Skip to main content
SpringerLink
Log in

Global coagulation assays in healthy controls: are there compensatory mechanisms within the coagulation system?

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Global coagulation assays (GCAs) may provide a more comprehensive individual hemostatic profiling. We aim to evaluate GCAs (thromboelastography, thrombin generation) in healthy controls, and correlate results with age, gender, lipid status, tissue factor pathway inhibitor (TFPI) and P-selectin. Blood samples were collected from healthy controls (> 18 years of age) not taking anticoagulation or antiplatelet agents and without known cardiovascular disease. Thromboelastography (TEG) was performed on citrated whole blood while calibrated automated thrombogram (CAT), P-selectin (endothelial marker) and TFPI (principle inhibitor of tissue factor-initiated coagulation) were performed on platelet-poor plasma. 153 healthy controls (mean age 42 years, 98 females (64%)) were recruited. Female controls demonstrated more hypercoagulable TEG and CAT parameters while those over 50 years of age demonstrated more hypercoagulable TEG parameters despite comparable thrombin generation. Paradoxically, individuals with “flattened” thrombin curves (lower velocity index (rate of thrombin generation) despite preserved endogenous thrombin potential (amount of thrombin)) were more likely to be male (49% vs 20%, p = 0.003) with increased low-density lipoprotein cholesterol (3.3 vs 2.6 mmol/L, p = 0.003), P-selectin (54.2 vs 47.3 ng/mL, p = 0.038) and TFPI (18.7 vs 8.6 ng/ml, p = 0.001). In addition to reduced velocity index and thrombin peak, controls in the highest TFPI tertile also demonstrated a poorer lipid profile. GCAs can detect subtle changes of the hemostatic profile. Interestingly, reduced thrombin generation was paradoxically associated with increased cardiovascular risk factors, possibly attributable to increased TFPI. This finding may suggest compensation by the coagulation system in response to endothelial activation and represent a biomarker for early cardiovascular disease. A larger prospective study evaluating these assays in the cardiovascular disease population is ongoing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Brummel KE, Paradis SG, Butenas S, Mann KG (2002) Thrombin functions during tissue factor induced blood coagulation. Blood 100:148–152

    Article  CAS  Google Scholar 

  2. Damen JA, Pajouheshnia R, Heus P et al (2019) Performance of the Framingham risk models and pooled cohort equations for predicting 10-year risk of cardiovascular disease: a systematic review and meta-analysis. BMC Med 17:109

    Article  Google Scholar 

  3. Rana JS, Tabada GH, Solomon MD et al (2016) Accuracy of the atherosclerotic cardiovascular risk equation in a large contemporary, multiethnic real-world population. J Am Coll Cardiol 67:2118–2130

    Article  Google Scholar 

  4. Wang J, Tan G-J, Han LN, Bai YY, He M, Liu HB (2017) Novel biomarkers for cardiovascular risk prediction. J Geriatr Cardiol 14:135–150

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Thomas MR, Lip GYH (2017) Novel risk markers and risk assessments for cardiovascular disease. Circ Res 120:133–149

    Article  CAS  Google Scholar 

  6. Brazzel C (2013) Thromboelastography-guided transfusion therapy in the trauma patient. AANA J 81:127–132

    PubMed  Google Scholar 

  7. Howley IW, Haut ER, Jacobs L, Morrison JJ, Scalea TM (2018) Is thromboelastography (TEG)-based resuscitation better than empirical 1:1 transfusion? Trauma Surg Acute Care Open 3:e000140

    Article  Google Scholar 

  8. Lancé MD (2015) A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis. Thromb J 13:1–6

    Article  Google Scholar 

  9. Lim HY, O’Malley C, Donnan G, Nandurkar H, Ho P (2019) A review of global coagulation assays—is there a role in thrombosis risk prediction? Thromb Res 179:45–55

    Article  CAS  Google Scholar 

  10. McCrath DJ, Cerboni E, Frumento RJ, Hirsh AL, Bennett-Guerrero E (2005) Thromboelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction. Anesth Analg 100:1576–1583

    Article  Google Scholar 

  11. Yao X, Dong Q, Song Y, Wang Y, Deng Y, Li Y (2014) Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke. Cerebrovasc Dis 38:182–190

    Article  CAS  Google Scholar 

  12. Winckers K, ten Cate H, Hackeng TM (2013) The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Rev 27:119–132

    Article  CAS  Google Scholar 

  13. Curry NS, Davenport R, Pavord S et al (2018) The use of viscoelastic haemostatic assays in the management of major bleeding: a British Society for Haematology Guideline. Br J Haematol 182:789–806

    Article  Google Scholar 

  14. Scarpelini S, Rhind SG, Nascimento B et al (2009) Normal range values for thromboelastography in healthy adult volunteers. Braz J Med Biol Res 42:1210–1217

    Article  CAS  Google Scholar 

  15. Ho P, Ng C, Rigano J et al (2017) Significant age, race and gender differences in global coagulation assays parameters in the normal population. Thromb Res 154:80–83

    Article  CAS  Google Scholar 

  16. Bowbrick VA, Mikhailidis DP, Stansby G (2000) The use of citrated whole blood in thromboelastography. Anesth Analg 90:1086–1088

    Article  CAS  Google Scholar 

  17. Hemker HC, Al Dieri R, De Smedt E, Beguin S (2006) Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost 96:553–561

    Article  CAS  Google Scholar 

  18. Grace L (2017) Menopause: the basics. O&G Magazine 19:12–14

    Google Scholar 

  19. Subramanian A, Venencia A, Saxena R, Agrawal D, Pandey RM (2014) Establishing a normal reference range for thromboelastography in North Indian healthy volunteers. Indian J Pathol Microbiol 57:43–50

    Article  Google Scholar 

  20. Roeloffzen WW, Kluin-Nelemans HC, Mulder AB, Veeger NJ, Bosman L, de Wolf JTM (2010) In normal controls, both age and gender affect coagulability as measured by thrombelastography. Anesth Analg 110:987–994

    Article  Google Scholar 

  21. Bontekoe IJ, van der Meer P, de Korte D (2019) Thromboelastography as a tool to evaluate blood of healthy volunteers and blood component quality: a review. Vox Sang 114:643–657

    Article  CAS  Google Scholar 

  22. Gatt A, van Veen JJ, Bowyer A et al (2008) Wide variation in thrombin generation in patients with atrial fibrillation and therapeutic International Normalized Ratio is not due to inflammation. Br J Haematol 142:949–952

    Article  Google Scholar 

  23. Devreese K, Wijns W, Combes I, Van kerckhoven S, Hoylaerts MF (2007) Thrombin generation in plasma of healthy adults and children: chromogenic versus fluorogenic thrombogram analysis. Thromb Haemost 98:600–613

    Article  Google Scholar 

  24. Bagot CN, Marsh M, Whitehead M et al (2010) The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J Thromb Haemost 8:1736–1744

    Article  CAS  Google Scholar 

  25. Pinto S, Bruni V, Rosati D et al (1997) Effects of estrogen replacement therapy on thrombin generation. Thromb Res 85:185–193

    Article  CAS  Google Scholar 

  26. Rosano GM, Vitale C, Marazzi G, Volterrani M (2007) Menopause and cardiovascular disease: the evidence. Climacteric 10(Suppl 1):19–24

    Article  CAS  Google Scholar 

  27. Mari D, Ogliari G, Castaldi D, Vitale G, Bollini E, Lio D (2008) Hemostasis and ageing. Immun Ageing 5:12

    Article  Google Scholar 

  28. Haidl H, Cimenti C, Leschnik B, Zach D, Muntean W (2006) Age-dependency of thrombin generation measured by means of calibrated automated thrombography (CAT). Thromb Haemost 95:772–775

    Article  CAS  Google Scholar 

  29. Appel IM, Grimminck B, Geerts J, Stigter R, Cnossen MH, Beishuizen A (2012) Age dependency of coagulation parameters during childhood and puberty. J Thromb Haemost 10:2254–2263

    Article  CAS  Google Scholar 

  30. Carcaillon L, Alhenc-Gelas M, Bejot Y et al (2011) Increased thrombin generation is associated with acute ischemic stroke but not with coronary heart disease in the elderly: the Three-City cohort study. Arterioscler Thromb Vasc Biol 31:1445–1451

    Article  CAS  Google Scholar 

  31. Schneider JG, Isermann B, Kleber ME et al (2014) Inverse association of the endogenous thrombin potential (ETP) with cardiovascular death: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Int J Cardiol 176:139–144

    Article  Google Scholar 

  32. Loeffen R, van Oerle R, Leers MP et al (2016) Factor XIa and thrombin generation are elevated in patients with acute coronary syndrome and predict recurrent cardiovascular events. PLoS ONE 11:e0158355

    Article  Google Scholar 

  33. Loeffen R, Winckers K, Ford I et al (2015) Associations between thrombin generation and the risk of cardiovascular disease patients: results from the PROSPER study. J Gerontol A 70:982–988

    Article  CAS  Google Scholar 

  34. Frenette PS, Johnson RC, Hynes RO, Wagner DD (1995) Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci USA 92:7450–7454

    Article  CAS  Google Scholar 

  35. Blann AD, Dobrotova M, Kubisz P, McCollum CN (1995) von Willebrand factor, soluble P-selectin, tissue plasminogen activator and plasminogen activator inhibitor in atherosclerosis. Thromb Haemost 74:626–630

    Article  CAS  Google Scholar 

  36. Johnson-Tidey RR, McGregor JL, Taylor PR, Poston RN (1994) Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques: coexpression with intercellular adhesion molecule-1. Am J Pathol 144:952–961

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ridker PM, Buring JE, Rifai N (2001) Soluble P-Selectin and the risk of future cardiovascular events. Circulation 103:491–495

    Article  CAS  Google Scholar 

  38. Crawley JTB, Lane DA (2008) The haemostatic role of tissue factor pathway. Arterioscler Thromb Vasc Biol 28:233–242

    Article  CAS  Google Scholar 

  39. Ellery P, Hilden I, Sejling K et al (2018) Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S. Res Pract Thromb Haemost 2:93–104

    Article  CAS  Google Scholar 

  40. Mitchell CT, Kamineni A, Palmas W, Cushman M (2009) Tissue factor pathway inhibitor, vascular risk factors and subclinical atherosclerosis: the multi-Ethnic study of atherosclerosis. Atherosclerosis 207:277–283

    Article  CAS  Google Scholar 

Download references

Funding

Dr Lim is a recipient of the co-funded National Health and Medical Research Council (NHMRC) postgraduate scholarship and Heart Foundation Health Professional Scholarship.

Author information

Authors and Affiliations

  1. Department of Haematology, Northern Hospital, 185 Cooper St, Epping, VIC, 3076, Australia

    Hui Yin Lim, Brandon Lui & Prahlad Ho

  2. Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia

    Hui Yin Lim, Carly Selan, Harshal Nandurkar & Prahlad Ho

  3. Department of Medicine, Northern Health, University of Melbourne, Heidelberg, VIC, Australia

    Hui Yin Lim & Prahlad Ho

  4. The Northern Hospital, Epping, VIC, Australia

    Mark Tacey

  5. Department of Medicine and Radiology, University of Melbourne, Parkville, VIC, Australia

    Mark Tacey

  6. The Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia

    Geoffrey Donnan

  7. Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC, Australia

    Louise M. Burrell

Authors
  1. Hui Yin Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brandon Lui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark Tacey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carly Selan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geoffrey Donnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Louise M. Burrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Harshal Nandurkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Prahlad Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HYL, BL and CS performed the research. GD, LB, HN and PH designed the research study. HYL, BL, MT and PH analysed the data. HYL and PH drafted the paper while all authors critically revised it. All authors approved the submitted draft.

Corresponding author

Correspondence to Hui Yin Lim.

Ethics declarations

Conflict of interest

No conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lim, H.Y., Lui, B., Tacey, M. et al. Global coagulation assays in healthy controls: are there compensatory mechanisms within the coagulation system?. J Thromb Thrombolysis 52, 610–619 (2021). https://doi.org/10.1007/s11239-021-02400-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-021-02400-y

Keywords

Search

Navigation