plasma levels of coagulation factor VIII tend to be associated with an increased risk for recurrent early pregnancy loss.

Keywords

Antiphospholipid syndrome - coagulation factor VIII - pregnancy loss - thrombophilia

• References

• 1 Kupferminc MJ. et al.. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340 (01) 9-13.
• 2 Walker ID. Thrombophilia in pregnancy. J Clin Pathol 2000; 53: 573-80.
• 3 Sanson BJ. et al.. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women. Thromb Haemost 1996; 75 (03) 387-8.
• 4 Brenner B. Inherited thrombophilia and pregnancy loss. Thromb Haemost 1999; 82 (02) 634-40.
• 5 Blumenfeld Z, Brenner B. Thrombophiliaassociated pregnancy wastage. Fertil Steril 1999; 72 (05) 765-74.
• 6 Lockshin MD. Pregnancy loss in the Antiphospholipide Syndrome. Thromb Haemost 1999; 82 (02) 641-8.
• 7 Martinelli I, Taioli E, Cetin I. et al.. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343 (14) 1015-8.
• 8 Preston FE. et al.. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-6.
• 9 Glueck CJ. et al.. The 4G/4G polymorphism of the hypofibrinolytic plasminogen activator inhibitor type 1 gene: an independent risk factor for serious pregnancy complications. Metabolism 2000; 49 (07) 845-52.
• 10 Gris JC. et al.. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study. Thromb Haemost 1997; 77 (06) 1096-103.
• 11 Gris JC. et al.. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent – the Nimes Obstetricians and Haematologists Study 5 (NOHA5). Thromb Haemost 1999; 81 (06) 891-9.
• 12 Gris JC, Quere I, Sanmarco M. et al.. Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. The Nimes Obstetricians and Haematologists Study—NOHA. Thromb Haemost 2000; 84 (02) 228-36.
• 13 Koster T, Blann AD, Briet E. et al.. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345 8943 152-5.
• 14 Kraaijenhagen RA. et al.. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
• 15 O’Donnell J, Tuddenham EG, Manning R. et al.. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77 (05) 825-8.
• 16 O’Donnell J. et al.. Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2000; 83 (01) 10-13.
• 17 Kamphuisen PW. et al.. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost 1999; 81 (05) 680-3.
• 18 Brandt JT. et al.. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/ Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 1995; Oct 74 (04) 1185-90.
• 19 Hezard N. et al.. Detection of factor V Leiden using ASO (allele specific oligonucleotide). Thromb Haemost 1997; 78 (04) 1296.
• 20 Oberkanins C, Moritz A, Kury F. Reversehybridization analysis of multiple genetic risk factors for cardiovascular disease. Thromb Haemost. 2001 86. Suppl 863.
• 21 Kahn S, Rey E, David MM. Factor V Leiden and fetal loss: a meta-analysis by type and tyming of fetal loss. Blood 2001; 98 (11) 50a.
• 22 Eldor A. Thrombophilia, thrombosis and pregnancy. Thromb Haemost 2001; 86: 104-11.
• 23 Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 1999; Jun 71 (06) 1048-53.
• 24 Sarig G. et al.. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002; Feb 77 (02) 342-7.
• 25 Mansvelt EP, Laffan M, McVey JH. et al.. Analysis of the F8 gene in individuals with high plasma factor VIII: C levels and associated venous thrombosis. Thromb Haemost 1998; Oct 80 (04) 561-5.
• 26 Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; May 21 (05) 731-8.
• 27 Blanco AN. et al.. A chromogenic substrate method for detecting and titrating anti-factor VIII antibodies in the presence of lupus anticoagulant. Haematologica 2002; 87 (03) 271-8.
• 28 Kjellberg U. et al.. APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb Haemost 1999; 81 (04) 527-31.
• 29 Craven CM, Chedwick LR, Ward K. Placental basal plate formation is associated with fibrin deposition in decidual veins at sites of trophoblast cell invasion. Am J Obstet Gynecol 2002; 186 (02) 291-6.
• 30 O’Donnell J. et al.. Marked elevation of thrombin generation in patients with elevated FVIII:C and venous thromboembolism. Br J Haematol 2001; Dec 115 (03) 687-91.
• 31 Nielsen S, Hahlin M. Expectant management of first-trimester spontanous abortion. Lancet 1995; 345: 84-6.
• 32 Sheppard BL, Bonnar J. Uteroplacental hemostasis in intrauterine fetal growth retardation. Semin Thromb Hemost 1999; 25 (05) 443-6.
• 33 Schambeck CM. et al.. Familial clustering of high factor VIII levels in patients with venous thromboembolism. Arterioscler Thromb Vasc Biol 2001; Feb 21 (02) 289-92.