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Thrombin activatable fibrinolysis inhibitor and its fibrinolytic effect in normal pregnancyFiancial support: This study was supported by an unrestricted educational grant from NovoNordisk.
22 June 2004
Accepted after revision 03 September 2004
04 December 2017 (online)
We investigated changes in both thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels and its functional effect on in vitro fibrinolysis in normal pregnancy. 152 pregnant women and 31 women in the immediate postpartum period were studied, with pregnancy divided into 6 windows at 4 weekly intervals. As TAFI influences and is in turn influenced by components of the protein C (PC) pathway, its measurements were correlated with levels of soluble thrombomodulin, PC, protein S (PS) and the overall phenotype of activated PC resistance (APCR). Compared with mean TAFI levels at booking gestation (6.6 +1.2 μg/ml), levels peaked at 35-39 weeks gestation (9.6 +2 μg/ml, p = 0.001), followed by a significant drop within 24 hours of delivery (7.2 + 1.1 μg/ml). In functional terms, the mean clot lysis time (CLT) (101 + 13 min at booking) also peaked at 35-39 weeks gestation (141 + 42 min, p = 0.007) and dropped after delivery (99 + 33 min), and was significantly correlated with gestational age (r = 0.410, p = 0.001) and could be abrogated in the presence of an inhibitor to TAFI activation. A significant negative correlation was found between TAFI levels and APCR (r = −0.478, p <0.001), APCRV (r = −0.598; p <0.001), PS (r = −0.490, P <0.001) and PC (r = −0.198, p = 0.02). In summary, there is a significant increase in TAFI levels, which translates into increased CLT during pregnancy. Furthermore, changes in TAFI contribute to the increasing APCR of pregnancy.
- 1 Bremme K, Ostlund E, Almqvist I. et al. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium. Obstet Gynecol 1992; 80: 132-7.
- 2 Comeglio P, Fedi S, Liotta AA. et al. Blood clotting activation during normal pregnancy. Thromb Res 1996; 84: 199-202.
- 3 He S, Bremme K, Blomback M. A laboratory method for determination of overall haemostatic potential in plasma. I. Method design and preliminary results. Thromb Res 1999; 96: 145-56.
- 4 Lindoff C, Lecander I, Astedt B. Fibrinolytic components in individual consecutive plasma samples during normal pregnancy. Fibrinolysis 1993; 07: 190-4.
- 5 Lecander I, Astedt B. Isolation of a new specific plasminogen activator inhibitor from pregnancy plasma. Br J Haematol 1986; 62: 221-8.
- 6 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: 253-8.
- 7 Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996; 271: 16603-8.
- 8 Nesheim M, Wang W, Boffa M. et al. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997; 78: 386-91.
- 9 Wang W, Boffa MB, Bajzar L. et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998; 273: 27176-81.
- 10 Colucci M, D’Aprile AM, Italia A. et al. Thrombin activatable fibrinolysis inhibitor (TAFI) does not inhibit in vitro thrombolysis by pharmacological concentrations of t-PA. Thromb Haemost 2001; 85: 661-6.
- 11 Lijnen HR, Collen D. Fibrinolytic agents: mechanisms of activity and pharmacology. Thromb Haemost 1995; 74: 387-90.
- 12 Bajzar L, Nesheim M, Morser J. et al. Both cellular and soluble forms of thrombomodulin inhibit fibrinolysis by potentiating the activation of thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998; 273: 2792-8.
- 13 Rosing J, Tans G. Coagulation factor V: an old star shines again. Thromb Haemost 1997; 78: 427-33.
- 14 Esmon CT. The regulation of natural anticoagulant pathways. Science 1987; 235: 1348-52.
- 15 Bajzar L, Nesheim M. The effect of activated protein C on fibrinolysis in cell-free plasma can be attributed specifically to attenuation of prothrombin activation. J Biol Chem 1993; 268: 8608-16.
- 16 Mosnier LO, Meijers JC, Bouma BN. Regulation of fibrinolysis in plasma by TAFI and protein C is dependent on the concentration of thrombomodulin. Thromb Haemost 2001; 85: 5-11.
- 17 Bouma BN, Meijers JC. New insights into factors affecting clot stability: A role for thrombin activatable fibrinolysis inhibitor (TAFI; plasma procarboxypeptidase B, plasma procarboxypeptidase U, procarboxypeptidase R). Semin Hematol 2004; 41 1 Suppl 1 13-9.
- 18 Boffa MC, Valsecchi L, Fausto A. et al. Predictive value of plasma thrombomodulin in preeclampsia and gestational hypertension. Thromb Haemost 1998; 79: 1092-5.
- 19 de Moerloose P, Mermillod N, Amiral J. et al. Thrombomodulin levels during normal pregnancy, at delivery and in the postpartum: comparison with tissue-type plasminogen activator and plasminogen activator inhibitor-1. Thromb Haemost 1998; 79: 554-6.
- 20 Chetaille P, Alessi MC, Kouassi D. et al. Plasma TAFI antigen variations in healthy subjects. Thromb Haemost 2000; 83: 902-5.
- 21 Chabloz P, Reber G, Boehlen F. et al. TAFI antigen and D-dimer levels during normal pregnancy and at delivery. Br J Haematol 2001; 115: 150-2.
- 22 Schneider M, Boffa M, Stewart R. et al. Two naturally occurring variants of TAFI (Thr-325 and Ile-325) differ substantially with respect to thermal stability and antifibrinolytic activity of the enzyme. J Biol Chem 2002; 277: 1021-30.
- 23 Scott CF, Colman RW. Fibrinogen blocks the autoactivation and thrombin-mediated activation of factor XI on dextran sulfate. Proc Natl Acad Sci U S A 1992; 89: 11189-93.
- 24 Hellgren M. hemostatsis during normal pregnancy and puerperium. Semin Thromb Hemostat 2003; 29: 125-30.
- 25 Walker MC, Garner PR, Keely EJ. et al. Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 1997; 177: 162-9.
- 26 O’Riordan MN, Higgins JR. Haemostasis in normal and abnormal pregnancy. Best Pract Res Clin Obstet Gynaecol 2003; 17: 385-96.
- 27 Bajzar L, Kalafatis M, Simioni P. et al. An antifibrinolytic mechanism describing the prothrombotic effect associated with factor V Leiden. J Biol Chem 1996; 271: 22929-52.
- 28 Eichinger S, Schonauer V, Weltermann A. et al. Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism. Blood 2004; 103: 3773-6.
- 29 van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-9.
- 30 Zorio E, Castello R, Falco C. et al. Thrombinactivatable fibrinolysis inhibitor in young patients with myocardial infarction and its relationship with the fibrinolytic function and the protein C system. Br J Haematol 2003; 122: 958-65.
- 31 Antovic JP, Rafik RHamad, Antovic A. et al. Does thrombin activatable fibrinolysis inhibitor (TAFI) contribute to impairment of fibrinolysis in patients with preeclampsia and/or intrauterine fetal growth retardation?. Thromb Haemost 2002; 88: 644-7.