Kinetics and mechanics of clot contraction are governed by the molecular and cellular composition of the blood

Tutwiler, Valerie; Litvinov, Rustem I.; Lozhkin, Andrey; Peshkova, Alina D.; Lebedeva, Tatiana; Ataullakhanov, Fazoil I.; Spiller, Kara L.; Cines, Douglas B.; Weisel, John W.

doi:10.1182/blood-2015-05-647560

Cited by 136 publications

(245 citation statements)

References 53 publications

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“…Additionally, we are able to visualize the structure of polyhedrocytes within the clot volume. Our results show significant impairment of clot contraction in the presence of blebbistatin, confirming previous findings indicating an important role for actomyosin in platelet-driven clot contraction [32].…”

Section: Application Of Cclot Methods To Human Bloodsupporting

confidence: 82%

Whole blood clot optical clearing for nondestructive 3D imaging and quantitative analysis

Höök¹,

Brito-Robinson²,

Ким³

et al. 2017

Biomed. Opt. Express

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A technological revolution in both light and electron microscopy imaging now allows unprecedented views of clotting, especially in animal models of hemostasis and thrombosis. However, our understanding of three-dimensional high-resolution clot structure remains incomplete since most of our recent knowledge has come from studies of relatively small clots or thrombi, due to the optical impenetrability of clots beyond a few cell layers in depth. Here, we developed an optimized optical clearing method termed cCLOT that renders large whole blood clots transparent and allows confocal imaging as deep as one millimeter inside the clot. We have tested this method by investigating the 3D structure of clots made from reconstituted pre-labeled blood components yielding new information about the effects of clot contraction on erythrocytes. Although it has been shown recently that erythrocytes are compressed to form polyhedrocytes during clot contraction, observations of this phenomenon have been impeded by the inability to easily image inside clots. As an efficient and nondestructive method, cCLOT represents a powerful research tool in studying blood clot structure and mechanisms controlling clot morphology. Additionally, cCLOT optical clearing has the potential to facilitate imaging of ex vivo clots and thrombi derived from healthy or pathological conditions. W. Weisel, I. N. Chernysh, C. Nagaswami, P. R. Williams, and K. Hawkins, "Effects of unidirectional flow shear stresses on the formation, fractal microstructure and rigidity of incipient whole blood clots and fibrin gels," Clin. Hemorheol. Microcirc. 60(4), 451-464 (2015).

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Section: Application Of Cclot Methods To Human Bloodsupporting

confidence: 82%

Whole blood clot optical clearing for nondestructive 3D imaging and quantitative analysis

Höök¹,

Brito-Robinson²,

Ким³

et al. 2017

Biomed. Opt. Express

Self Cite

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“…Sample clot sizes were then tracked using a Thrombodynamics Analyzer System (HemaCore, Moscow, Russia) by accumulating digitized images based on the light-scattering properties of the clot every 15 s for 20 min (24). Measuring contractile stress in constrained clot contraction…”

Section: Measuring the Kinetics Of Unconstrained Clot Contractionmentioning

confidence: 99%

“…It is possible to theoretically understand the origin of the macroscopic viscoelastic properties of the blood clot by modeling the biopolymer as a semiflexible polymer network (20)(21)(22). The incorporation of RBCs into the blood clot volume disrupts the uniformity of the fibrin network (23), affects the mechanical properties of the clot (24), and influences the process of clot contraction (24). RBCs are easily deformed (25), and when subjected to compressive forces such as those generated by contracting platelets, they become packed in the core of the blood clot and take on a polyhedral shape (14).…”

Section: Introductionmentioning

confidence: 99%

Interplay of Platelet Contractility and Elasticity of Fibrin/Erythrocytes in Blood Clot Retraction

Tutwiler

Wang

Litvinov

et al. 2017

Biophysical Journal

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Blood clot contraction (retraction) is driven by platelet-generated forces propagated by the fibrin network and results in clot shrinkage and deformation of erythrocytes. To elucidate the mechanical nature of this process, we developed a model that combines an active contractile motor element with passive viscoelastic elements. Despite its importance for thrombosis and wound healing, clot contraction is poorly understood. This model predicts how clot contraction occurs due to active contractile platelets interacting with a viscoelastic material, rather than to the poroelastic nature of fibrin, and explains the observed dynamics of clot size, ultrastructure, and measured forces. Mechanically passive erythrocytes and fibrin are present in series and parallel to active contractile cells. This mechanical interplay induces compressive and tensile resistance, resulting in increased contractile force and a reduced extent of contraction in the presence of erythrocytes. This experimentally validated model provides the fundamental mechanical basis for understanding contraction of blood clots.

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“…Although some studies have suggested platelet FXIII is essential for platelet contraction(45), we and others have detected only moderate or no influence of platelet FXIII on platelet contractile events. (31, 46, 47)…”

Section: Fibrin Formation Structure and Function In Vtmentioning

confidence: 99%

Fibrinogen and factor XIII: newly recognized roles in venous thrombus formation and composition

Wolberg

2018

Current Opinion in Hematology

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Purpose of review In spite of significant morbidity and mortality associated with venous thromboembolism, the underlying pathogenesis remains poorly understood. Recent findings Clues to operant pathogenic mechanisms are found in the unique morphology and composition of these thrombi, which have substantial red blood cell and fibrin content. Recent studies have revealed biochemical and biophysical mechanisms that dictate fibrin structure in venous thrombi and promote retention of red blood cells within the contracted clots. These mechanisms include newly-recognized contributions of fibrin network structure and factor XIII(a)-mediated fibrin crosslinking to venous thrombus composition, size, and stability. Summary Continued work to elucidate mechanisms by which fibrin(ogen), factor XIII, and red blood cells contribute to venous thrombus formation, structure, and stability may expose novel molecular targets and strategies for reducing thrombosis and thrombotic complications in certain at-risk patients.

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Kinetics and mechanics of clot contraction are governed by the molecular and cellular composition of the blood

Abstract: Key Points Clot contraction has 3 phases differentially affected by platelet and fibrin mechanics, RBC compaction, and various blood components. A new dynamic quantitative clot contraction assay can reveal novel aspects of formation and evolution of hemostatic clots and thrombi.

Cited by 136 publications

References 53 publications

Whole blood clot optical clearing for nondestructive 3D imaging and quantitative analysis

Whole blood clot optical clearing for nondestructive 3D imaging and quantitative analysis

Interplay of Platelet Contractility and Elasticity of Fibrin/Erythrocytes in Blood Clot Retraction

Fibrinogen and factor XIII: newly recognized roles in venous thrombus formation and composition

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