Porcine von Willebrand Factor Binding to Human Platelet GPIb Induces Transmembrane Calcium Influx

Mazzucato, M.; L, De Marco; Pradella, Paola; Masotti, Adriana; Fi, Pareti

doi:10.1055/s-0038-1650338

Cited by 66 publications

(57 citation statements)

References 27 publications

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“…For example, porcine-but not human-von Willebrand factor binds and activates human platelets in the absence of shear stress (32). Similar "heteroclytic" phenomena have been shown across other species, particularly in respect of lymphocyte interactions (33,34).…”

Section: Discussionmentioning

confidence: 67%

The Neutrophil: The Unnoticed Threat in Xenotransplantation?

Cardozo

Rouw²,

Ambrose³

et al. 2004

Transplantation

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Section: Discussionmentioning

confidence: 67%

The Neutrophil: The Unnoticed Threat in Xenotransplantation?

Cardozo

Rouw²,

Ambrose³

et al. 2004

Transplantation

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“…In stirred systems, asialo-human VWF or porcine VWF binds spontaneously to platelets via GP Ib-IX and triggers Ca 2ϩ influx, fibrinogen binding to ␣ IIb ␤ 3 , and platelet aggregation (52,71). Similarly, VWF binding in response to ristocetin or botrocetin leads to Ca 2ϩ influx, activation of protein kinase C and phosphatidylinositol 3-kinase, production of thromboxane A 2 , and platelet aggregation (72)(73)(74).…”

Section: Discussionmentioning

confidence: 99%

Lateral Clustering of Platelet GP Ib-IX Complexes Leads to Up-regulation of the Adhesive Function of Integrin αIIbβ3

Kasirer-Friede

Ware

Leng

et al. 2002

Journal of Biological Chemistry

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Binding of von Willebrand factor (VWF) to GPThe GP Ib-IX-V complex consists of four leucine-rich, type I transmembrane polypeptides, two linked by disulfide bonds (GP Ib␣ and GP Ib␤), and two linked noncovalently (GP IX and GP V). The postulated subunit stoichiometry is 2:2:2:1, respectively (1-3), and each platelet expresses ϳ25,000 copies of GP Ib (4, 5). Interaction between GP Ib-IX and its principal ligand, von Willebrand factor (VWF), 1 mediates platelet capture onto exposed extracellular matrices under conditions of flow (6, 7); consequently, it is required for initial platelet adhesion during hemostasis (8). In addition, recent studies using platelets and heterologous expression systems, such as CHO cells, have concluded that GP Ib-IX can function as an excitatory receptor whose occupancy by VWF leads to up-regulation of other platelet responses, most notably platelet aggregation and spreading mediated by integrin ␣ IIb ␤ 3 (reviewed in Ref. 8). These stimulatory properties of GP Ib-IX may be facilitated by: 1) direct interactions of the cytoplasmic tails of GP Ib-IX with intracellular proteins, such as 14-3-3 (9 -13), calmodulin (14), and the cytoskeletal protein filamin A (15, 16); and 2) direct or indirect interactions of GP Ib-IX with other signaling receptors, such as Fc␥ RIIA (17, 18), or signaling receptor subunits, such as the FcR ␥ chain (19). However, the precise mechanism(s) whereby VWF binding to GP Ib-IX triggers ␣ IIb ␤ 3 -dependent functions remains unclear.One structural change in the GP Ib-IX complex that could play a role in its adhesive and signaling functions is oligomerization or clustering within the plane of the plasma membrane. For example, GP Ib-IX might exist as individual 2:2:2:1 complexes or as a series of larger-order oligomers, either constitutively or in response to VWF binding. Consistent with the latter, it has long been known that there is a correlation between VWF multimer size and GP Ib-IX-mediated platelet function, as seen in variant von Willebrand disease patients lacking the largest VWF multimers (20) and in patients with thrombotic thrombocytopenic purpura, in whom ultra-large VWF multimers may cause pathological platelet thrombi (21). Further support for the functional significance of GP Ib-IX clustering comes from the following observations: 1) the binding of multivalent but not monovalent forms of VWF or antibodies to GP Ib-IX stimulates platelets (22), 2) a subset of palmitoylated GP Ib-IX complexes may be organized into highdensity patches within platelet membrane lipid rafts (23), and 3) deletion of the binding sites on GP Ib␣ for 14-3-3 and filamin A increases the lateral mobility of GP Ib-IX in the plane of the membrane, a possible prerequisite for regulated clustering of this receptor (24).Based on these considerations, we hypothesized that clustering of GP Ib-IX may play a prominent role in the adhesive and signaling functions of this receptor. Because multivalent ligands like VWF or anti-GP Ib-IX antibodies may have effects in addition to clustering of t...

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“…In normal individuals, vWF binds to GPIb on platelets only if the platelets are subjected to shear stress (14,15), resulting in platelet activation and adhesion (16)(17)(18)(19). In contrast, porcine von Willebrand Factor (pvWF) binds human (or primate) GPIb on quiescent platelets, leading to platelet aggregation even in the absence of shear stress (20,21). Thus, aberrant interactions between pvWF and human or primate GPIb could lead to widespread activation of the coagulation system, resulting in DIC.…”

Section: Introductionmentioning

confidence: 99%

Prolonged Function of Macrophage, von Willebrand Factor-Deficient Porcine Pulmonary Xenografts

Cantu

Balsara

et al. 2007

American Journal of Transplantation

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Porcine von Willebrand factor (vWF) activates human and primate platelets. Having determined the importance of pulmonary intravascular macrophages (PIMs) in pulmonary xenotransplantation, we evaluated whether, in the absence of PIMs, vWF might play a role in pulmonary xenograft dysfunction.Utilizing a left single-lung transplant model, baboons depleted of anti-a Gal antibodies received lungs from either vWF-deficient (n = 2); MCP-expressing (n = 5); MCP PIM-depleted (n = 5); or vWF-deficient PIMdepleted swine (n = 3).Two out of three of the PIM-depleted, pvWF deficient grafts survived longer than any previously reported pulmonary xenografts, including PIM-depleted xenografts expressing human complement regulatory proteins. Depletion of PIM's from vWF-deficient lungs, like depletion of PIM's from hMCP lungs, resulted in abrogation of the coagulopathy associated with pulmonary xenotransplantation.Thus, in terms of pulmonary graft survival, control of adverse reactions involving pvWF appears to be equally or even more important than is complement regulation using hMCP expression. However, based on the rapid failure of PIM-sufficient, pvWFdeficient pulmonary xenografts, pVWF-deficient pulmonary xenografts appear to be particularly sensitive to macrophage-mediated damage. These data provide initial evidence that vWF plays a role in the 'delayed' (24 h) dysfunction observed in pulmonary xenotransplantation using PIM depleted hMCP organs.

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Porcine von Willebrand Factor Binding to Human Platelet GPIb Induces Transmembrane Calcium Influx

Cited by 66 publications

References 27 publications

The Neutrophil: The Unnoticed Threat in Xenotransplantation?

The Neutrophil: The Unnoticed Threat in Xenotransplantation?

Lateral Clustering of Platelet GP Ib-IX Complexes Leads to Up-regulation of the Adhesive Function of Integrin αIIbβ3

Prolonged Function of Macrophage, von Willebrand Factor-Deficient Porcine Pulmonary Xenografts

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