Thrombin generation and low-molecular-weight heparin prophylaxis in pregnant women with thrombophilia

Anna Selmeczi; Rachel E. J. Roach; Csaba Móré; Zoltán Batta; Jolán Hársfalvi; Johanna G. Bom van der; Zoltán Boda; Zsolt Oláh

doi:10.1160/TH14-05-0452

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(02): 283-289
DOI: 10.1160/TH14-05-0452

Coagulation and Fibrinolysis

Schattauer GmbH

Thrombin generation and low-molecular-weight heparin prophylaxis in pregnant women with thrombophilia

Anna Selmeczi

¹Center of Thrombosis and Haemostasis, Institute of Internal Medicine, University of Debrecen, Debrecen, Hungary

,

Rachel E. J. Roach

²Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

,

Csaba Móré

³Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

,

Zoltán Batta

⁴Clinical Research Center, University of Debrecen, Debrecen, Hungary

,

Jolán Hársfalvi

⁴Clinical Research Center, University of Debrecen, Debrecen, Hungary

,

Johanna G. Bom van der

²Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

,

Zoltán Boda

¹Center of Thrombosis and Haemostasis, Institute of Internal Medicine, University of Debrecen, Debrecen, Hungary

,

Zsolt Oláh

¹Center of Thrombosis and Haemostasis, Institute of Internal Medicine, University of Debrecen, Debrecen, Hungary

› Author Affiliations

Abstract

Summary

Pregnancy is associated with increased risk of venous thromboembolism, especially in the presence of thrombophilia. However, there is no consensus on the optimal approach for thromboprophylaxis in this population. Recent evidence suggests that thrombin generation correlates with the overall procoagulant state of the plasma. Our aim was to evaluate thrombin generation in a prospective cohort of thrombophilic pregnant women, and investigate the effectiveness of low-molecular- weight heparin (LMWH) prophylaxis in pregnancy. Women with severe (n=8), mild (n=47) and no (n=15) thrombophilia were followed throughout their pregnancies. Thrombin generation was evaluated in each trimester as well as five days and eight weeks postpartum (as a reference category). In women undergoing LMWH prophylaxis, thrombin generation and anti-Factor-Xa activity were measured just before and 4 hours after administration (peak effect). Thrombin generation was determined using Technothrombin TGA assay system. For the analysis, median peak thrombin and endogenous thrombin potential were used. Peak thrombin and endogenous thrombin potential were increased during pregnancy compared to the non-pregnant state with the highest results in the severe thrombophilia group. In women receiving LMWH prophylaxis a decrease was observed in thrombin generation at peak effect but over the progression of pregnancy the extent of this decrease reduced in a stepwise fashion. Our results show that thrombin generation demonstrates the hypercoagulable state in thrombophilic pregnancies. In addition, we found the effect of LMWH prophylaxis to progressively decrease with advancing stages of pregnancy.

Keywords

Thrombophilia - pregnancy - LMWH prophylaxis - thrombin generation

Full Text

References

References
1 Naess IA, Christiansen SC, Romundstad P. et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 05: 692-699.
2 Stirling Y, Woolf L, North WR. et al. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52: 176-182.
3 Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003; 29: 125-130.
4 Heit JA, Kobbervig CE, James AH. et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005; 143: 697-706.
5 Barco S, Nijkeuter M, Middeldorp S. Pregnancy and venous thromboembolism. Semin Thromb Hemost 2013; 39: 549-558.
6 Pomp ER, Lenselink AM, Rosendaal FR. et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 06: 632-637.
7 Martinelli I, Legnani C, Bucciarelli P. et al. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 2001; 86: 800-803.
8 Martinelli I, De Stefano V, Taioli E. et al. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium. Thromb Haemost 2002; 87: 791-795.
9 Robertson L, Wu O, Langhorne P. et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171-196.
10 Bates SM. Pregnancy-associated venous thromboembolism: prevention and treatment. Semin Hematol 2011; 48: 271-284.
11 Bates SM, Greer IA, Middeldorp S. et al. VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e691S-736S.
12 Roeters van Lennep JE, Meijer E, Klumper FJCM. et al. Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective?. J Thromb Haemost 2011; 09: 473-480.
13 Kovacs MJ, Keeney M, Mackinnon K. et al. Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin. Clin Lab Haematol 1999; 21: 55-60.
14 Kitchen S, Iampietro R, Woolley a M, Preston FE. Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: inter-assay variability. Thromb Haemost 1999; 82: 1289-1293.
15 Hammerstingl C. Monitoring therapeutic anticoagulation with low molecular weight heparins: is it useful or misleading?. Cardiovasc Hematol Agents Med Chem 2008; 06: 282-286.
16 Al Dieri R, De Laat B, Hemker HC. Thrombin generation: what have we learned?. Blood 2012; 26: 197-203.
17 Ay C, Dunkler D, Simanek R. et al. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2011; 29: 2099-2103.
18 Hron G, Kollars M, Binder BR. et al. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. J Am Med Assoc 2006; 296: 397-402.
19 Lutsey PL, Folsom a R, Heckbert SR, Cushman M. Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study. J Thromb Haemost 2009; 07: 1639-1648.
20 Benyo M, Flasko T, Molnar Z. et al. Follow-up of thrombin generation after prostate cancer surgery: global test for increased hypercoagulability. PLoS One 2012; 07: e51299.
21 Hemker HC, Giesen P, AlDieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-253.
22 Rosenkranz A, Hiden M, Leschnik B. et al. Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost 2008; 99: 331-337.
23 Rossetto V, Spiezia L, Dabrilli P. et al. Effect on thrombin generation of the “in vitro” addition of low-dose LMWH to plasma of healthy pregnant and nonpreg-nant women. Clin Appl Thromb 2012; 18: 331-333.
24 McLean KC, Bernstein IM, Brummel-Ziedins K. Tissue factor dependent thrombin generation across pregnancy. Am J Obstet Gynecol 2013; 207: 1-12.
25 Eichinger S, Weltermann A, Philipp K. et al. Prospective evaluation of hemos-tatic system activation and thrombin potential in healthy pregnant women with and without factor V Leiden. Thromb Haemost 1999; 82: 1232-1236.
26 Gibson PS, Newell K, Sam DX. et al. Weight-adjusted dosing of tinzaparin in pregnancy. Thromb Res 2013; 131: e71-75.
27 Gyamfi C, Cohen R, Desancho MT. et al. Prophylactic dosing adjustment in pregnancy based upon measurements of anti-factor Xa levels. J Matern Neonatal Med 2005; 18: 329-331.
28 Bombeli T, Raddatz Mueller P, Fehr J. Evaluation of an optimal dose of low-molecular-weight heparin for thromboprophylaxis in pregnant women at risk of thrombosis using coagulation activation markers. Haemostasis 2001; 31: 90-98.
29 Fox NS, Laughon SK, Bender SD. et al. Anti-factor Xa plasma levels in pregnant women receiving low molecular weight heparin thromboprophylaxis. Obstet Gynecol 2008; 112: 884-889.
30 Norris LA, Bonnar J, Smith MP. et al. Low molecular weight heparin (tinzapa-rin) therapy for moderate risk thromboprophylaxis during pregnancy. A phar-macokinetic study. Thromb Haemost 2004; 92: 791-796.
31 Rey E, Rivard GE. Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin. Int J Gynaecol Obstet 2000; 71: 19-24.
32 Smith MP, Norris LA, Steer PJ. et al. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 2004; 190: 495-501.