Plasma fibronectin promotes thrombus growth and stability in injured arterioles

Ni, Heyu; Yuen, Peter S.T.; Papalia, Jessie M.; Trevithick, Jane E.; Sakai, Takao; Fässler, Reinhard; Hynes, Richard O.

doi:10.1073/pnas.2628067100

Cited by 201 publications

(197 citation statements)

References 33 publications

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“…Using the ferric-chloride injury model, our group has shown that under arterial conditions thrombosis depends on VWF, fibrinogen, and fibronectin in vivo. 16,31 Using the same model, we have documented that the absence 31 or lower levels (50%) of plasma fibronectin result in serious arterial thrombosis defect 32 but not a venous thrombosis defect. 32 Thus fibronectin is important in thrombosis only at arterial shear rates, while VWF plays an important role at both arterial and venous shear rates.…”

Section: Role Of Vwf In Venous Thrombosis 2427mentioning

confidence: 83%

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

Chauhan

Kisucka

Lamb

et al. 2006

Blood

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von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using genetargeted mice, we show that in ferric chloride-injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF ؊/؊ mice when compared with wild type (WT). We also observed increased embolization in the VWF ؊/؊ mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF ؊/؊ venules did not occlude. Introductionvon Willebrand factor (VWF) is a large adhesive glycoprotein synthesized in megakaryocytes and endothelial cells and stored in platelet ␣-granules and Weibel-Palade bodies, respectively. VWF circulates in plasma as a series of multimers ranging from 500 to 20 000 kDa. The size of the multimers is regulated through proteolysis 1,2 by a specific protease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13). [3][4][5] There are 3 pools of VWF: (1) soluble plasma VWF, (2) subendothelial (ECM) VWF, and (3) cellular VWF in storage granules. 6 VWF is a carrier for factor VIII (FVIII) and protects it from inactivation. 7 The formation of a thrombus on an injured vessel wall is a complex process that involves multiple adhesion molecules (VWF, collagen, fibrinogen, and fibronectin) and their respective receptors on the platelet surface (GPIb␣, GPVI, ␤1 and ␤3 integrins). VWF has 2 main receptors, GPIb␣ in the GPIb-IX-V complex and the integrin ␣IIb␤3. 8 Pathological thrombosis can occur in arteries and veins. Arterial thrombosis is often linked to inappropriate platelet activation and can result in myocardial infarction and ischemic stroke, while venous thrombosis (eg, deep vein thrombosis) is commonly linked to high procoagulant activity, which produces fibrin-rich thrombi. In the clinical setting, elevated levels of FVIII and VWF are associated with an increased risk of venous thrombosis. The Leiden Thrombophilia Study suggested that the effect of elevated VWF on the risk of venous thrombosis was due to increased FVIII levels. 9 In contrast, the Longitudinal Investigation of Thromboembolism Etiology (LITE) Study showed FVIII and VWF were independently associated with venous thromboembolism. 10 Under high shear, the VWF-GPIb␣ interaction is necessary for initial platelet contact with the subendothelium, while irreversible platelet aggregation also requires interaction between the VWF and integrin ␣IIb␤3. 8,[11][12][13] Although an important role for VWF in platelet-platelet cohesion and thrombus formation at arterial shear rates was demonstrated both in vitro 13,14 and in vivo, 15,...

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Section: Role Of Vwf In Venous Thrombosis 2427mentioning

confidence: 83%

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

Chauhan

Kisucka

Lamb

et al. 2006

Blood

Self Cite

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“…Falati et al (14) later provided additional information on tissue factor accumulation in developing thrombi. Plasma fibronectin is also known to have a role in thrombus growth and stability (15).…”

Section: Biological Modelmentioning

confidence: 99%

Blood flow velocity effects and role of activation delay time on growth and form of platelet thrombi

Pivkin

Richardson

Karniadakis

2006

Proc. Natl. Acad. Sci. U.S.A.

148

120

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Mural thrombi are composed dominantly of platelets and develop under a blood flow. Portions can break off and are carried in the blood flow as emboli. Thrombus growth rates are affected by the velocity of the blood flow, but they do not simply increase with it, they exhibit a maximum, with subsequent decrease. Whereas this variation indicates an interaction of biochemical and physical processes, studies have concentrated widely on understanding only the biochemical processes. Here we show results of simulation of thrombus formation in 3D flows by accounting for the movements of individual platelets. Each platelet follows prescribed rules for interactions while the local flow around the thrombus continuously adjusts to the growing structure of the thrombus, also when embolization occurs. With an activation delay time assigned to each platelet we demonstrate the dependence of thrombus growth rate on blood velocity as found experimentally by Begent and Born [Begent N, Born GV (1970) Nature 227:926 -930]. With activated platelets having mutual tensile action sustainable up to a prescribed distance we achieve thrombus growth faster than with shorter maximum distances that make a thrombus less porous; when the prescribed maximum distance is large enough the thrombus shape is not like a ''hill'' but like a ''carpet.'' We find that thrombus growth rate is enhanced by modest pulsatility but less so when pulsations are amplified in part because of more embolization.direct numerical simulations ͉ platelet aggregation ͉ in vivo comparison ͉ stochastic modeling A cute thrombogenesis in a flowing bloodstream can occur on damaged tissues in normal circulation (1). It has also been observed in blood flow over vascular prostheses (2) and in artificial internal organs, such as prosthetic heart valves (3). The thrombi are composed predominantly of platelets, and they can develop even in the presence of systemic anticoagulants such as heparin (4).Blood flow velocity effects were investigated systematically in vivo by Begent and Born (1), who obtained quantitative data on thrombus growth rates for a range of blood flow rates. Their study remains the clearest time-resolved in vivo study of the effect of blood flow rates on thrombus formation. Richardson (5) subsequently proposed that Begent and Born's observations were consistent with a shear-flow aggregation process (6, 7) in which an activation delay time of the platelets is allowed for, a delay time between each platelet's close encounter with the thrombus and its development of ability to adhere to the thrombus, and which was estimated then to be the order of 0.1-0.2 s. A predicted consequence of this finding was that the height-to-length ratio for thrombi would be lower in blood flows, where a significant fraction of the activated platelets escaped the primary thrombus before their activation delay time had elapsed; this was demonstrated later by Born and Richardson (8). More recent experiments by Petrishchev and Mikhailova (9) in vivo and van Gestel et al. (10) in vitro produc...

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“…This concept is supported by experimental findings demonstrating that platelet activation inhibitors have no effect on the ability of platelets to form stable adhesive interactions with a purified fibrinogen matrix under flow (11)(12)(13). This contrasts with all other platelet adhesive interactions, involving substrates such as vWf, collagen, fibronectin, and vitronectin, in which the formation of stable adhesive bonds with these surfaces is considered activation-dependent (10,(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Integrin αIIbβ3-dependent Calcium Signals Regulate Platelet-Fibrinogen Interactions under Flow

Goncalves

Hughan

Schoenwaelder

et al. 2003

Journal of Biological Chemistry

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Platelet adhesion to fibrinogen is important for platelet aggregation and thrombus growth. In this study we have examined the mechanisms regulating platelet adhesion on immobilized fibrinogen under static and shear conditions. We demonstrate that integrin ␣ IIb ␤ 3 engagement of immobilized fibrinogen is sufficient to induce an oscillatory calcium response, necessary for lamellipodial formation and platelet spreading. Released ADP increases the proportion of platelets exhibiting a cytosolic calcium response but is not essential for calcium signaling or lamellipodial extension. Pretreating platelets with the Src kinase inhibitor PP2, the inositol 1,4,5-trisphosphate (IP 3 ) receptor antagonist 2-aminoethoxydiphenyl borate (APB-2), or the phospholipase C (PLC) inhibitor U73122 abolished calcium signaling and platelet spreading, suggesting a major role for Src kinase-regulated PLC isoforms in these processes. Analysis of PLC␥2 ؊/؊ mouse platelets revealed a major role for this isoform in regulating cytosolic calcium flux and platelet spreading on fibrinogen. Under flow conditions, platelets derived from PLC␥2 ؊/؊ mice formed less stable adhesive interactions with fibrinogen, particularly in the presence of ADP antagonists. Our studies define an important role for PLC␥2 in integrin ␣ IIb ␤ 3 -dependent calcium flux, necessary for stable platelet adhesion and spreading on fibrinogen. Furthermore, they establish an important cooperative signaling role for PLC␥2 and ADP in regulating platelet adhesion efficiency on fibrinogen.Platelet adhesion and aggregation at sites of vascular injury are critical for the arrest of bleeding in traumatized vessels and also for the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and stroke. The two principle adhesive ligands promoting platelet aggregation are von Willebrand factor (vWf) 1 and fibrinogen, with each having distinct, complementary roles in this process (1-5). Fibrinogen acts as a bridging molecule between adjacent activated platelets and is the principle adhesive ligand promoting platelet aggregation under low and intermediate shear flow conditions (1, 2). In addition, it also contributes to stable aggregate formation under high shear (1,5,6). It is well established that the binding of fluid-phase fibrinogen to the platelet surface is dependent on the activation of integrin ␣ IIb ␤ 3 (GPIIb-IIIa) through intracellular signaling processes linked to various G protein-coupled and tyrosine kinase-linked receptors (7).Platelets can also adhere to immobilized fibrinogen, a process that is important for primary platelet adhesion onto artificial surfaces, including vascular prostheses (8, 9), and for normal thrombus development (5, 6). In the case of thrombus formation, active integrin ␣ IIb ␤ 3 on the surface of firmly adherent platelets adsorbs soluble fibrinogen to the thrombus surface, thereby providing a reactive substrate for the recruitment of additional platelets. In contrast to soluble fibrinogen, the adhesion of platelets onto...

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Plasma fibronectin promotes thrombus growth and stability in injured arterioles

Cited by 201 publications

References 33 publications

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

Blood flow velocity effects and role of activation delay time on growth and form of platelet thrombi

Integrin αIIbβ3-dependent Calcium Signals Regulate Platelet-Fibrinogen Interactions under Flow

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