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Semin Thromb Hemost 2021; 47(02): 120-128
DOI: 10.1055/s-0041-1723798
Review Article

Point-of-Care Diagnostic Assays and Novel Preclinical Technologies for Hemostasis and Thrombosis

Christina Caruso
1   Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia
,
Wilbur A. Lam
1   Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia
2   Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine, Georgia Institute of Technology, Atlanta, Georgia
› Author Affiliations Funding Financial support was provided by NIH R35 HL145000 to W.A.L. and by ASH RTAF to C.C.
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Abstract

Hemostasis is a complex wound-healing process involving numerous mechanical and biochemical mechanisms and influenced by many factors including platelets, coagulation factors, and endothelial components. Slight alterations in these mechanisms can lead to either prothrombotic or bleeding consequences, and such hemostatic imbalances can lead to significant clinical consequences with resultant morbidity and mortality. An ideal hemostasis assay would not only address all the unique processes involved in clot formation and resolution but also take place under flow conditions to account for endothelial involvement. Global assays do exist; however, these assays are not flow based. Flow-based assays have been limited secondary to their large blood volume requirements and low throughput, limiting potential clinical applications. Microfluidic-based assays address the aforementioned limitations of both global and flow-based assays by utilizing standardized devices that require low blood volumes, offer reproducible analysis, and have functionality under a range of shear stresses and flow conditions. While still largely confined to the preclinical space, here we aim to discuss these novel technologies and potential clinical implications, particularly in comparison to the current, commercially available point-of-care assays.

Keywords

hemostasis - platelet function - coagulation assays - point-of-care testing - microfluidics


Publication History

Article published online:
26 February 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Wolberg AS, Aleman MM, Leiderman K, Machlus KR. Procoagulant activity in hemostasis and thrombosis: Virchow's triad revisited. Anesth Analg 2012; 114 (02) 275-285
    CrossrefPubMedGoogle Scholar
  • 2 Tynngård N, Lindahl TL, Ramström S. Assays of different aspects of haemostasis - What do they measure?. Thromb J 2015; 13 (08) 8
    CrossrefPubMedGoogle Scholar
  • 3 Branchford BR, Ng CJ, Neeves KB, Di Paola J. Microfluidic technology as an emerging clinical tool to evaluate thrombosis and hemostasis. Thromb Res 2015; 136 (01) 13-19
    CrossrefPubMedGoogle Scholar
  • 4 Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986; 78 (06) 1456-1461
    CrossrefPubMedGoogle Scholar
  • 5 Neeves KB, Illing DAR, Diamond SL. Thrombin flux and wall shear rate regulate fibrin fiber deposition state during polymerization under flow. Biophys J 2010; 98 (07) 1344-1352
    CrossrefPubMedGoogle Scholar
  • 6 Baumgartner HR. The role of blood flow in platelet adhesion, fibrin deposition, and formation of mural thrombi. Microvasc Res 1973; 5 (02) 167-179
    CrossrefPubMedGoogle Scholar
  • 7 Hochmuth RM, Mohandas N, Blackshear Jr PL. Measurement of the elastic modulus for red cell membrane using a fluid mechanical technique. Biophys J 1973; 13 (08) 747-762
    CrossrefPubMedGoogle Scholar
  • 8 Mooney M, Ewart RH. The conicylindrical viscometer. Physics 1934; 5: 350
    CrossrefPubMedGoogle Scholar
  • 9 Weiss HJ, Turitto VT, Vicic WJ, Baumgartner HR. Fibrin formation, fibrinopeptide A release, and platelet thrombus dimensions on subendothelium exposed to flowing native blood: greater in factor XII and XI than in factor VIII and IX deficiency. Blood 1984; 63 (05) 1004-1014
    CrossrefPubMedGoogle Scholar
  • 10 Escolar G, Galán AM, Mazzara R, Castillo R, Ordinas A. Measurement of platelet interactions with subendothelial substrata: relevance to transfusion medicine. Transfus Med Rev 2001; 15 (02) 144-156
    CrossrefPubMedGoogle Scholar
  • 11 Weiss HJ, Tschopp TB, Baumgartner HR. Impaired interaction (adhesion-aggregation) of platelets with the subendothelium in storage-pool disease and after aspirin ingestion. A comparison with von Willebrand's disease. N Engl J Med 1975; 293 (13) 619-623
    CrossrefPubMedGoogle Scholar
  • 12 Multiplate ® Analyzer. Roche website. Updated May 2020. Accessed May 10, 2020 at: https://diagnostics.roche.com/global/en/products/instruments/multiplate-6-analyzer.html
    PubMedGoogle Scholar
  • 13 Sibbing D, Aradi D, Jacobshagen C. et al; TROPICAL-ACS Investigators. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017; 390 (10104): 1747-1757
    CrossrefPubMedGoogle Scholar
  • 14 Plateletworks ® POC Platelet Function Test. Helena Laboratories website. Updated 2020. Accessed May 10, 2020 at: https://www.helena.com/plateletworks.html
    PubMedGoogle Scholar
  • 15 PFA-100 System. Siemens Healthineers USA website. Updated 2020. Accessed May 11, 2020 at: https://www.siemens-healthineers.com/en-us/hemostasis/systems/pfa-100
    PubMedGoogle Scholar
  • 16 Koscielny J, Ziemer S, Radtke H. et al. A practical concept for preoperative identification of patients with impaired primary hemostasis. Clin Appl Thromb Hemost 2004; 10 (03) 195-204
    CrossrefPubMedGoogle Scholar
  • 17 Koscielny J, von Tempelhoff GF, Ziemer S. et al. A practical concept for preoperative management of patients with impaired primary hemostasis. Clin Appl Thromb Hemost 2004; 10 (02) 155-166
    CrossrefPubMedGoogle Scholar
  • 18 Shaydakov ME, Sigmon DF, Blebea J. Thromboelastography (TEG). StatPearls Publishing. 2020 . Accessed May 15, 2020 at: https://www.ncbi.nlm.nih.gov/books/NBK537061/
    PubMedGoogle Scholar
  • 19 Shore-Lesserson L, Manspeizer HE, DePerio M, Francis S, Vela-Cantos F, Ergin MA. Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg 1999; 88 (02) 312-319
    CrossrefPubMedGoogle Scholar
  • 20 Agarwal S, Johnson RI, Shaw M. Preoperative point-of-care platelet function testing in cardiac surgery. J Cardiothorac Vasc Anesth 2015; 29 (02) 333-341
    CrossrefPubMedGoogle Scholar
  • 21 TEG System. Haemonetics website. Updated 2020. Accessed May 15, 2020 at: http://teg.haemonetics.com/en
    PubMedGoogle Scholar
  • 22 Kim BJ, Lee SY, Jee S, Atajanov A, Yang S. Micro-viscometer for measuring shear-varying blood viscosity over a wide-ranging shear rate. Sensors (Basel) 2017; 17 (06) 1442
    CrossrefPubMedGoogle Scholar
  • 23 Sonoclot ® Coagulation & Platelet Function Analyzer. Sienco website. Updated 2018. Accessed May 1, 2020 at: https://www.sienco.com/sonoclot-world/training-and-support/principle-of-operation-2018.pdf
    PubMedGoogle Scholar
  • 24 Bischof DB, Ganter MT, Shore-Lesserson L. et al. Viscoelastic blood coagulation measurement with Sonoclot predicts postoperative bleeding in cardiac surgery after heparin reversal. J Cardiothorac Vasc Anesth 2015; 29 (03) 715-722
    CrossrefPubMedGoogle Scholar
  • 25 Matsumoto T, Nogami K, Shima M. Simultaneous measurement of thrombin and plasmin generation to assess the interplay between coagulation and fibrinolysis. Thromb Haemost 2013; 110 (04) 761-768
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Koltsova EM, Balandina AN, Grischuk KI. et al. The laboratory control of anticoagulant thromboprophylaxis during the early postpartum period after cesarean delivery. J Perinat Med 2018; 46 (03) 251-260
    CrossrefPubMedGoogle Scholar
  • 27 Okorie UM, Diamond SL. Matrix protein microarrays for spatially and compositionally controlled microspot thrombosis under laminar flow. Biophys J 2006; 91 (09) 3474-3481
    CrossrefPubMedGoogle Scholar
  • 28 Gutierrez E, Petrich BG, Shattil SJ, Ginsberg MH, Groisman A, Kasirer-Friede A. Microfluidic devices for studies of shear-dependent platelet adhesion. Lab Chip 2008; 8 (09) 1486-1495
    CrossrefPubMedGoogle Scholar
  • 29 Neeves KB, Maloney SF, Fong KP. et al. Microfluidic focal thrombosis model for measuring murine platelet deposition and stability: PAR4 signaling enhances shear-resistance of platelet aggregates. J Thromb Haemost 2008; 6 (12) 2193-2201
    CrossrefPubMedGoogle Scholar
  • 30 Neeves KB, Onasoga AA, Wufsus AR. The use of microfluidics in hemostasis: clinical diagnostics and biomimetic models of vascular injury. Curr Opin Hematol 2013; 20 (05) 417-423
    CrossrefPubMedGoogle Scholar
  • 31 Hansen RR, Wufsus AR, Barton ST, Onasoga AA, Johnson-Paben RM, Neeves KB. High content evaluation of shear dependent platelet function in a microfluidic flow assay. Ann Biomed Eng 2013; 41 (02) 250-262
    CrossrefPubMedGoogle Scholar
  • 32 Tsai M, Kita A, Leach J. et al. In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology. J Clin Invest 2012; 122 (01) 408-418
    CrossrefPubMedGoogle Scholar
  • 33 Westein E, van der Meer AD, Kuijpers MJ, Frimat JP, van den Berg A, Heemskerk JW. Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner. Proc Natl Acad Sci U S A 2013; 110 (04) 1357-1362
    CrossrefPubMedGoogle Scholar
  • 34 Neeves KB, Onasoga AA, Hansen RR. et al. Sources of variability in platelet accumulation on type 1 fibrillar collagen in microfluidic flow assays. PLoS One 2013; 8 (01) e54680
    CrossrefPubMedGoogle Scholar
  • 35 Karimi S, Farré-Lladós J, Mir E, Escolar G, Casals-Terré J. Hemostasis-on-a-chip: impedance spectroscopy meets microfluidics for hemostasis evaluation. Micromachines (Basel) 2019; 10 (08) 534
    CrossrefPubMedGoogle Scholar
  • 36 Hosokawa K, Ohnishi T, Kondo T. et al. A novel automated microchip flow-chamber system to quantitatively evaluate thrombus formation and antithrombotic agents under blood flow conditions. J Thromb Haemost 2011; 9 (10) 2029-2037
    CrossrefPubMedGoogle Scholar
  • 37 Li R, Fries S, Li X, Grosser T, Diamond SL. Microfluidic assay of platelet deposition on collagen by perfusion of whole blood from healthy individuals taking aspirin. Clin Chem 2013; 59 (08) 1195-1204
    CrossrefPubMedGoogle Scholar
  • 38 Li M, Hotaling NA, Ku DN, Forest CR. Microfluidic thrombosis under multiple shear rates and antiplatelet therapy doses. PLoS One 2014; 9 (01) e82493
    CrossrefPubMedGoogle Scholar
  • 39 Harris LF, Rainey P, Castro-López V, O'Donnell JS, Killard AJ. A microfluidic anti-Factor Xa assay device for point of care monitoring of anticoagulation therapy. Analyst (Lond) 2013; 138 (17) 4769-4776
    CrossrefPubMedGoogle Scholar
  • 40 Kim DY, Steckl AJ. Electrowetting on paper for electronic paper display. ACS Appl Mater Interfaces 2010; 2 (11) 3318-3323
    CrossrefPubMedGoogle Scholar
  • 41 Ogawa S, Szlam F, Dunn AL. et al. Evaluation of a novel flow chamber system to assess clot formation in factor VIII-deficient mouse and anti-factor IXa-treated human blood. Haemophilia 2012; 18 (06) 926-932
    CrossrefPubMedGoogle Scholar
  • 42 Colace TV, Fogarty PF, Panckeri KA, Li R, Diamond SL. Microfluidic assay of hemophilic blood clotting: distinct deficits in platelet and fibrin deposition at low factor levels. J Thromb Haemost 2014; 12 (02) 147-158
    CrossrefPubMedGoogle Scholar
  • 43 Sakurai Y, Hardy ET, Ahn B. et al. A microengineered vascularized bleeding model that integrates the principal components of hemostasis. Nat Commun 2018; 9 (01) 509
    CrossrefPubMedGoogle Scholar
  • 44 Sugimoto M, Matsui H, Mizuno T. et al. Mural thrombus generation in type 2A and 2B von Willebrand disease under flow conditions. Blood 2003; 101 (03) 915-920
    CrossrefPubMedGoogle Scholar
  • 45 Li R, Elmongy H, Sims C, Diamond SL. Ex vivo recapitulation of trauma-induced coagulopathy and preliminary assessment of trauma patient platelet function under flow using microfluidic technology. J Trauma Acute Care Surg 2016; 80 (03) 440-449
    CrossrefPubMedGoogle Scholar
  • 46 de Witt SM, Swieringa F, Cavill R. et al. Identification of platelet function defects by multi-parameter assessment of thrombus formation. Nat Commun 2014; 5: 4257
    CrossrefPubMedGoogle Scholar
  • 47 Kosaka PM, Pini V, Ruz JJ. et al. Detection of cancer biomarkers in serum using a hybrid mechanical and optoplasmonic nanosensor. Nat Nanotechnol 2014; 9 (12) 1047-1053
    CrossrefPubMedGoogle Scholar
  • 48 Thrombodynamics Analyser T2-T. Hemacore website. . Updated 2020. Accessed May 25, 2020 at: https://thrombodynamics.com/products/analyser-t2-t
    PubMedGoogle Scholar