Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter


IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

Online
ISSN
1437-4331
See all formats and pricing
More options …
Volume 57, Issue 11

Issues

Influence of hypertriglyceridemia, hyperbilirubinemia and hemolysis on thrombin generation in human plasma

Gian Luca Salvagno / Emmanuel J. Favaloro
  • Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Davide Demonte / Matteo Gelati / Giovanni Poli / Giovanni Targher
  • Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Verona, Verona, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Giuseppe Lippi
Published Online: 2019-04-02 | DOI: https://doi.org/10.1515/cclm-2019-0135

Abstract

Background

Although accumulating evidence suggests that the hemostatic balance is impaired in patients with hypertriglyceridemia, hyperbilirubinemia or hemolytic anemias, little is known on the underlying biological mechanisms. This experimental study was aimed at exploring whether increasing values of triglycerides, bilirubin or cell-free hemoglobin promote thrombin generation in plasma.

Methods

Three different pools were prepared from three different sets of 20 normal routine plasma citrate samples. The native pools were spiked with increasing amounts of exogenous triglycerides (up to 8.8 mmol/L), bilirubin (up to 350 μmol/L) or autologous hemolyzed blood (up to 3.5 g/L cell-free hemoglobin). Using the fully-automated thrombin generation analyzer ST Genesia, we measured the following parameters: lag time (LT), time to peak (TP), peak height (PH) and endogenous thrombin potential (ETP).

Results

A sustained increase of PH and ETP was found in parallel with increasing triglyceride concentrations, peaking in the aliquot with 8.8 mmol/L. Conversely, LT and TP displayed an opposite trend, reaching a maximum decrease in the 8.8 mmol/L aliquot. Increasing bilirubin concentrations promoted remarkable increases of PH and ETP and decreases of TP and LT, up to 211 μmol/L. After this threshold, all parameters tended to return towards baseline values. A constant increase of PH and ETP was also noted in hemolyzed samples, peaking in the 3.5 g/L cell-free hemoglobin aliquot, whereas the TP and LT remained unchanged in all hemolyzed aliquots.

Conclusions

Our findings suggest that hypertriglyceridemia, hyperbilirubinemia and hemolysis may promote a hypercoagulable state in human plasma.

Keywords: bilirubin; hemolysis; thrombin generation; thrombosis; triglycerides

References

  • 1.

    Tripodi A. Thrombin generation assay and its application in the clinical laboratory. Clin Chem 2016;62:699–707.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 2.

    Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, Wagenvoord R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003;33:4–15.PubMedCrossrefGoogle Scholar

  • 3.

    Duarte RC, Ferreira CN, Rios DR, Reis HJ, Carvalho MD. Thrombin generation assays for global evaluation of the hemostatic system: perspectives and limitations. Rev Bras Hematol Hemoter 2017;39:259–65.CrossrefPubMedGoogle Scholar

  • 4.

    Farrell CJ, Carter AC. Serum indices: managing assay interference. Ann Clin Biochem 2016;53:527–38.Web of ScienceCrossrefPubMedGoogle Scholar

  • 5.

    Lippi G, Cadamuro J, von Meyer A, Simundic AM. Local quality assurance of serum or plasma (HIL) indices. Clin Biochem 2018;54:112–8.Web of ScienceCrossrefPubMedGoogle Scholar

  • 6.

    Lippi G, Plebani M, Favaloro EJ. Interference in coagulation testing: focus on spurious hemolysis, icterus, and lipemia. Semin Thromb Hemost 2013;39:258–66.Web of SciencePubMedGoogle Scholar

  • 7.

    Dentali F, Squizzato A, Ageno W. The metabolic syndrome as a risk factor for venous and arterial thrombosis. Semin Thromb Hemost 2009;35:451–7.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 8.

    Ataga K. Hypercoagulability and thrombotic complications in hemolytic anemias. Haematologica 2009;94:1481–4.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 9.

    Suh S, Cho YR, Park MK, Kim DK, Cho NH, Lee MK. Relationship between serum bilirubin levels and cardiovascular disease. PLoS One 2018;13:e0193041.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 10.

    Cervellin G, Buonocore R, Sanchis-Gomar F, Lippi G. Low serum bilirubin values are associated with pulmonary embolism in a case-control study. Clin Chem Lab Med 2016;54:e229–30.Web of ScienceGoogle Scholar

  • 11.

    Tripodi A, Anstee QM, Sogaard KK, Primignani M, Valla DC. Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 2011;9:1713–23.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 12.

    Hamur H, Duman H, Bakirci EM, Kucuksu Z, Demirelli S, Kalkan K, et al. Bilirubin levels and thrombus burden in patients with ST-segment elevation myocardial infarction. Angiology 2016;67:565–70.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 13.

    Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014;2: 655–66.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 14.

    Glick MR, Ryder KW, Jackson SA. Graphical comparisons of interferences in clinical chemistry instrumentation. Clin Chem 1986;32:470–5.PubMedGoogle Scholar

  • 15.

    Lippi G, Musa R, Avanzini P, Aloe R, Pipitone S, Sandei F. Influence of in vitro hemolysis on hematological testing on Advia 2120. Int J Lab Hematol 2012;34:179–84.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 16.

    Lippi G, Plebani M, Di Somma S, Cervellin G. Hemolyzed specimens: a major challenge for emergency departments and clinical laboratories. Crit Rev Clin Lab Sci 2011;48:143–53.Web of ScienceCrossrefGoogle Scholar

  • 17.

    Lippi G, Luca Salvagno G, Blanckaert N, Giavarina D, Green S, Kitchen S, et al. Multicenter evaluation of the hemolysis index in automated clinical chemistry systems. Clin Chem Lab Med 2009;47:934–9.Web of SciencePubMedGoogle Scholar

  • 18.

    Salvagno GL, Berntorp E. Thrombin generation assays (TGAs). Methods Mol Biol 2017;1646:515–22.PubMedCrossrefGoogle Scholar

  • 19.

    Favaloro EJ, Lippi G. On the complexity of hemostasis and the need for harmonization of test practice. Clin Chem Lab Med 2018;56:1568–74.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 20.

    Dargaud Y, Wolberg AS, Gray E, Negrier C, Hemker HC. Proposal for standardized preanalytical and analytical conditions for measuring thrombin generation in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2017;15:1704–7.Web of SciencePubMedCrossrefGoogle Scholar

  • 21.

    Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor. Cardiovasc Diabetol 2014;13:159.Web of SciencePubMedCrossrefGoogle Scholar

  • 22.

    Mi Y, Yan S, Lu Y, Liang Y, Li C. Venous thromboembolism has the same risk factors as atherosclerosis: A PRISMA-compliant systemic review and meta-analysis. Medicine (Baltimore) 2016;95:e4495.Web of ScienceCrossrefPubMedGoogle Scholar

  • 23.

    Aoki I, Aoki N, Kawano K, Shimoyama K, Maki A, Homori M, et al. Platelet-dependent thrombin generation in patients with hyperlipidemia. J Am Coll Cardiol 1997;30:91–6.CrossrefPubMedGoogle Scholar

  • 24.

    Franchini M, Targher G, Lippi G. Serum bilirubin levels and cardiovascular disease risk: a Janus Bifrons? Adv Clin Chem 2010;50:47–63.CrossrefWeb of ScienceGoogle Scholar

  • 25.

    Kundur AR, Singh I, Bulmer AC. Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert’s syndrome? Atherosclerosis 2015;239: 73–84.Web of SciencePubMedCrossrefGoogle Scholar

  • 26.

    Cakir T, Cingi A, Yeğen C. Coagulation dynamics and platelet functions in obstructive jaundiced patients. J Gastroenterol Hepatol 2009;24:748–51.Web of ScienceCrossrefPubMedGoogle Scholar

  • 27.

    Ataga KI, Cappellini MD, Rachmilewitz EA. Beta-thalassaemia and sickle cell anaemia as paradigms of hypercoagulability. Br J Haematol 2007;139:3–13.Web of ScienceCrossrefPubMedGoogle Scholar

  • 28.

    Noubouossie DC, Lê PQ, Rozen L, Ziereisen F, Willems D, Demulder A, et al. Thrombin generation in children with sickle cell disease: relationship with age, hemolysis, transcranial Doppler velocity, and hydroxyurea treatment. Eur J Haematol 2013;91:46–54.CrossrefPubMedWeb of ScienceGoogle Scholar

About the article

Corresponding author: Prof. Giuseppe Lippi, Section of Clinical Biochemistry, University of Verona, University Hospital of Verona, Piazzale LA Scuro, 37134 Verona, Italy


Received: 2019-02-05

Accepted: 2019-03-05

Published Online: 2019-04-02

Published in Print: 2019-10-25


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

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(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.


Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 57, Issue 11, Pages 1784–1789, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2019-0135.

Export Citation

©2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Comments (0)

Please log in or register to comment.
Log in