Changes in thrombin generation and D-dimer concentrations in women injecting enoxaparin during pregnancy and the puerperium

BMC Pregnancy and Childbirth

Roopen Arya³  J Graham Davies²  Bruce Green¹  Michael S Marsh⁴  Lara N Roberts³  Raj K Patel³  Jignesh P Patel² 

[1] Model Answers Pty Ltd, Brisbane, Australia;Institute of Pharmaceutical Science, King’s College London, London, UK;Department of Haematological Medicine, King’s Thrombosis Centre, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK;Department of Obstetrics and Gynaecology, King’s College Hospital NHS Foundation Trust, London, UK

关键词: Venous thromboembolism;    Thrombin generation;    Pregnancy;    Postpartum period;    Enoxaparin;    D-dimers;    Blood coagulation;   

Others  :  1091714
DOI  :  10.1186/s12884-014-0384-0

 received in 2014-07-04, accepted in 2014-10-27,  发布年份 2014

【 摘 要 】

Background

It is well accepted that the gravid state is hypercoagulable and a significant cause of both maternal morbidity and mortality in the Western world. Although thrombin generation is reported to be increased in pregnant women, uncertainty exists on the pattern of thrombin generation change during this time. The aim of this study is to describe thrombin generation changes and D-dimer concentrations in women injecting enoxaparin during pregnancy the postnatal period.

Methods

One hundred and twenty-three women injecting enoxaparin had their thrombin generation, as measured by Calibrated Automated Thombinography (CAT), repeatedly assayed during pregnancy, once in each trimester, at delivery and 8 weeks post-partum. Furthermore, to understand the impact enoxaparin has on D-dimer concentrations during pregnancy, D-dimer concentrations were measured monthly in the recruited women.

Results

Thrombin generation was found to increase in the first trimester (mean endogenous thrombin potential (ETP): 1391 nmol/L.min), further increasing during the second trimester (mean ETP: 1757 nmol/L.min), after which it plateaued through to delivery, where it peaked (mean ETP: 1857 nmol/L.min) and then fell back at 8 weeks post-partum (ETP: 1293 nmol/L.min). In contrast D-dimer concentrations increased exponentially during the antenatal period, despite the enoxaparin prescription.

Conclusion

Our results provide further evidence on alterations of thrombin generation during pregnancy and the postnatal period.

【 授权许可】

   
2014 Patel et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Castoldi E, Rosing J: Thrombin generation tests. Thromb Res 2011, 127:s21-s25.
• [2]Dielis AW, Castoldi E, Spronk HM, van Oerle R, Hamulyak K, Ten Cate H, Rosing J: Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost 2008, 6:125-131.
• [3]Fritsch P, Kleber M, Rosenkranz A, Fritsch M, Muntean W, Mangge H, Reinehr T: Haemostatic alterations in overweight children: Associations between metabolic syndrome, thrombin generation, and fibrinogen levels. Atherosclerosis 2010, 212:650-655.
• [4]Segers O, van Oerle R, ten Cate H, Rosing J, Castoldi E: Thrombin generation as an intermediate phenotype for venous thrombosis. Thromb Haemost 2010, 103:114-122.
• [5]Tchaikovski SN, van Vliet HA, Thomassen MC, Bertina RM, Rosendaal FR, Sandset PM, Helmerhorst FM, Tans G, Rosing J: Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb Haemost 2007, 98:1350-1356.
• [6]Bagot CN, Marsh MS, Whitehead M, Sherwood R, Roberts L, Patel RK, Arya R: The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J Thromb Haemost 2010, 8:1736-1744.
• [7]Roberts LN, Patel RK, Chitongo P, Bonner L, Arya R: African-Caribbean ethnicity is associated with a hypercoagulable state as measured by thrombin generation. Blood Coag Fibrin 2013, 24:40-49.
• [8]Brenner B: Haemostatic changes in pregnancy. Thromb Res 2004, 114:409-414.
• [9]Rosenkranz A, Hiden M, Leschnik B, Weiss EC, Schlembach D, Lang U, Gallistl S, Muntean W: Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost 2008, 99:331-337.
• [10]Dargaud Y, Hierso S, Rugeri L, Chatard B, Battie C, Gaucherand P, Negrier C, Trzeciak MC: Endogenous thrombin potential, prothrombin fragment 1 + 2 and D-dimers during pregnancy. Thromb Haemost 2010, 103:469-471.
• [11]McLean KC, Bernstein IM, Brummel-Ziedins KE: Tissue factor-dependent thrombin generation across pregnancy. Am J Obstet Gynecol 2012, 207:135.e1-6.
• [12]Joly B, Barbay V, Borg J-Y, Cam-Duchez VL: Comparison of markers of coagulation activation and thrombin generation test in uncomplicated pregnancies.Thromb Res 2013, doi:10.1016/j.thromres.2013.07.022.
• [13]Ballegeer V, Mombaerts P, Declerck PJ, Spitz B, Van Assche FA, Collen D: Fibrinolytic response to venous occlusion and fibrin fragment D-dimer levels in normal and complicated pregnancy. Thromb Haemost 1987, 58:1030-1032.
• [14]Francalanci I, Comeglio P, Liotta AA, Cellai AP, Fedi S, Parretti E, Mello G, Prisco D, Abbate R: D-dimer concentrations during normal pregnancy, as measured by ELISA. Thromb Res 1995, 78:399-405.
• [15]Chabloz P, Reber G, Boehlen F, Hohlfeld P, De Moerloose P: TAFI antigen and D-dimer levels during normal pregnancy and at delivery. Br J Haematol 2001, 115:150-152.
• [16]Kline JA, Williams GW, Hernandez-Nino J: D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005, 51:825-829.
• [17]Szecsi PB, Jorgensen M, Klajnbard A, Andersen MR, Colov NP, Stender S: Haemostatic reference intervals in pregnancy. Thromb Haemost 2010, 103:718-727.
• [18]Murphy N, Broadhurst D, Khashan AS, Gilligan O, Kenny LC, O’Donoghue K: Gestation-specific D-dimer reference ranges: a cross-sectional study.BJOG 2014, doi:10.1111/1471-0528.12855.
• [19]Hoke M, Kyrle PA, Philipp K, Pabinger I, Kaider A, Schonauer V, Quehenberger P, Eichinger S: Prospective evaluation of coagulation activation in pregnant women receiving low molecular weight heparin. Thromb Haemost 2004, 91:935-940.
• [20]Abou-Nassar K, Kovacs MJ, Kahn SR, Wells P, Doucette S, Ramsay T, Clement AM, Khurana R, Mackinnon K, Blostein M, Solymoss S, Kingdom J, Sermer M, Rey E, Rodger M: The effect of dalteparin on coagulation activation during pregnancy with thrombophilia. A randomized trial. Thromb Haemost 2007, 98:163-171.
• [21]Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, Wagenvoord R, Lecompte T, Beguin S: Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003, 33:4-15.
• [22]Habib M, Roberts LN, Patel RK, Wendon J, Bernal W, Arya R: Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation.Liver Intl 2014, doi:10.111/liv.12369.
• [23]Eichinger S, Weltermann A, Philipp K, Hafner E, Kaider A, Kittl EM, Brenner B, Mannhalter C, Lechner K, Kyrle PA: Prospective evaluation of haemostatic system activation and thrombin potential in healthy pregnant women with and without Factor V Leiden. Thromb Haemost 1999, 82:1232-1236.
• [24]Jacobsen AF, Skjeldestad FE, Sandset PM: Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium – a register-based case–control study. Am J Obstet Gynecol 2008, 198:233.e231-233.e237.
• [25]Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ: Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005, 143:697-706.
• [26]Voke JM, Keidan J, Parvod S, Spencer NH, Hunt BJ: The management of antenatal venous thromboembolism in the UK and Ireland: a prospective multi-centre survey. Br J Haematol 2007, 139:545-558.
• [27]Knight M: Antenatal pulmonary embolism: risk factors, management and outcomes. BJOG 2008, 115:453-461.
• [28]Gerotziafas GT, Petropoulou AD, Verdy E, Samama MM, Elalamy I: Effect of the anti-factor Xa and anti-factor IIa activities of low-molecular weight heparins upon the phases of thrombin generation. J Thromb Haemost 2007, 5:955-962.
• [29]Adamidou A, Riddell A, Priest P, Mughaddam L, Aghighi S, Gatt A, Tuddenham EG, Chowdary P: Thrombin generation test (TGT) in pregnant women at risk of thrombosis on LMWH (low molecular weight heparin): correlation with anti-Xa activity. Br J Haematol 2011, 153(Suppl 1):77 (Abstract 179).
• [30]Green L, Lawrie AS, Patel S, Hossain F, Chitolie A, Mackie IJ, Haddad FS, Machin SJ: The impact of elective knee/hip replacement surgery and thromboprophylaxis with rivaroxaban or dalteparin on thrombin generation. BJH 2010, 151:469-476.
• [31]Morse M: Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonary embolism and deep vein thrombosis. J Thromb Haemost 2004, 2:1202-1204.
• [32]Chan WS, Lee A, Spencer FA, Chunilal S, Crowther M, Wu W, Johnston M, Rodger M, Ginsberg JS: D-dimer testing in pregnant patients: towards determining the next ‘level’ in the diagnosis of deep vein thrombosis. J Thromb Haemost 2010, 8:1004-1011.
• [33]Kovac M, Mikovic Z, Rakicevic L, Srzentic S, Mandric V, Djordjevic V, Radojkovic D, Elezovic I: The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy. Eur J Obstet Gynecol Reprod Biol 2010, 148:27-30.
• [34]HTA no 13/21 – Suspected acute pulmonary embolism in pregnancy Health Technology Assessment Programme 2013.
• [35]Saving Mothers’ Lives: Reviewing maternal deaths to make motherhood safer: 2006–2008 BJOG 2011, 118:1-203.
• [36]Patel RK, Arya R: Tests for hereditary thrombophilia are of limited value in the black population. Stroke 2003, 34:e236.