Shape changes of erythrocytes during blood clot contraction and the structure of polyhedrocytes

Tutwiler, Valerie; Mukhitov, Alexander R.; Peshkova, Alina D.; Minh, Giang Le; Khismatullin, Rafael R.; Vicksman, Jacqueline; Nagaswami, Chandrasekaran; Litvinov, Rustem I.; Weisel, John W.

doi:10.1038/s41598-018-35849-8

Cited by 70 publications

(59 citation statements)

References 43 publications

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“…Figure 3C) are reminiscent of polyhedrocytes observed in contracted thrombi. 15,16 Thrombus contraction was reported to be reduced in patients with ischemic stroke, but could have profound effects on thrombus organization, thrombus volume (and thus blood flow past thrombo-embolic occlusions) and thrombus density. 17 More studies are needed to fully understand the potential effect of thrombus contraction in ischemic stroke patients.…”

Section: Discussionmentioning

confidence: 99%

Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance

et al. 2019

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Ischemic stroke is caused by a thromboembolic occlusion of cerebral arteries. Treatment is focused on fast and efficient removal of the occluding thrombus, either via intravenous thrombolysis or via endovascular thrombectomy. Recanalization, however, is not always successful and factors contributing to failure are not completely understood. Although the occluding thrombus is the primary target of acute treatment, little is known about its internal organization and composition. The aim of this study, therefore, was to better understand the internal organization of ischemic stroke thrombi on a molecular and cellular level. A total of 188 thrombi were collected from endovascularly treated ischemic stroke patients and analyzed histologically for fibrin, red blood cells, von Willebrand factor , platelets, leukocytes and DNA, using bright field and fluorescence microscopy. Our results show that stroke thrombi are composed of two main types of areas: red blood cell-rich areas and platelet-rich areas. Red blood cell-rich areas have limited complexity as they consist of red blood cells that are entangled in a meshwork of thin fibrin. In contrast, platelet-rich areas are characterized by dense fibrin structures aligned with von Willebrand factor and abundant amounts of leukocytes and DNA that accumulate around and in these platelet-rich areas. These findings are important to better understand why platelet-rich thrombi are resistant to thrombolysis and difficult to retrieve via thrombectomy and can guide further improvements of acute ischemic stroke therapy.

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Section: Discussionmentioning

confidence: 99%

Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance

et al. 2019

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“…Polyhedrocytes have been observed in human coronary thrombi21; it is hypothesized that this shape allows for more efficient packing of RBCs,11 thus creating an impermeable seal at the site of vessel injury to prevent bleeding 10. This decreased permeability may impact the effectiveness of medical thrombolytic therapy in AIS.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, clot contraction acts to create an impermeable seal at the site of vessel injury. It has been found that the extent of clot contraction is sensitive to hematocrit—the volume percentage of red blood cells (RBCs) in the blood (%H),11 fibrinogen concentration and platelet function.…”

Section: Introductionmentioning

confidence: 99%

Mechanical behavior of in vitro blood clots and the implications for acute ischemic stroke treatment

Johnson

Chueh

Gounis

et al. 2019

J NeuroIntervent Surg

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BackgroundClot mechanical properties are influenced by composition and the arrangement of components within the clot. This work investigates the effects of platelet-driven contraction on blood clot microstructure and mechanical behavior, and provides insight into some implications for mechanical thrombectomy.MethodsPlatelet-contracted clot analogues (PCCs) and non-contracted clot analogues (NCCs) were prepared from blood mixtures of various hematocrits (%H), that is, the volume percentage of red blood cells (RBCs) in the mixture. Mechanical testing was performed to compare the behavior of the analogues with previously tested human thromboemboli. Scanning electron microscopy and histology investigated the clot microstructure and composition. The association between clot properties and their behavior during mechanical behavior was also investigated.ResultsOverall, PCCs were found to be stiffer than NCCs, across all hematocrits. PCCs with a low %H resisted complete ingestion via contact aspiration alone or complete retrieval with stent-retrievers. PCCs with a higher %H and all NCCs were fully retrievable, although the likelihood of fragmentation was increased in clots with a greater %H. Histologically, there was little difference in the RBC and fibrin content between PCCs and NCCs with the same %H. However, the microstructure of the two groups differed significantly.ConclusionA selection of repeatable clot analogues with a range of mechanical properties have been developed for in vitro modeling of acute ischemic stroke. Platelet contraction significantly affects clot volume and microstructure, and in turn clot stiffness. The significant difference in mechanical properties and microstructure, but without an appreciable difference in histology, implies that histological studies of explanted human clots alone may not prove to be predictive of the mechanical behavior of the clots in thrombectomy.

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“…Thus, other studies have also considered the role of cellularity in thrombus mechanics (Gersh et al, 2009;Kim et al, 2017). These studies have found that closely-packed elements significantly alter the mechanical behavior of thrombus (Tutwiler et al, 2018;van Oosten et al, 2019) requiring a holistic approach toward studying thrombus. Additionally, the constitution and thus mechanics of in-vivo thrombi are not time-invariant (Rausch and Humphrey, 2017).…”

Section: Introductionmentioning

confidence: 99%

A Whole Blood Thrombus Mimic: Constitutive Behavior Under Simple Shear

Sugerman

Kakaletsis

Thakkar

et al. 2020

Preprint

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Deep vein thrombosis and pulmonary embolism affect 300,000-600,000 patients each year in the US. The progression from deep vein thrombus to pulmonary embolism occurs when blood clots, as a whole or partially, break off from the deep veins and eventually occlude the pulmonary arteries. Venous thromboembolism is the cause of up to 100,000 deaths per year in the US alone. To date, we don't fully understand this mechanical process among other reasons because in-vivo samples are difficult to obtain, highly heterogeneous, and their shapes are inappropriate for most mechanical tests. Toward overcoming these obstacles, we have set out to develop an in-vitro thrombus mimic and to test this mimic under large deformation simple shear. In addition to reporting on the mechanics of our mimics under simple shear, we explore the sensitivity of their mechanics to coagulation conditions and blood storage time, and compare three hyperelastic material models for their ability to fit our data. We found that thrombus mimics made from whole blood demonstrate strain-stiffening, a negative Poynting effect, and hysteresis when tested quasi-statically to 50% strain under simple shear. Additionally, we found that the stiffness of these mimics does not significantly vary with coagulation conditions or blood storage times. Of the three hyperelastic constitutive models that we tested, the Ogden model provided the best fits to both shear stress and normal stress. In conclusion, we developed a robust protocol to generate regularly-shaped, homogeneous thrombus mimics that lend themselves to simple shear testing under large deformation. Future studies will extend our model to include the effect of maturation and explore its fracture properties toward a better understanding of embolization.

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Shape changes of erythrocytes during blood clot contraction and the structure of polyhedrocytes

Cited by 70 publications

References 43 publications

Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance

Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance

Mechanical behavior of in vitro blood clots and the implications for acute ischemic stroke treatment

A Whole Blood Thrombus Mimic: Constitutive Behavior Under Simple Shear

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