Transplantation of normal bone marrow into a pig with severe von Willebrand's disease.

Bowie, E. J. W.; Solberg, Lawrence A.; Fass, David N.; Johnson, Christopher M.; Knutson, Gaylord J.; Stewart, Mary Lou; Zoecklein, Laurie

doi:10.1172/jci112560

Cited by 133 publications

(86 citation statements)

References 30 publications

(14 reference statements)

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“…Additional evidence for a role for platelet vWf in hemostasis stems from studies of vWD pigs following transplantation with normal bone marrow. The bleeding times in these pigs, expressing normal levels of platelet vWf, was significantly shortened despite low levels of the plasma protein (34). Moreover, in ex vivo perfusion experiments these platelets adhere poorly to fibrillar collagen and have impaired thrombus formation at elevated shear rates (35,36).…”

Section: Discussionmentioning

confidence: 94%

A revised model of platelet aggregation

Kulkarni¹,

Dopheide²,

Yap³

et al. 2000

J. Clin. Invest.

326

236

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IntroductionPlatelet aggregation at sites of vascular injury is essential for the formation of the primary hemostatic plug and also for the development of pathological thrombi at sites of atherosclerotic plaque rupture. The initial contact of platelets with the injured vessel wall (platelet adhesion) is a complex process involving multiple adhesive substrates (von Willebrand factor [vWf], collagen) and receptors on the platelet surface (GPIb/V/IX, integrins α IIb β 3 and α 2 β 1 ) (1). The interaction between matrix-bound vWf and GPIbα on the platelet surface serves primarily to tether platelets to the area of vascular injury (2, 3), particularly under conditions of high shear stress, as a prerequisite step for integrin-mediated cell arrest (4). Whereas the molecular events underlying platelet adhesion under different shear conditions have been well delineated, the mechanism(s) by which platelets in freeflowing blood subsequently adhere to the initial layer of adherent platelets (platelet cohesion or aggregation) under flow have been less clearly defined.The traditional model of platelet aggregation, in which integrin α IIb β 3 was thought to have an exclusive role in mediating platelet-platelet adhesion contacts, has been largely determined from studies using a platelet aggregometer (5). With this method, the addition of a soluble agonist to a stirred platelet suspension induces activation of integrin α IIb β 3, converting it from a low-to a high-affinity receptor capable of binding soluble fibrinogen. The dimeric nature of fibrinogen enables it to cross-link adjacent activated platelets leading to stable platelet aggregation. Studies of platelet aggregation under high shear conditions, using a coneplate viscometer, have demonstrated that plasma vWf becomes the relevant ligand responsible for platelet activation (6). Shear-induced binding of soluble vWf to GPIbα initiates platelet activation independent of the addition of exogenous stimuli. Whereas the vWf-GPIbα interaction is indispensable for the initiation of platelet-platelet adhesion contacts under high shear, irreversible platelet aggregation requires a second adhesive interaction between vWf and integrin α IIb β 3 (7).The molecular events governing the formation of stable adhesion contacts between platelets in suspension have been well delineated; however, the mechanism by In this study we have examined the mechanism of platelet aggregation under physiological flow conditions using an in vitro flow-based platelet aggregation assay and an in vivo rat thrombosis model. Our studies demonstrate an unexpected complexity to the platelet aggregation process in which platelets in flowing blood continuously tether, translocate, and/or detach from the luminal surface of a growing platelet thrombus at both arterial and venous shear rates. Studies of platelets congenitally deficient in von Willebrand factor (vWf) or integrin α IIb β 3 demonstrated a key role for platelet vWf in mediating platelet tethering and translocation, whereas integrin α IIb β 3 mediated cell ...

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Section: Discussionmentioning

confidence: 94%

A revised model of platelet aggregation

Kulkarni¹,

Dopheide²,

Yap³

et al. 2000

J. Clin. Invest.

326

236

View full text Add to dashboard Cite

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“…28 The origin of the increase in plasma vWf was next investigated. Plasma vWf usually comes almost exclusively from the endothelial cells, 42 but we could not exclude the possibility that the stimulated bone marrow megakaryocytes and/or the increased circulating platelets could also be a source of vWf. However, we could not detect any increase of soluble P-selectin after rhIL-11 treatment, which would indicate ␣-granule release following platelet activation.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models

Denis

Kwack

Saffaripour

et al. 2001

Blood

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Interleukin (IL)-11 is a cytokine with thrombopoietic activity that has been shown to increase plasma von Willebrand factor (vWf) in preliminary clinical studies. This led to further evaluation of the effect of recombinant human (rh)IL-11 on vWf and factor VIII (FVIII) secretion. In vitro, rhIL-11 did not increase vWf production by cultured endothelial cells, which suggests an indirect mechanism. Also, in vivo, plasma vWf was not elevated in mice shortly after a single intravenous (IV) bolus injection of 250 or 1000 g/kg rhIL-11. The effect of continuous exposure to rhIL-11 was accessed by treating wild type mice for 7 consecutive days with subcutaneous 250 g/kg/d rhIL-11. Platelet counts increased by 25% and 40% after 4 and 7 days, respectively. Plasma vWf and FVIII levels increased 2-fold after 4 and 7 days. Surprisingly, no effect of rhIL-11 on vWf or FVIII messenger RNA was observed, which suggests that the regulation by rhIL-11 occurs after transcription. No increase in soluble P-selectin was observed after rhIL-11 treatment, indicating that platelet activation is not the source of elevated vWf. Similarly to wild type mice, vWf heterozygous mice responded to rhIL-11 treatment by a significant increase in platelet counts and vWf and FVIII levels. Importantly, in vWf-deficient mice, rhIL-11 also induced a significant increase in FVIII independent of vWf and was able to reduce skin bleeding time. These results suggest that a clinical evaluation of the effects of rhIL-11-induced vWf/FVIII elevation in maintaining hemostasis in mild hemophilia A or von Willebrand disease would be worthwhile. (Blood. 2001;97: 465-472)

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“…Transfusion of vWF into a pig with VWD also results in the correction of bleeding time showing that efficient hemostasis can be achieved in the absence of endogenous endothelial vWF if plasma vWF is present. 23 The exclusive plasma expression of vWF in our model mimics the clinical situation where VWD patients are treated with vWF concentrates that replenish only the plasma compartment. Our model thus allows the direct comparison of hemostatic capacities of WT versus mutant plasma vWF by testing the ability of various mutants to correct bleeding time in vWF-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Correction of Bleeding Symptoms in von Willebrand Factor–Deficient Mice by Liver-Expressed von Willebrand Factor Mutants

Marx

Lenting²,

Adler³

et al. 2008

ATVB

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Objective-von Willebrand Factor (vWF) structure-function relationship has been studied only in vitro. To investigate the physiological importance of particular vWF domains, we have introduced mutations into murine vWF (mvWF) cDNA inhibiting vWF binding to glycoprotein (Gp) Ib, GpIIbIIIa, and to fibrillar collagen. Methods and Results-We delivered wild-type (WT) or mutant mvWF cDNA into vWF-deficient (Vwf Ϫ/Ϫ ) mice using hydrodynamic injection and assessed whether hemorrhagic symptoms could be corrected. Hydrodynamic gene transfer resulted in high expression of plasma mvWF 24 hours after injection (438Ϯ63% for 50 g of cDNA). Factor VIII activity was normalized in Vwf Ϫ/Ϫ mice injected with mvWF cDNA and multimerization was achieved. Bleeding time was corrected after injection of WT mvWF cDNA in Vwf Ϫ/Ϫ mice whereas noninjected mice did not stop bleeding. Injection of the GpIIbIIIa and the collagen binding mutants in VwfϪ/Ϫ mice also resulted in a correction of bleeding time whereas mice injected with the GpIb binding mutant were bleeding for as long they were observed, although blood loss was decreased compared with noninjected mice (61Ϯ21 L versus 232Ϯ63 L). on Willebrand Factor (vWF) is a multimeric plasma glycoprotein (Gp) playing an essential role in adhesion and aggregation of platelets at sites of vascular damage. At high shear stress, vWF acts as a molecular bridge between components of the subendothelium such as collagen and platelet receptors GpIb and GpIIbIIIa. 1 Furthermore, vWF acts as a carrier protein for coagulation factor VIII (FVIII) and protects it from premature clearance. vWF is produced and stored in endothelial cells and megakaryocytes and is released into the plasma as a series of multimers with a molecular weight ranging from 500 to 20 000 kDa, the largest multimers being the most biologically active. The mature subunit of vWF contains 2050 amino acid (aa) residues organized in 5 types of repeated domains arranged in the order DЈ-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK. 2 A number of functional domains have been identified on vWF sequence, mostly through in vitro approaches. The A3 domain is important for vWF binding to collagen 3 whereas the A1 domain contains the binding site of vWF to platelet GpIb. 4 The binding site of vWF for its other platelet receptor, GpIIbIIIa, has been located near the carboxyl-terminal end of the C1 domain encompassing the RGD sequence. 5,6 Further insight in the structure-function relationship of vWF was gained from the analysis of patients suffering from von Willebrand disease (VWD), the heterogeneous bleeding disorder resulting from defects in vWF gene. VWD can be classified in quantitative deficiencies (types 1 and 3) or qualitative abnormalities (type 2). 7,8 Point mutations represent the molecular basis underlying VWD type 2. 9 These molecular variants have proven useful in establishing the link between a specific functional domain and its physiological relevance. However, this approach is limited by the identification of patients. So far, no patient has be...

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Transplantation of normal bone marrow into a pig with severe von Willebrand's disease.

Cited by 133 publications

References 30 publications

A revised model of platelet aggregation

A revised model of platelet aggregation

Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models

Correction of Bleeding Symptoms in von Willebrand Factor–Deficient Mice by Liver-Expressed von Willebrand Factor Mutants

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