Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome

Kanaji, Taisuke; Russell, Susan; Ware, Jerry

doi:10.1182/blood-2002-03-0997

Cited by 160 publications

(173 citation statements)

References 28 publications

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“…Together, the data show that FlnA is required for normal platelet morphology and circulation and confirm that the macrothrombocytopenia associated with BernardSoulier syndrome results from the lack of the FlnA-GPIb linkage to the actin cytoskeleton (Ware et al, 2000;Kanaji et al, 2002). Low platelet counts and large platelets have been described in periventricular heterotopia female patients (Parrini et al, 2006).…”

Section: Discussionmentioning

confidence: 51%

“…FlnA deficiency in mice results in lethality in utero as a result of pericardiac and visceral hemorrhage, severe cardiac structural the cytoplasmic tail of GPIb constitutively interacts with FlnA Ig repeat 17 , and the loss of GPIb in mice results in enlarged platelets, a phenotype which can be rescued by expression of a chimeric protein construct containing the cytoplasmic domain of human GPIb (Ware et al, 2000;Kanaji et al, 2002). FlnA binding facilitates GPIb surface expression in Chinese hamster ovary (CHO) cells (Feng et al, 2005), and the interaction between FlnA and GPIb has been reported to influence VWF receptor function, although conflicting effects are found in the literature.…”

Section: Mild Thrombocytopenia In Female Mice Carriers For Flna Deficmentioning

confidence: 99%

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A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

Falet¹,

Pollitt²,

Begonja³

et al. 2010

J Cell Biol

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Section: Discussionmentioning

confidence: 51%

Section: Mild Thrombocytopenia In Female Mice Carriers For Flna Deficmentioning

confidence: 99%

A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

Falet¹,

Pollitt²,

Begonja³

et al. 2010

J Cell Biol

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“…16 Therefore, in order to understand the in vivo role of VWF and FVIII in experimental thrombosis under venous flow conditions, we decided to evaluate thrombosis in VWF Ϫ/Ϫ , FVIII Ϫ/Ϫ , and transgenic mice lacking the GPIb␣ extracellular domain that was replaced by human interleukin-4 receptor (IL4R␣/GPIb␣-tg). 17 Our results suggest that optimal platelet adhesion to subendothelial matrix in injured veins requires VWF and that both VWF and FVIII are essential for the formation of occlusive thrombi in injured venules. …”

mentioning

confidence: 81%

“…17 These transgenic mice lack the GPIb␣ extracellular domain, which is replaced by that of interleukin-4 receptor. 17 We evaluated the role of GPIb␣ in platelet tethering to subendothelium. We infused fluorescent WT or IL4R␣/GPIb␣-tg platelets in WT (c57BL/6) mice to study adhesion under identical conditions.…”

Section: Role Of Gpib␣ In Venous Thrombosismentioning

confidence: 99%

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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“…This implies a role for GPIb-IX-V in maintaining normal platelet size and biconcave discoid shape. In a mouse model of Bernard-Soulier syndrome, where platelets are deficient in wild-type GPIb-IX-V, introduction of just the cytoplasmic portion of GPIba as part of a chimera with the IL-2 receptor extracellular domain substantively rescued the large-platelet phenotype (6); without the extracellular von Willebrand factor-binding domain of GPIba, however, the mice still bled abnormally. These and other studies have revealed a two-way regulatory relationship between GPIb-IX-V and the platelet cytoskeleton (1, 7 -11).…”

Section: Gpib-ix-vmentioning

confidence: 99%

Platelet Interactions in Thrombosis

et al. 2004

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SummaryPatho/physiological platelet aggregate (thrombus) formation is initiated by engagement of platelet surface receptors, glycoprotein (GP)Ib-IX-V and GPVI that bind von Willebrand factor or collagen. Although beneficial in response to vascular injury by preventing blood loss (haemostasis), platelet aggregation in a sclerotic coronary artery or other diseased blood vessel (thrombosis) can cause thrombotic diseases like heart attack and stroke. At the molecular level, ligand interactions with GPIb-IX-V or GPVI trigger signalling responses, including elevation of cytosolic Ca 2 + , dissociation of calmodulin from their cytoplasmic domains, cytoskeletal actin-filament rearrangements, activation of src-family kinases or PI 3-kinase, and 'inside-out' activation of the integrin, aIIbb3 (GPIIb-IIIa), that binds von Willebrand factor or fibrinogen and mediates platelet aggregation. Furthermore, emerging evidence supports a topographical coassociation of these receptors of the leucine-rich repeat family (GPIb-IX-V) and immunoglobulin superfamily (GPVI) in an adhesive cluster or 'adhesosome'. This arrangement may underlie common mechanisms of initiating thrombus formation in haemostasis or thrombotic disease. IUBMB Life, 56: 13-18, 2004

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Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome

Cited by 160 publications

References 28 publications

A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

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

Platelet Interactions in Thrombosis

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