Shear rate gradients promote a bi-phasic thrombus formation on weak adhesive proteins, such as fibrinogen in a VWF-dependent manner

Receveur, Nicolas; Nechipurenko, Dmitry; Knapp, Yannick; Yakusheva, Alexandra; Maurer, Éric; Denis, Cécile V.; Lanza, François; Panteleev, Mikhail A.; Gachet, Christian; Mangin, P

doi:10.3324/haematol.2019.235754

Cited by 25 publications

(11 citation statements)

References 26 publications

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“…Similar observations have recently been reported by Receveur et al . 32 who used a flow model which introduced SRG of the same magnitude as those used in this study. VWF unfolding in an accelerating flow field is likely to be very transient, with apparent rapid refolding in areas downstream of SRG where shear rates resume a constant level again.…”

Section: Discussionmentioning

confidence: 99%

Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation <i>in vitro</i>

et al. 2020

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Intraluminal thrombus formation precipitates conditions such as acute myocardial infarction and disturbs local blood flow resulting in areas of rapidly changing blood flow velocities and steep gradients of blood shear rate. Shear rate gradients are known to be pro-thrombotic with an important role for the shear-sensitive plasma protein von Willebrand factor (VWF). Here, we developed a single-chain antibody (scFv) that targets a shear gradient specific conformation of VWF to specifically inhibit platelet adhesion at sites of SRGs but not in areas of constant shear. Microfluidic flow channels with stenotic segments were used to create shear rate gradients during blood perfusion. VWF-GPIbα interactions were increased at sites of shear rate gradients compared to constant shear rate of matched magnitude. The scFv-A1 specifically reduced VWF-GPIbα binding and thrombus formation at sites of SRGs but did not block platelet deposition and aggregation under constant shear rate in upstream sections of the channels. Significantly, the scFv A1 attenuated platelet aggregation only in the later stages of thrombus formation. In the absence of shear, direct binding of scFv-A1 to VWF could not be detected and scFV-A1 did not inhibit ristocetin induced platelet agglutination. We have exploited the pro-aggregatory effects of SRGs on VWF dependent platelet aggregation and developed the shear-gradient sensitive scFv-A1 antibody that inhibits platelet aggregation exclusively at sites of shear rate gradients. The lack of VWF inhibition in non-stenosed vessel segments places scFV-A1 in an entirely new class of anti-platelet therapy for selective blockade of pathological thrombus formation while maintaining normal haemostasis.

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Section: Discussionmentioning

confidence: 99%

Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation <i>in vitro</i>

et al. 2020

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“…The creation of stenotic geometry is usually accomplished by microfluidic technique (using soft lithography) and was realized by imitating the atherosclerotic geometry with a semicircle [20] or by creating a local perturbation intended for a sharp increase in the shear rate up to 1800 s -1 in combination with an immediate deceleration of the shear to 200 s -1 [21]. Using chambers that mimic stenosis, shear rate gradients have been recently shown to promote biphasic thrombus formation on weak adhesion proteins such as fibrinogen in a von Willebrand factor-dependent manner [22]. The design of a standard plane-parallel flow chamber has been modified (Figure 4) to allow the comparison of two channels -direct and stenotic (reduction of the vessel lumen area by 90%).…”

Section: Models With Stenotic Geometriesmentioning

confidence: 99%

In vitro models of thrombosis and hemostasis

Asadov

Chudinov

Nechipurenko

2021

SBPR

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Abnormalities in hemostatic response are responsible for a large number of life-threatening conditions, however, despite many decades of research, today there are no reliable ways to correct hemostasis without significant risks of thrombosis or bleeding. This situation reflects a poor understanding of the key mechanisms that regulate the hemostatic response. To uncover the principles underlying the regulation of hemostasis, both experimental models and theoretical approaches are actively used. This review focuses on current in vitro models of thrombosis and hemostasis and describes key approaches and tools for studying blood coagulation outside the human/animal body. To reconstruct this process, both microfluidic technologies and approaches based on manufacturing artificial vessels using a variety of hydrogels are actively used. In vitro models of thrombosis traditionally mimic non-penetrating damage to the vessel wall and have been used for more than 30 years to uncover the key processes responsible for the formation of arterial thrombi. Models of in vitro hemostasis have been actively developed only in recent years and are focused ono crucial mechanisms governing the formation of hemostatic plugs -clots that stop bleeding upon a penetrating vascular injury. Modern in vitro models of thrombosis and hemostasis are used not only as tools for fundamental research but are also introduced into clinical practice.

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“…In silico models of the process revealed the importance of both the discoid platelet shape 26 and vWF length for efficient adhesion. 27 Formation of the platelet aggregate in the case of disturbed flow described in various experimental models 28,29 seems to represent another biomechanical phenomenon which strongly depends on the vWF-GPIbalpha interaction. It has been demonstrated that activation of A1 domain interaction of vWF with GPIbalpha follows the flow-induced unfolding of the multimers, 30,31 which might happen both on the surface and in the bulk solution.…”

Section: In Silico Modeling Of Arterial Thrombus Formationmentioning

confidence: 99%

“…Such a possibility has been recently analyzed using the coarse-grained model of vWF dynamics under conditions corresponding to an in vitro model of vessel stenosis. 29 During the last decades, dozens of thrombus formation models were developed addressing various knowledge gaps in this complex phenomenon. One of the intriguing questions regarding the mechanism triggering the occlusion has been addressed by the simplified model of thrombus growth under constant pressure boundary conditions.…”

Section: In Silico Modeling Of Arterial Thrombus Formationmentioning

confidence: 99%

In Silico Hemostasis Modeling and Prediction

et al. 2020

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Computational physiology, i.e., reproduction of physiological (and, by extension, pathophysiological) processes in silico, could be considered one of the major goals in computational biology. One might use computers to simulate molecular interactions, enzyme kinetics, gene expression, or whole networks of biochemical reactions, but it is (patho)physiological meaning that is usually the meaningful goal of the research even when a single enzyme is its subject. Although exponential rise in the use of computational and mathematical models in the field of hemostasis and thrombosis began in the 1980s (first for blood coagulation, then for platelet adhesion, and finally for platelet signal transduction), the majority of their successful applications are still focused on simulating the elements of the hemostatic system rather than the total (patho)physiological response in situ. Here we discuss the state of the art, the state of the progress toward the efficient “virtual thrombus formation,” and what one can already get from the existing models.

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Shear rate gradients promote a bi-phasic thrombus formation on weak adhesive proteins, such as fibrinogen in a VWF-dependent manner

Abstract: Shear rate gradients promote a bi-phasic thrombus formation on weak adhesive proteins, such as fibrinogen in a VWF-dependent manner.

Cited by 25 publications

References 26 publications

Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation <i>in vitro</i>

Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation <i>in vitro</i>

In vitro models of thrombosis and hemostasis

In Silico Hemostasis Modeling and Prediction

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