Home Thrombin generation, D-dimer and protein S in uncomplicated pregnancy
Article
Licensed
Unlicensed Requires Authentication

Thrombin generation, D-dimer and protein S in uncomplicated pregnancy

  • Mirjana K. Kovac EMAIL logo , Sanja Z. Lalic-Cosic , Jelena M. Dmitrovic , Valentina J. Djordjevic and Dragica P. Radojkovic
Published/Copyright: May 6, 2015
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 53 Issue 12

Abstract

Background: Gestational age-specific reference values are essential for the accurate interpretation of haemostatic tests during pregnancy.

Methods: Our 1-year prospective study included 40 healthy pregnant women with a median age of 30 (range 22–40) years; the subjects were followed in order to establish the gestational age dependent values for endogenous thrombin potential (ETP), D-dimer and protein S (activity and free).

Results: During the first trimester 50% of studied women had ETP >100% (reference values out of pregnancy); in the second trimester an ETP over 100% was observed in all women; ETP values remained unchanged during the third trimester. In the first trimester, the median D-dimer concentration of 0.30 mg/L, in the second 0.91 mg/L and in the third of 1.45 mg/L were observed. During the first trimester 14/40 subjects had protein S activity below reference range (<59%, out of pregnancy); the median value of 61.35; interquartile range (IQR) 20.38; in the second 21/37; the median value of 53.1 (IQR 15.65); in the third trimester 28/37 had low level of protein S activity with the median value of 49.0 (IQR 18.8). Free protein S showed a slight decrease from the first trimester; it remained almost stable during the rest of pregnancy, with the equal number of pregnant women with reduced free protein S.

Conclusions: Related to the gestational age, a significant increase of ETP and D-dimer, from the second trimester was observed; the decrease of protein S was observed already from the early pregnancy, with more pronounced variability of protein S activity.

Keywords: D-dimer; global coagulation test; pregnancy; protein S
Corresponding author: Mirjana K. Kovac, Blood Transfusion Institute of Serbia, Hemostasis Department, Belgrade, Serbia, Sv. Save 39, 11 000 Belgrade, Serbia, Phone: +381 11 3812804, Fax: +381 11 2458328, E-mail: ; and Faculty of Medicine, University of Belgrade, Belgrade, Serbia

Acknowledgments:

This work was supported by grant 173008 from the Ministry of Education, Science and Technological Development, Serbia.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Financial support: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Brenner B. Haemostatic changes in pregnancy. Thromb Res 2004;114:409–14.10.1016/j.thromres.2004.08.004Search in Google Scholar PubMed

2. Bremme K. Haemostasis in normal pregnancy. In: Brenner B, Marder V, Conard J, editors. Women’s issues in thrombosis and haemostasis. London: Martin Dunitz Ltd., 2002:151–65.Search in Google Scholar

3. Bremme K, Ostlund E, Almqvist I, Heinonen K, Blombäck M. Enhanced thrombin generation and fibrinolytic activity in the normal pregnancy and the puerperium. Obstet Gynecol 1992;80:132–7.Search in Google Scholar

4. Comp P, Thurnau G, Welsh J, Esmon C. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986;68:881–5.10.1182/blood.V68.4.881.881Search in Google Scholar

5. Kjellberg U, Andersson NE, Rosén S, Tengborn L, Hellgren M. APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb Haemost 1999;81:527–31.10.1055/s-0037-1614518Search in Google Scholar

6. Clark P, Greer IA, Walker ID. Interaction of the protein C/protein S anticoagulant system, the endothelium and pregnancy. Blood Rev 1999;13:127–46.10.1054/blre.1999.0114Search in Google Scholar PubMed

7. Shen O, Younis JS, Samuelof A. Human gestation and pregnancy complications. In: Brenner B, Marder V, Conard J, editors. Women’s issues in thrombosis and haemostasis. London: Martin Dunitz Ltd., 2002:34–43.Search in Google Scholar

8. Kist WJ, Janssen NG, Kalk JJ, Hague WM, Dekker GA, de Vries JI. Thrombophilias and adverse pregnancy outcome – A confounded problem! Thromb Haemost 2008;99:77–85.10.1160/TH07-05-0373Search in Google Scholar PubMed

9. 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;79:1166–70.10.1055/s-0037-1615035Search in Google Scholar

10. Dählback B, Villoutreix BO. The anticoagulant protein C pathway. FEBS Lett 2005;579:3310–6.10.1016/j.febslet.2005.03.001Search in Google Scholar PubMed

11. Castoldi E, Hackeng TM. Regulation of coagulation by protein S. Curr Opin Hemat 2008;15:529–36.10.1097/MOH.0b013e328309ec97Search in Google Scholar PubMed

12. ten Kate MK, van deer Meer J. Protein S deficiency. A clinical perspective. Haemophilia 2008;14:1222–8.Search in Google Scholar

13. Lijfering WM, Mulder R, ten Kate MK, Veeger NJ, Mulder AB, van deer Meer J. Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives. Blood 2009;113:1225–30.10.1182/blood-2008-08-174128Search in Google Scholar PubMed

14. Kline J A, Williams GW, Hernandes-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005;51:825–9.10.1373/clinchem.2004.044883Search in Google Scholar PubMed

15. Kovac M, Mikovic Z, Rakicevic LJ, Srzentic S, Mandic V, Djordjevic V, et al. The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy. Eur J Obst Gynecol Reprod Biol 2010;148:27–30.10.1016/j.ejogrb.2009.09.005Search in Google Scholar PubMed

16. Reger B, Petrfalvi A, Litter I. Challenges in the evaluation of D-dimer and fibrinogen levels in pregnant women. Thromb Res 2013;131:183–7.10.1016/j.thromres.2013.02.005Search in Google Scholar PubMed

17. Wang M, Lu S, Li S, Shen F. Reference intervals of D-dimer during the pregnancy and puerperium period on the STA-R evolution coagulation analyzer. Clin Chim Acta 2013;425:176–80.10.1016/j.cca.2013.08.006Search in Google Scholar PubMed

18. Khalafallah A, Morse M, Al-Barzan A, Adams M, Dennis A, Bates G, et al. D-dimer levels at different stages of pregnancy in Australian women: a single centre study using two different immunoturbodimetric assays. Thromb Res 2012;130:171–7.10.1016/j.thromres.2012.05.022Search in Google Scholar PubMed

19. Eichinger S, Weltermann A, Philipp K, Hafner E, Kaider A, Kittl EA, et al. Prospective evaluation of hemostatic system activation and thrombin potential in healthy pregnant women with and without factor V Leiden. Thromb Haemost 1999;82:1232–6.10.1055/s-0037-1614366Search in Google Scholar

20. Rosenkranz A, Hiden M, Leschnik B, Weiss EC, Schlembach D, Lang U, et al. Calibrated automated thrombin generation in normal uncomplicated pregnancy. Thromb Haemost 2008;99:331–7.10.1160/TH07-05-0359Search in Google Scholar PubMed

21. Tchalkovski S, Thomassen MC, Costa S, Peeters LL, Rosing J. Role of protein S and tissue factor pathway inhibitor in the development of activated protein C resistance early in pregnancy in women with a history of preeclampsia. Thromb Haemost 2011;106:914–21.10.1160/TH11-04-0244Search in Google Scholar PubMed

22. De Bonis M, Sabattini L, Galeazzi L, Torricelli M, Calzoni P, Fineschi D, et al. Maternal serum protein S forms in pregnancies complicated by intrauterine growth restriction. Eur J Obst Gynecol Reprod Biol 2012;160:142–6.10.1016/j.ejogrb.2011.10.008Search in Google Scholar PubMed

23. Hojo S, Tsukimori K, Kinikawa N, Hattori S, Kang D, Hamasaki N, et al. Decreased maternal protein S activity is associated with fetal growth restriction. Thromb Res 2008;123:55–9.10.1016/j.thromres.2008.01.016Search in Google Scholar PubMed

24. Rosenkranz A, Hiden M, Leschnik B, Weiss EC, Schlembach D, Lang U, et al. Thrombin generation in women with preeclampsia. Hamostaseologie 2008;28:S81–2.10.1055/s-0037-1621429Search in Google Scholar

25. Szecsi PB, Jorgensen M, Klajnbard A, Andersen MR, Colov NP, Stender S. Haemostatic reference intervals in pregnancy. Thromb Haemost 2010;103:718–27.10.1160/TH09-10-0704Search in Google Scholar PubMed

26. Lutsey PL, Cushman M, Steffen LM, Green D, Barr RG, Herrington D, et al. Plasma hemostatic factors and endothelial markers in four racial/ethnic groups: the MESA study. J Thromb Haemost 2006;4:2629–35.10.1111/j.1538-7836.2006.02237.xSearch in Google Scholar PubMed

27. Lange LA, Reiner AP, Carty CL, Jenny NS, Cushman M, Lange EM. Common genetic variants associated with plasma fibrin D-dimer concentration in older European- and African-American adults. J Thromb Haemost 2008;6:654–9.10.1111/j.1538-7836.2008.02906.xSearch in Google Scholar PubMed

28. Woodhams B, Girardot O, Blanco MJ, Colesse G, Gourmelin Y. Stability of coagulation proteins in frozen plasma. Blood Coagul Fibrinolysis 2001;12:229–36.10.1097/00001721-200106000-00002Search in Google Scholar PubMed

29. Joly B, Barbay V, Borg JI, Le Cam-Duchez V. Comparison of makers of coagulation and thrombin generation test in uncomplicated pregnancies. Throm Res 2013;132:386–91.10.1016/j.thromres.2013.07.022Search in Google Scholar PubMed

30. Hron G, Kyrle P, Kaider A, Philipp K, Pabinger I, Kollars M, et al. Pro C Global and endogenous thrombin potential during pregnancy. Am J Obstet Gynecol 2010;203:463–6.10.1016/j.ajog.2010.05.034Search in Google Scholar PubMed

31. Marlar R, Gausman J. Protein S abnormalities: a diagnostic nightmare. Am J Hematol 2011;86:418–21.10.1002/ajh.21992Search in Google Scholar PubMed

Received: 2014-10-21
Accepted: 2015-4-8
Published Online: 2015-5-6
Published in Print: 2015-11-1

©2015 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Biomarkers of inflammatory bowel disease: ready for prime time?
  4. Review
  5. Discriminant indices for distinguishing thalassemia and iron deficiency in patients with microcytic anemia: a meta-analysis
  6. Mini Reviews
  7. Cell-free DNA for diagnosing myocardial infarction: not ready for prime time
  8. The Laboratory Medicine and the care of patients infected by the Ebola virus. Experience in a reference hospital of Madrid, Spain
  9. Opinion Papers
  10. Theranos phenomenon − part 2
  11. Considerations in parathyroid hormone testing
  12. Quantity quotient reporting. Comparison of various models
  13. Genetics and Molecular Diagnostics
  14. Assessing quality and functionality of DNA isolated from FFPE tissues through external quality assessment in tissue banks
  15. Influence of storage conditions and extraction methods on the quantity and quality of circulating cell-free DNA (ccfDNA): the SPIDIA-DNAplas External Quality Assessment experience
  16. Non-invasive fetal ABO genotyping in maternal plasma using real-time PCR
  17. Screening non-deletion α-thalassaemia mutations in the HBA1 and HBA2 genes by high-resolution melting analysis
  18. General Clinical Chemistry and Laboratory Medicine
  19. European views on patients directly obtaining their laboratory test results
  20. Diagnostic performances of clinical laboratory tests using Triton X-100 to reduce the biohazard associated with routine testing of Ebola virus-infected patients
  21. Thrombin generation, D-dimer and protein S in uncomplicated pregnancy
  22. Multi-analyte analysis of non-vitamin K antagonist oral anticoagulants in human plasma using tandem mass spectrometry
  23. Second generation analysis of antinuclear antibody (ANA) by combination of screening and confirmatory testing
  24. Faecal leukocyte esterase activity is an alternative biomarker in inflammatory bowel disease
  25. Reference Values and Biological Variations
  26. Total folate and 5-methyltetrahydrofolate in the cerebrospinal fluid of children: correlation and reference values
  27. Effect of age and gender on reference intervals of red blood cell distribution width (RDW) and mean red cell volume (MCV)
  28. Infectious Diseases
  29. Inosine triphosphate pyrophosphohydrolase activity: more accurate predictor for ribavirin-induced anemia in hepatitis C infected patients than ITPA genotype
  30. The ratio of calprotectin to total protein as a diagnostic and prognostic marker for spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites
  31. Letter to the Editors
  32. Misleading high-sensitivity troponin algorithm for NSTEMI in the ESC guidelines
  33. Adjustment of serum potassium for age and platelet count. A simple step forward towards personalized medicine
  34. The impact of Tween 20 on repeatability of amyloid β and tau measurements in cerebrospinal fluid
  35. Effect of storage time and temperature on the generation of reactive oxygen species in peripheral blood leukocytes
  36. Iohexol interference in the α2-globulin fraction of the serum protein capillary electrophoresis
  37. A functional variant in the γ-glutamyltransferase (GGT)1 gene is associated with airflow obstruction in smokers
  38. Comparison of measured venous carbon dioxide and calculated arterial bicarbonates according to the PaCO2 and PaO2 cut-off values of obesity hypoventilation syndrome
  39. Creatinine, Jaffe, and glucose: another inconvenient truth
  40. Analytical evaluation of a new liquid immunoturbidimetric assay for the determination of ferritin in serum
  41. Analytical assessment of the novel homocysteine liquid enzymatic assay on Beckman Coulter AU5800
  42. Immunoglobulin IgA, IgD, IgG, IgM and IgG subclass reference values in adults
https://doi.org/10.1515/cclm-2014-1030
Keywords for this article
D-dimer; global coagulation test; pregnancy; protein S

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Biomarkers of inflammatory bowel disease: ready for prime time?
  4. Review
  5. Discriminant indices for distinguishing thalassemia and iron deficiency in patients with microcytic anemia: a meta-analysis
  6. Mini Reviews
  7. Cell-free DNA for diagnosing myocardial infarction: not ready for prime time
  8. The Laboratory Medicine and the care of patients infected by the Ebola virus. Experience in a reference hospital of Madrid, Spain
  9. Opinion Papers
  10. Theranos phenomenon − part 2
  11. Considerations in parathyroid hormone testing
  12. Quantity quotient reporting. Comparison of various models
  13. Genetics and Molecular Diagnostics
  14. Assessing quality and functionality of DNA isolated from FFPE tissues through external quality assessment in tissue banks
  15. Influence of storage conditions and extraction methods on the quantity and quality of circulating cell-free DNA (ccfDNA): the SPIDIA-DNAplas External Quality Assessment experience
  16. Non-invasive fetal ABO genotyping in maternal plasma using real-time PCR
  17. Screening non-deletion α-thalassaemia mutations in the HBA1 and HBA2 genes by high-resolution melting analysis
  18. General Clinical Chemistry and Laboratory Medicine
  19. European views on patients directly obtaining their laboratory test results
  20. Diagnostic performances of clinical laboratory tests using Triton X-100 to reduce the biohazard associated with routine testing of Ebola virus-infected patients
  21. Thrombin generation, D-dimer and protein S in uncomplicated pregnancy
  22. Multi-analyte analysis of non-vitamin K antagonist oral anticoagulants in human plasma using tandem mass spectrometry
  23. Second generation analysis of antinuclear antibody (ANA) by combination of screening and confirmatory testing
  24. Faecal leukocyte esterase activity is an alternative biomarker in inflammatory bowel disease
  25. Reference Values and Biological Variations
  26. Total folate and 5-methyltetrahydrofolate in the cerebrospinal fluid of children: correlation and reference values
  27. Effect of age and gender on reference intervals of red blood cell distribution width (RDW) and mean red cell volume (MCV)
  28. Infectious Diseases
  29. Inosine triphosphate pyrophosphohydrolase activity: more accurate predictor for ribavirin-induced anemia in hepatitis C infected patients than ITPA genotype
  30. The ratio of calprotectin to total protein as a diagnostic and prognostic marker for spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites
  31. Letter to the Editors
  32. Misleading high-sensitivity troponin algorithm for NSTEMI in the ESC guidelines
  33. Adjustment of serum potassium for age and platelet count. A simple step forward towards personalized medicine
  34. The impact of Tween 20 on repeatability of amyloid β and tau measurements in cerebrospinal fluid
  35. Effect of storage time and temperature on the generation of reactive oxygen species in peripheral blood leukocytes
  36. Iohexol interference in the α2-globulin fraction of the serum protein capillary electrophoresis
  37. A functional variant in the γ-glutamyltransferase (GGT)1 gene is associated with airflow obstruction in smokers
  38. Comparison of measured venous carbon dioxide and calculated arterial bicarbonates according to the PaCO2 and PaO2 cut-off values of obesity hypoventilation syndrome
  39. Creatinine, Jaffe, and glucose: another inconvenient truth
  40. Analytical evaluation of a new liquid immunoturbidimetric assay for the determination of ferritin in serum
  41. Analytical assessment of the novel homocysteine liquid enzymatic assay on Beckman Coulter AU5800
  42. Immunoglobulin IgA, IgD, IgG, IgM and IgG subclass reference values in adults
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 11.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2014-1030/html
Scroll to top button