Calibrated automated thrombin generation in normal uncomplicated pregnancy

Summary

Pregnancy is associated with substantial changes in the haemostatic system and a six-fold higher incidence of venous thromboembolism. Conventional global tests, such as prothrombin time and activated partial thromboplastin time, do not definitely detect this hypercoagulable condition. We investigated whether the changes in haemostatic system during pregnancy are reflected in the calibrated automated thrombography (CAT). Thrombin generation was measured in platelet-poor plasma (PPP) of 150 healthy pregnant women without any pregnancy associated diseases by means of CAT. In addition, prothrombin (FII), antithrombin (AT), protein S, protein C, tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), and prothrombin fragments 1+2 (F1+2) were measured. Endogenous thrombin potential (ETP) and peak of thrombin generation increased significantly with gestational weeks, while lag time and time to peak remained unchanged. A significant increase of PAI-1,TFPI,F1+2 and TAT as well as a significant decrease of free protein S, protein S antigen, and protein S activity was observed. Levels of AT and protein C remained stable during pregnancy. Division of population in trimester of pregnancy and analysis of differences between the trimesters showed rather similar results. Our study shows that endogenous thrombin potential does increase with duration of normal uncomplicated pregnancy. Whether parameters of continuous thrombin generation will correlate with thrombembolic disease remains to be shown.

keywords

Calibrated automated thrombography - endogenous thrombin potential - pregnancyw - pregnancy - thrombin generation

• References

• 1 Stirling Y, Woolf L, North WR. et al. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52: 176-182.
• 2 Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003; 16: 153-168.
• 3 Donohoe S, Quenby S, Mackie I. et al. Fluctuations in levels of antiphospholipid antibodies and increased coagulation activation markers in normal and heparintreated antiphospholipid syndrome pregnancies. Lupus 2002; 11: 11-20.
• 4 Brenner B. Haemostatic changes in pregnancy. Thromb Res 2004; 114: 409-414.
• 5 Hellgren M, Blomback M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition. Gynecol Obstet Invest 1981; 12: 141-154.
• 6 Clark P, Brennand J, Conkie JA. et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 1166-1170.
• 7 Faught W, Garner P, Jones G. et al. Changes in protein C and protein S levels in normal pregnancy. Am J Obstet Gynecol 1995; 172: 147-150.
• 8 Gilabert J, Fernandez JA, Espana F. et al. Physiological coagulation inhibitors (protein S, protein C and antithrombin III) in severe preeclamptic states and in users of oral contraceptives. Thromb Res 1988; 49: 319-329.
• 9 Kjellberg U, Andersson NE, Rosen S. et al. APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb Haemost 1999; 81: 527-531.
• 10 Comp PC, Thurnau GR, Welsh J. et al. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986; 68: 881-885.
• 11 Cumming AM, Tait RC, Fildes S. et al. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90: 725-727.
• 12 Mathonnet F, de Mazancourt P, Bastenaire B. et al. Activated protein C sensitivity ratio in pregnant women at delivery. Br J Haematol 1996; 92: 244-246.
• 13 Ishii A, Yamada S, Yamada R. et al. t-PA activity in peripheral blood obtained from pregnant women. J Perinat Med 1994; 22: 113-117.
• 14 Kruithof EK, Tran-Thang C, Gudinchet A. et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood 1987; 69: 460-466.
• 15 Wright JG, Cooper P, Astedt B. et al. Fibrinolysis during normal human pregnancy: complex inter-relationships between plasma levels of tissue plasminogen activator and inhibitors and the euglobulin clot lysis time. Br J Haematol 1988; 69: 253-258.
• 16 McColl MD, Ramsay JE, Tait RC. et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78: 1183-1188.
• 17 Bremme K, Ostlund E, Almqvist I. et al. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium. Obstet Gynecol 1992; 80: 132-137.
• 18 de Boer K, ten Cate JW, Sturk A. et al. Enhanced thrombin generation in normal and hypertensive pregnancy. Am J Obstet Gynecol 1989; 160: 95-100.
• 19 Eichinger S, Weltermann A, Philipp K. et al. Prospective evaluation of hemostatic system activation and thrombin potential in healthy pregnant women with and without factorV Leiden. Thromb Haemost 1999; 82: 1232-1236.
• 20 Hemker HC, Giesen P, Al Dieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper-and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-253.
• 21 Ku DH, Arkel YS, Paidas MP. et al. Circulating levels of inflammatory cytokines (IL-1 beta and TNFalpha), resistance to activated protein C, thrombin and fibrin generation in uncomplicated pregnancies. Thromb Haemost 2003; 90: 1074-1079.
• 22 Sandset PM, Hellgren M, Uvebrandt M. et al. Extrinsic coagulation pathway inhibitor and heparin cofactor II during normal and hypertensive pregnancy. Thromb Res 1989; 55: 665-670.
• 23 Warr TA, Warn-Cramer BJ, Rao LV. et al. Human plasma extrinsic pathway inhibitor activity: I. Standardization of assay and evaluation of physiologic variables. Blood 1989; 74: 201-206.
• 24 Uszynski M, Zekanowska E, Uszynski W. et al. Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in amniotic fluid and blood plasma: implications for the mechanism of amniotic fluid embolism. Eur J Obstet Gynecol Reprod Biol 2001; 95: 163-166.
• 25 Butenas S, van't Veer C, Mann KG. „Normal” thrombin generation. Blood 1999; 94: 2169-2178.
• 26 Cvirn G, Gallistl S, Rehak T. et al. Elevated thrombin-forming capacity of tissue factor-activated cord compared with adult plasma. J Thromb Haemost 2003; 1: 1785-1790.
• 27 Cvirn G, Koestenberger M, Leschnik B. et al. Protein S modulates the anticoagulant action of recombinant human activated protein C: a comparison between neonates and adults. Br J Pharmacol 2005; 146: 1082-1086.
• 28 van Hylckama Vlieg A, Christiansen SC, Luddington R. et al. Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence. Br J Haematol 2007; 138: 769-774.