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The Use of Total Thrombus Formation Analysis System As a Tool to Assess Platelet Function in Bleeding and Thrombosis Risk—A Systematic Review

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The Use of Total Thrombus Formation Analysis System As a Tool to Assess Platelet Function in Bleeding and Thrombosis Risk—A Systematic Review International Journal of Molecular Sciences Review The Use of Total Thrombus Formation Analysis System as a Tool to Assess Platelet Function in Bleeding and Thrombosis Risk—A Systematic Review Joanna Sikora 1,*,† , Aleksandra Karczmarska-Wódzka 1,†, Joanna Bugieda 1 and Przemysław Sobczak 2 1 Research and Education Unit for Experimental Biotechnology, Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru´n, 85-094 Bydgoszcz, Poland; [email protected] (A.K.-W.); [email protected] (J.B.) 2 Department of Hematology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru´n, 85-094 Bydgoszcz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-52-585-59-76; Fax: +48-52-585-43-80 † These authors contributed equally to this work. Abstract: Background. Today there are many devices that can be used to study blood clotting disorders by identifying abnormalities in blood platelets. The Total Thrombus Formation Analysis System is an automated microchip flow chamber system that is used for the quantitative analysis of clot formation under blood flow conditions. For several years, researchers have been using a tool to analyse various clinical situations of patients to identify the properties and biochemical processes occurring within platelets and their microenvironment. Methods. An investigation of recent published literature was conducted based on PRISMA. This review includes 52 science papers directly related to the use of the Total Clot Formation Analysis System in relation to bleeding, Citation: Sikora, J.; Karczmarska- surgery, platelet function assessment, anticoagulation monitoring, von Willebrand factor and others. Wódzka, A.; Bugieda, J.; Sobczak, P. The Use of Total Thrombus Conclusion. Most available studies indicate that The Total Thrombus Formation Analysis System Formation Analysis System as a Tool may be useful in diagnostic issues, with devices used to monitor therapy or as a significant tool for to Assess Platelet Function in predicting bleeding events. However, T-TAS not that has the potential for diagnostic indications, Bleeding and Thrombosis Risk—A but allows the direct observation of the flow and the interactions between blood cells, including the Systematic Review. Int. J. Mol. Sci. intensity and dynamics of clot formation. The device is expected to be of significant value for basic 2021, 22, 8605. https://doi.org/ research to observe the interactions and changes within platelets and their microenvironment. 10.3390/ijms22168605 Keywords: T-TAS; platelet function; bleeding; thrombosis; blood coagulation Academic Editor: Isabella Russo Received: 13 July 2021 Accepted: 6 August 2021 1. Introduction Published: 10 August 2021 Haemostasis is an important process that maintains the integrity of the circulatory Publisher’s Note: MDPI stays neutral system and minimises blood loss upon vascular damage. When a blood vessel-wall is with regard to jurisdictional claims in injured a number of concomitant events occur. Initially, circulating platelets are recruited published maps and institutional affil- to the site of the injury where they are activated to become a platelet plug. Secondly, blood iations. coagulation is triggered by tissue factors resulting in thrombin generation and fibrin forma- tion. Fibrin monomers are then cross-linked into insoluble strands that serve to stabilize the loose platelet clot. The formation of fibrin and the platelet plug become major components of the developing thrombus at the sight of injury to prevent bleeding [1]. Hemostasis is a complex process that is contingent on the complex interaction of platelets, plasma Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. coagulation cascades, fibrinolytic proteins, blood vasculatures and cytokine mediators, This article is an open access article which promote the inflammatory reaction and the accumulation of cells required for wound distributed under the terms and repair after injury [2]. A number of instruments have now become available to investigate conditions of the Creative Commons bleeding disorders by assessing platelet function defects. Attribution (CC BY) license (https:// The Total Thrombus Formation Analysis System (T-TAS) is an automated microchip creativecommons.org/licenses/by/ flow chamber system for the quantitative analysis of the thrombus formation process 4.0/). under blood flow conditions. Under arterial flow conditions, white thrombi consisting of Int. J. Mol. Sci. 2021, 22, 8605. https://doi.org/10.3390/ijms22168605 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 22 The Total Thrombus Formation Analysis System (T-TAS) is an automated microchip Int. J. Mol. Sci. 2021, 22, 8605 flow chamber system for the quantitative analysis of the thrombus formation process2 of 21 under blood flow conditions. Under arterial flow conditions, white thrombi consisting of numerous activated platelets and fibrin fibers are formed, whereas red thrombi forming numerousin the venous activated circulation platelets predominantly and fibrin fibers consis aret of formed, fibrin whereasand red redblood thrombi cells [1]. forming When inintroducing the venous flow circulation chambers predominantly into clinics, consistthe type of of fibrin flow and chamber, red blood coating cells of [1 ].surfaces, When introducingcollection and flow storage chambers of blood into before clinics, start the of typeanalysis, of flow recording chamber, of digital coating images of surfaces, and the collectionmethod of and image storage quantification of blood before should start be ofaddressed. analysis, recordingThe device, of therefore, digital images offers and the thepotential method advantage of image of quantification simultaneous should assessment be addressed. of both platelet The device, and therefore,coagulation offers defects. the potentialUsing advantage T-TAS for of research, simultaneous the white assessment thrombus of bothformation platelet occurring and coagulation in the chip defects. can be observedUsing and T-TAS quantitatively for research, theanalysed white thrombus under arterial formation and occurring venous inflow the chipconditions. can be observedMoreover, and it observes quantitatively the time analysed course under of thrombus arterial andformation venous in flow whole conditions. blood flowing Moreover, in a itsimulated observes theblood time vessel course at a of constant thrombus rate. formation White thrombus in whole bloodgrowth flowing rate and in astability simulated are bloodeasily vesselevaluated at a constantthrough pressu rate. Whitere waveforms thrombus and growth indicators. rate and In stabilityaddition, are real easily time evalu-visual atedobservation through of pressure thrombus waveforms formation and with indicators. a camera, In addition,the small realamount time of visual whole observation blood per ofassay thrombus (320 to formation 450 uL) and with rapid a camera, measurements the small (10 amount to 30 min) of whole are important blood per features. assay (320 There to 450are µtwoL) and types rapid of chips, measurements the PL-chip (10 and to 30 AR-chip. min) are important features. There are two types of chips,The the T-TAS PL-chip is a device and AR-chip. comprised of a tabletop instrument controlled by a dedicated PC andThe T-TASa disposable, is a device single-use comprised flow of chamber a tabletop (Figure instrument 1). The controlled PL-chip byis adesigned dedicated to PCspecifically and a disposable, measure platelet single-use thrombus flow chamberformation (Figure (PTF) under1). The physiological PL-chip is designedconditions to on specificallya collagen-coated measure analytical platelet pathway thrombus consisting formation of (PTF)microcapillary under physiological channels. PTF conditions is a direct onindicator a collagen-coated of the patient’s analytical primary pathway hemostatic consisting function. of microcapillary The assay is channels.performed PTF under is aarterial direct indicatorflow conditions of the patient’s using an primary anticoagulant hemostatic that function.inhibits thrombin The assay and is performed factor Xa, underblocking arterial the coagulation flow conditions cascade using and an anticoagulantallowing the PL-chip that inhibits to specifically thrombin andmeasure factor only Xa, blockingPTF. During the coagulation the assay, cascadethe blood and sample allowing is exposed the PL-chip to arterial to specifically shear stresses measure in only the PTF.presence During of thea assay,collagen-coated the blood samplesurface, is exposedwhich causes to arterial platelet shear attachment stresses in the to presencecollagen ofmediated a collagen-coated by the von surface,Willebrand which factor causes (vWF), platelet and platelet attachment activation. to collagen The vWF mediated represents by thea high-molecular-weight von Willebrand factor adhesive (vWF), and glycoprotein platelet activation. that plays Thean essential vWF represents role in primary a high- molecular-weighthemostasis by promoting adhesive glycoproteinplatelet adhesion that plays to the an essentialsubendothelium role in primary and platelet hemostasis plug byformation promoting at plateletthe sites adhesion of vascular to the injury. subendothelium [3] Platelet and activation platelet plugcauses formation the release at the of sitesendogenous of vascular factors injury contained [3]. Platelet within activation the platelets causes that
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