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CC BY 4.0 · TH Open 2024; 08(03): e283-e296
DOI: 10.1055/s-0044-1788281
Original Article

Establishing Expectancy Values for Fibrin Monomer in Uncomplicated Pregnancy

Holger Seidel 
1   Centrum für Blutgerinnungsstörungen und Transfusionsmedizin, Bonn, Germany
,
Melina Duncklenberg
1   Centrum für Blutgerinnungsstörungen und Transfusionsmedizin, Bonn, Germany
,
Hans-Jörg Hertfelder
1   Centrum für Blutgerinnungsstörungen und Transfusionsmedizin, Bonn, Germany
,
Christine Gnida
1   Centrum für Blutgerinnungsstörungen und Transfusionsmedizin, Bonn, Germany
,
Philipp Westhofen
1   Centrum für Blutgerinnungsstörungen und Transfusionsmedizin, Bonn, Germany
,
Anna Stremlau
1   Centrum für Blutgerinnungsstörungen und Transfusionsmedizin, Bonn, Germany
,
Joffrey Feriel
2   Clinical Development, Diagnostica Stago, Asnières sur Seine, France
,
François Depasse
2   Clinical Development, Diagnostica Stago, Asnières sur Seine, France
,
Hannah L. McRae
3   Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Germany
,
Johannes Philipp Kruppenbacher
1   Centrum für Blutgerinnungsstörungen und Transfusionsmedizin, Bonn, Germany
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Abstract

Background During pregnancy, a physiological increase of molecular activation markers (MAM) of hemostasis such as prothrombin fragments 1 + 2, thrombin–antithrombin complex, and D-dimers (DD) occurs. Therefore, monitoring MAM levels during pregnancy to evaluate the risk of venous thromboembolism (VTE) may be unreliable; nevertheless, DD analysis in pregnancy is widely performed. In contrast to DD, fibrin monomer (FM) levels have been reported to remain stable during pregnancy.

Objectives The main aim of this study was to define the expected range for FM levels in pregnant outpatients. In addition, we examined the impact of the individual VTE risk, as calculated by the pregnancy risk score of the Royal College of Obstetricians and Gynaecologists (RCOG), as well as that of antithrombotic treatment on FM levels.

Methods A total of 342 pregnant women seen at our hemostasis unit were included throughout 350 pregnancies in 899 samples.

Results Low-risk thrombophilia, but not the RCOG score itself, was found to influence all MAM levels, whereas antithrombotic treatment had only an impact on DD. For FM, a reference range could be calculated irrespective of the pregnancy term, in contrast to other MAMs, which fluctuated throughout pregnancy.

Conclusions Our findings suggest a stronger impact of inherited thrombophilia on hemostasis activity during pregnancy as compared with acquired or other predisposing thrombophilic risk factors. FM levels showed a marginal increase during pregnancy in contrast to other MAM and remain a potential candidate to improve the laboratory assessment of VTE risk during pregnancy. Further prospective studies in pregnant patients with suspicion of VTE are needed.

Keywords

fibrin monomer test - D-dimer - pregnancy - postpartum period - thrombophilia

Authors' Contribution

H.S., P.W., and J.P.K. conceived and designed this study. H.S. contributed to acquisition, analysis, and interpretation of the data and was responsible for drafting, editing, and submission of the manuscript. M.D. contributed to data input and analysis. C.G. contributed to the recruitment of patients. A.S. was responsible for sample management, laboratory analyses, and method validation of FM and DD (STA). J.F. and F.D. played a significant role in the statistical analysis of the data and helped to draft the manuscript. H.J.H. and H.L.M. had a significant influence on interpretation of the data and critical appraisal of the manuscript. All authors have read and agreed to the published version of the manuscript.


Supplementary Material



Publication History

Received: 15 April 2024

Accepted: 12 June 2024

Article published online:
11 July 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Clark P, Brennand J, Conkie JA, McCall F, Greer IA, Walker ID. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79 (06) 1166-1170
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Lanir N, Aharon A, Brenner B. Haemostatic mechanisms in human placenta. Best Pract Res Clin Haematol 2003; 16 (02) 183-195
    CrossrefPubMedSearch in Google Scholar
  • 3 Holmes VA, Wallace JM. Haemostasis in normal pregnancy: a balancing act?. Biochem Soc Trans 2005; 33 (Pt 2): 428-432
    CrossrefPubMedSearch in Google Scholar
  • 4 Rosenkranz A, Hiden M, Leschnik B. et al. Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost 2008; 99 (02) 331-337
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Anderson Jr FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151 (05) 933-938
    CrossrefPubMedSearch in Google Scholar
  • 6 Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton III LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005; 143 (10) 697-706
    CrossrefPubMedSearch in Google Scholar
  • 7 Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6 (04) 632-637
    CrossrefPubMedSearch in Google Scholar
  • 8 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 (02) 233.e1-233.e7
    CrossrefPubMedSearch in Google Scholar
  • 9 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. 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 (2 Suppl): e691S-e736S
    CrossrefPubMedSearch in Google Scholar
  • 10 Chan WS, Rey E, Kent NE. et al; VTE in Pregnancy Guideline Working Group, Society of Obstetricians and Gynecologists of Canada. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can 2014; 36 (06) 527-553
    CrossrefPubMedSearch in Google Scholar
  • 11 Nelson-Piercy C, MacCallum P, Mackillop MA. Reducing the risk of venous thromboembolism during pregnancy and the puerperium: RCOG green-top guideline No.37a. London: RCOG; 2015
    Search in Google Scholar
  • 12 ACOG Practice Bulletin No. ACOG practice bulletin no. 196 summary: thromboembolism in pregnancy. Obstet Gynecol 2018; 132 (01) 243-248
    CrossrefPubMedSearch in Google Scholar
  • 13 Bates SM, Rajasekhar A, Middeldorp S. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018; 2 (22) 3317-3359
    CrossrefPubMedSearch in Google Scholar
  • 14 Hart C, Bauersachs R, Scholz U. et al. Prevention of venous thromboembolism during pregnancy and the puerperium with a special focus on women with hereditary thrombophilia or prior VTE-Position Paper of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH). Hamostaseologie 2020; 40 (05) 572-590
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Yang Y, Feng G, Yan J. et al. Plasminogen activator inhibitor-1, thrombin-antithrombin, and prothrombin fragment F1+2 have higher diagnostic values than D-dimer for venous thromboembolism after TKA. Clin Appl Thromb Hemost 2022 ;28:10760296221097383
    PubMedSearch in Google Scholar
  • 16 van Wersch JW, Ubachs JM. Blood coagulation and fibrinolysis during normal pregnancy. Eur J Clin Chem Clin Biochem 1991; 29 (01) 45-50
    PubMedSearch in Google Scholar
  • 17 Onishi H, Kaniyu K, Iwashita M, Tanaka A, Watanabe T. Fibrin monomer complex in normal pregnant women: a potential thrombotic marker in pregnancy. Ann Clin Biochem 2007; 44 (Pt 5): 449-454
    CrossrefPubMedSearch in Google Scholar
  • 18 Sekiya A, Hayashi T, Kadohira Y. et al. Thrombosis prediction based on reference ranges of coagulation-related markers in different stages of pregnancy. Clin Appl Thromb Hemost 2017; 23 (07) 844-850
    CrossrefPubMedSearch in Google Scholar
  • 19 Iwamoto T, Hatayama Y, Namba H. et al. Fibrin monomer complex as a potential thrombosis marker related to venous thromboembolism risk in pregnant women. Ann Clin Biochem 2023; 60 (04) 279-285
    CrossrefPubMedSearch in Google Scholar
  • 20 Joly B, Barbay V, Borg JY, Le Cam-Duchez V. Comparison of markers of coagulation activation and thrombin generation test in uncomplicated pregnancies. Thromb Res 2013; 132 (03) 386-391
    CrossrefPubMedSearch in Google Scholar
  • 21 Kawamura M, Fukuda N, Suzuki A. et al. Use of fibrin monomer complex for screening for venous thromboembolism in the late pregnancy and post-partum period. J Obstet Gynaecol Res 2014; 40 (03) 700-704
    CrossrefPubMedSearch in Google Scholar
  • 22 Grossman KB, Arya R, Peixoto AB, Akolekar R, Staboulidou I, Nicolaides KH. Maternal and pregnancy characteristics affect plasma fibrin monomer complexes and D-dimer reference ranges for venous thromboembolism in pregnancy. Am J Obstet Gynecol 2016; 215 (04) 466.e1-466.e8
    CrossrefPubMedSearch in Google Scholar
  • 23 Kristoffersen AH, Petersen PH, Bjørge L, Røraas T, Sandberg S. Concentration of fibrin monomer in pregnancy and during the postpartum period. Ann Clin Biochem 2019; 56 (06) 692-700
    CrossrefPubMedSearch in Google Scholar
  • 24 James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194 (05) 1311-1315
    CrossrefPubMedSearch in Google Scholar
  • 25 Kane EV, Calderwood C, Dobbie R, Morris C, Roman E, Greer IA. A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005. Eur J Obstet Gynecol Reprod Biol 2013; 169 (02) 223-229
    CrossrefPubMedSearch in Google Scholar
  • 26 Bombeli T, Raddatz-Mueller P, Fehr J. Coagulation activation markers do not correlate with the clinical risk of thrombosis in pregnant women. Am J Obstet Gynecol 2001; 184 (03) 382-389
    CrossrefPubMedSearch in Google Scholar
  • 27 Joly BS, Sudrié-Arnaud B, Barbay V, Borg JY, Le Cam Duchez V. Thrombin generation test as a marker for high risk venous thrombosis pregnancies. J Thromb Thrombolysis 2018; 45 (01) 114-121
    CrossrefPubMedSearch in Google Scholar
  • 28 Elmas E, Suvajac N, Jilma B, Weiler H, Borggrefe M, Dempfle CE. Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model. Blood 2010; 116 (05) 801-805
    CrossrefPubMedSearch in Google Scholar
  • 29 Simioni P, Scarano L, Gavasso S. et al. Prothrombin fragment 1+2 and thrombin-antithrombin complex levels in patients with inherited APC resistance due to factor V Leiden mutation. Br J Haematol 1996; 92 (02) 435-441
    CrossrefPubMedSearch in Google Scholar
  • 30 Lambropoulos AF, Foka Z, Makris M, Daly M, Kotsis A, Makris PE. Factor V Leiden in Greek thrombophilic patients: relationship with activated protein C resistance test and levels of thrombin-antithrombin complex and prothrombin fragment 1 + 2. Blood Coagul Fibrinolysis 1997; 8 (08) 485-489
    PubMedSearch in Google Scholar
  • 31 Rühl H, Berens C, Winterhagen FI. et al. Increased activated protein C response rates reduce the thrombotic risk of factor V Leiden carriers but not of prothrombin 20210G>A carriers. Circ Res 2019; 125 (05) 523-534
    CrossrefPubMedSearch in Google Scholar
  • 32 Reda S, Schwarz N, Müller J. et al. Fibrinolysis biomarker, thrombin, and activated protein C level alterations after coagulation activation depend on type of thrombophilia and clinical phenotype. Res Pract Thromb Haemost 2024; 8 (02) 102351
    CrossrefPubMedSearch in Google Scholar
  • 33 Paidas MJ, Ku DH, Urban G. et al. Elevated first trimester soluble fibrin polymer is associated with adverse pregnancy outcome in thrombophilic patients. Blood Coagul Fibrinolysis 2008; 19 (08) 824-826
    CrossrefPubMedSearch in Google Scholar
  • 34 van der Graaf F, van den Borne H, van der Kolk M, de Wild PJ, Janssen GW, van Uum SH. Exclusion of deep venous thrombosis with D-dimer testing–comparison of 13 D-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard. Thromb Haemost 2000; 83 (02) 191-198
    Thieme ConnectPubMedSearch in Google Scholar
  • 35 Tang J, Lin Y, Mai H. et al. Meta-analysis of reference values of haemostatic markers during pregnancy and childbirth. Taiwan J Obstet Gynecol 2019; 58 (01) 29-35
    CrossrefPubMedSearch in Google Scholar