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Drop-of-blood acoustic tweezing technique for integrative turbidimetric and elastometric measurement of blood coagulation

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Abstract

Many patients develop coagulation abnormalities due to chronic and hereditary disorders, infectious disease, blood loss, extracorporeal circulation, and oral anticoagulant misuse. These abnormalities lead to bleeding or thrombotic complications, the risk of which is assessed by coagulation analysis. Current coagulation tests pose safety concerns for neonates and small children due to large sample volume requirement and may be unreliable for patients with coagulopathy. This study introduces a containerless drop-of-blood method for coagulation analysis, termed “integrated quasi-static acoustic tweezing thromboelastometry” (i-QATT™), that addresses these needs. In i-QATT™, a single drop of blood is forced to levitate and deform by the acoustic radiation force. Coagulation-induced changes in drop turbidity and firmness are measured simultaneously at different instants. The parameters describing early, intermediate, and late stages of the coagulation process are evaluated from the resulting graphical outputs. i-QATT™ rapidly (<10 min) detected hyper- and hypo-coagulable states and identified single deficiency in coagulation factors VII, VIII, IX, X, and XIII. The linear relationship (r2 > 0.9) was established between fibrinogen concentration and two i-QATT™ parameters: maximum clot firmness and maximum fibrin level. Factor XIII activity was uniquely measured by the fibrin network formation time (r2 = 0.9). Reaction time, fibrin formation rate, and time to firm clot formation were linearly correlated with heparin concentration (r2 > 0.7). tPA-induced hyperfibrinolysis was detected in the clot firmness output at 10 min. i-QATT™ provides comprehensive coagulation analysis in point-of-care or laboratory settings, well suited to the needs of neonatal and pediatric patients and adult patients with anemia or blood collection issues.

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Data availability

All the information about acoustic tweezing technology including the description of the methods to generate blood coagulation data is proprietary. However, the clinical data produced using this technology, such as graphical outputs (“tweezographs”) and values of coagulation parameters, is available to the public. If accepted for publication, this manuscript will be submitted to the digital archive PubMed Central for sharing with general public, according to the NIH Public Access Policy.

Code availability

Not applicable

References

  1. Herbstreit F, Winter EM, Peters J, Hartmann M. Monitoring of haemostasis in liver transplantation: comparison of laboratory based and point of care tests. Anaesthesia. 2010;65(1):44–9.

    Article  CAS  PubMed  Google Scholar 

  2. Levi M, Hunt BJ. A critical appraisal of point-of-care coagulation testing in critically ill patients. J Thromb Haemost. 2015;13(11):1960–7.

    Article  CAS  PubMed  Google Scholar 

  3. Chitlur M, Young G. Global assays in hemophilia. Semin Hematol. 2016;53(1):40–5.

    Article  CAS  PubMed  Google Scholar 

  4. Jennings I, Cooper P. Screening for thrombophilia: a laboratory perspective. Br J Biomed Sci. 2003;60(1):39–51.

    Article  CAS  PubMed  Google Scholar 

  5. Salmela B, Joutsi-Korhonen L, Armstrong E, Lassila R. Active online assessment of patients using new oral anticoagulants: bleeding risk, compliance, and coagulation analysis. Semin Thromb Hemost. 2012;38(1):23–30.

    Article  CAS  PubMed  Google Scholar 

  6. Taralov S, Kukladgiev B. Nephelometric study of the clotting of blood plasma (fibrinogen-fibrin phase) by patients with delirium tremens and chronic alcoholics. Folia Med (Plovdiv). 1976;18(2):171–6.

    CAS  Google Scholar 

  7. Koepke JA. Technologies for coagulation instruments. Lab Med. 2000;31(4):211–6.

    Article  Google Scholar 

  8. Chen A, Teruya J. Global hemostasis testing thromboelastography: old technology, new applications. Clin Lab Med. 2009;29(2):391–407.

    Article  PubMed  Google Scholar 

  9. Durila M, Malosek M. Rotational thromboelastometry along with thromboelastography plays a critical role in the management of traumatic bleeding. Am J Emerg Med. 2014;32(3):288 e1–3.

    Article  Google Scholar 

  10. Wang JS, Lin CY, Hung WT, O’Connor MF, Thisted RA, Lee BK, et al. Thromboelastogram fails to predict postoperative hemorrhage in cardiac patients. Ann Thorac Surg. 1992;53(3):435–9.

    Article  CAS  PubMed  Google Scholar 

  11. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg. 2008;106(5):1366–75.

    Article  PubMed  Google Scholar 

  12. Chuang J, Sadler MA, Witt DM. Impact of evacuated collection tube fill volume and mixing on routine coagulation testing using 2.5-ml (pediatric) tubes. Chest. 2004;126(4):1262–6.

    Article  PubMed  Google Scholar 

  13. Pruthi RK. Abnormal partial thromboplast in time in adults and children. Clin Adv Hematol Oncol. 2011;9(6):466–7.

    PubMed  Google Scholar 

  14. Lippi G, Favaloro EJ, Salvagno GL, Franchini M. Laboratory assessment and perioperative management of patients on antiplatelet therapy: from the bench to the bedside. Clin Chim Acta. 2009;405(1–2):8–16.

    Article  CAS  PubMed  Google Scholar 

  15. Capoor MN, Stonemetz JL, Baird JC, Ahmed FS, Awan A, Birkenmaier C, et al. Prothrombin time and activated partial thromboplastin time testing: a comparative effectiveness study in a million-patient sample. PLoS One. 2015;10(8):e0133317.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147–56.

    Article  CAS  Google Scholar 

  17. Pollack CV Jr. Coagulation assessment with the new generation of oral anticoagulants. Emerg Med J. 2016;33(6):423–30.

    Article  PubMed  Google Scholar 

  18. Holt RG, Luo D, Gruver N, Khismatullin DB. Quasi-static acoustic tweezing thromboelastometry. J Thromb Haemost. 2017;15(7):1453–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ansari Hosseinzadeh V, Brugnara C, Emani S, Khismatullin D, Holt RG. Monitoring of blood coagulation with non-contact drop oscillation rheometry. J Thromb Haemost. 2019;17(8):1345–53.

    Article  CAS  PubMed  Google Scholar 

  20. Jeger V, Zimmermann H, Exadaktylos AK. Can RapidTEG accelerate the search for coagulopathies in the patient with multiple injuries? J Trauma Acute Care Surg. 2009;66(4):1253–7.

    Article  CAS  Google Scholar 

  21. Brill-Edwards P, Ginsberg JS, Johnston M, Hirsh J. Establishing a therapeutic range for heparin therapy. Ann Intern Med. 1993;119(2):104–9.

    Article  CAS  PubMed  Google Scholar 

  22. Toulon P, Boutiere B, Horellou MH, Trzeciak MC, Samama MM. Monitoring heparin therapy using activated partial thromboplastin time--results of a multicenter trial establishing the therapeutic range for SILIMAT, a reagent with high sensitivity to heparin. Thromb Haemost. 1998;80(1):104–8.

    CAS  PubMed  Google Scholar 

  23. Tyler HM. Fibrin crosslinking demonstrated by thrombelastography. Thromb Diath Haemorrh. 1969;22(2):398–400.

    CAS  PubMed  Google Scholar 

  24. Carroll RC, Craft RM, Chavez JJ, Snider CC, Kirby RK, Cohen E. Measurement of functional fibrinogen levels using the thrombelastograph. J Clin Anesth. 2008;20(3):186–90.

    Article  CAS  PubMed  Google Scholar 

  25. Im SB, Kim SC, Shim JS. A smart pipette for equipment-free separation and delivery of plasma for on-site whole blood analysis. Anal Bioanal Chem. 2016;408(5):1391–7.

    Article  CAS  PubMed  Google Scholar 

  26. Kuo J-N, Zhan Y-H. Microfluidic chip for rapid and automatic extraction of plasma from whole human blood. Microsyst Technol. 2015;21(1):255–61.

    Article  CAS  Google Scholar 

  27. Maria MS, Rakesh PE, Chandra TS, Sen AK. Capillary flow-driven microfluidic device with wettability gradient and sedimentation effects for blood plasma separation. Sci Rep. 2017;7:43457.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zavadil DP, Stammers AH, Willett LD, Deptula JJ, Christensen KA, Sydzyik RT. Hematological abnormalities in neonatal patients treated with extracorporeal membrane oxygenation (ECMO). J Extra Corpor Technol. 1998;30(2):83–90.

    CAS  PubMed  Google Scholar 

  29. Hoylaerts M, Rijken D, Lijnen H, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem. 1982;257(6):2912–9.

    Article  CAS  PubMed  Google Scholar 

  30. Lo EH, Broderick JP, Moskowitz MA. tPA and proteolysis in the neurovascular unit. Stroke. 2004;35(2):354–6.

    Article  PubMed  Google Scholar 

  31. Adibhatla RM, Hatcher JF. Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets. 2008;7(3):243–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Goldstein LB. Acute ischemic stroke treatment in 2007. Circulation. 2007;116(13):1504–14.

    Article  PubMed  Google Scholar 

  33. Loewy AG, College H (2001) Structure and function of factor XIII

  34. Wiegering V, Andres O, Schlegel PG, Deinlein F, Eyrich M, Sturm A. Hyperfibrinolysis and acquired factor XIII deficiency in newly diagnosed pediatric malignancies. Haematologica. 2013;98:e90–1.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dirkmann D, Gorlinger K, Gisbertz C, Dusse F, Peters J. Factor XIII and tranexamic acid but not recombinant factor VIIa attenuate tissue plasminogen activator-induced hyperfibrinolysis in human whole blood. Anesth Analg. 2012;114(6):1182–8.

    Article  CAS  PubMed  Google Scholar 

  36. Rodeghiero F, Barbui T, Battista R, Chisesi T, Rigoni G, Dini E. Molecular subunits and transamidase activity of factor XIII during disseminated intravascular coagulation in acute leukaemia. Thromb Haemost. 1980;43(01):006–9.

    Article  CAS  Google Scholar 

  37. Song JW, Choi JR, Song KS, Rhee JH. Plasma factor XIII activity in patients with disseminated intravascular coagulation. Yonsei Med J. 2006;47(2):196–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Muszbek L, Bagoly Z, Bereczky Z, Katona E. The involvement of blood coagulation factor XIII in fibrinolysis and thrombosis. Cardiovasc Hematol Agents Med Chem. 2008;6(3):190–205.

    Article  CAS  PubMed  Google Scholar 

  39. Dorgalaleh A, Kazemi A, Zaker F, Shamsizadeh M, Rashidpanah J, Mollaei M. Laboratory diagnosis of factor XIII deficiency, routine coagulation tests with quantitative and qualitative methods. Clin Lab. 2016;62(4):491–8.

    CAS  PubMed  Google Scholar 

  40. Chernysh IN, Weisel JW. Dynamic imaging of fibrin network formation correlated with other measures of polymerization. Blood. 2008;111(10):4854–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wiman B, Ranby M. Determination of soluble fibrin in plasma by a rapid and quantitative spectrophotometric assay. Thromb Haemost. 1986;55(2):189–93.

    Article  CAS  PubMed  Google Scholar 

  42. Dassi C, Seyve L, Garcia X, Bigo E, Marlu R, Caton F, et al. Fibrinography: a multiwavelength light-scattering assay of fibrin structure. Hemasphere. 2019;3(1):e166.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank R. Glynn Holt for help with the experimental system design and Nathan Nelson for fruitful discussion.

Funding

This study was supported by U.S. National Science Foundation grants No. 1438537 and 1725033 (to D.K.), U.S. National Science Foundation grant No. 1843479 (to. D.L), American Heart Association grant No. 13GRNT17200013 (to D.K.), and U.S. National Institutes of Health grant No. GM104940 (to Tulane University).

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Authors and Affiliations

  1. Department of Biomedical Engineering and Tulane Institute for Integrative Engineering for Health and Medicine, Tulane University, 6823 St. Charles Avenue 500 Lindy Boggs Center, New Orleans, LA, 70118, USA

    Daishen Luo, Erika M. Chelales, Millicent M. Beard, Nithya Kasireddy & Damir B. Khismatullin

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  1. Daishen Luo
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  2. Erika M. Chelales
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  3. Millicent M. Beard
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  4. Nithya Kasireddy
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  5. Damir B. Khismatullin
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Contributions

D. Luo designed the study and the acoustic tweezing system, performed experiments, analyzed the data, and wrote the manuscript. M. Beard performed the fibrinogen, heparin, and tPA experiments. E. Chelales analyzed the data, helped with the code development, and performed factor deficiency plasma experiments. N. Kasireddy developed the data analysis code. D. Khismatullin conceived, designed, and supervised the study and wrote the manuscript.

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Correspondence to Damir B. Khismatullin.

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Conflict of interest

D. Luo, N. Kasireddy, and D. Khismatullin have a financial interest in Levisonics Inc. The other authors have no competing interests. i-QATT™ technology is protected by two pending patents: PCT/US14/55559 and PCT/US2018/014879.

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Luo, D., Chelales, E.M., Beard, M.M. et al. Drop-of-blood acoustic tweezing technique for integrative turbidimetric and elastometric measurement of blood coagulation. Anal Bioanal Chem 413, 3369–3379 (2021). https://doi.org/10.1007/s00216-021-03278-8

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