Platelet von Willebrand factor in inherited and acquired bleeding disorders.

Mannucci, Pier Mannuccio

doi:10.1073/pnas.92.7.2428

Cited by 60 publications

(61 citation statements)

References 63 publications

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“…Our findings that platelet vWf plays a key role in initiating platelet aggregation under flow are in keeping with previous clinical and experimental studies suggesting an important hemostatic function for this pool of vWf (see review by Mannucci [31]). For example, it is well established that the level of platelet vWf acts as a major determinant of the skin bleeding time in healthy individuals and in Type 1 vWD (25,32).…”

Section: Discussionsupporting

confidence: 79%

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: Discussionsupporting

confidence: 79%

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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“…Patients with type 3 vWD have no measurable vWF levels in plasma, platelets, and endothelial cells 14 and therefore form the ideal group to study the pathogenic role of vWF in human atherogenesis. The results show that individuals with a complete deficiency are not protected against the development of early and advanced atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 99%

Patients With Type 3 Severe von Willebrand Disease Are Not Protected Against Atherosclerosis

et al. 2004

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Background-The results of a number of studies in pigs and mice suggest that absence of von Willebrand factor (vWF) protects against the development of atherosclerosis. We studied whether patients with a complete deficiency of vWF (type 3 von Willebrand disease [vWD]) develop fewer atherosclerotic vessel wall changes than healthy controls. Methods and Results-This study included 47 individuals with type 3 vWD and 84 healthy controls. Early atherosclerotic changes were assessed by measuring the thickness of the intima-media in the carotid and femoral arteries by B-mode ultrasonography. Advanced atherosclerotic changes were quantified by summing the maximal thickness of atherosclerotic plaques in the carotid and femoral arteries and were expressed as a plaque score. Established risk factors were determined to adjust for possible differences between the groups. We found no substantial difference in intima-media thickness between vWD patients and controls (adjusted difference for carotid artery 0.007 mm, 95% CI Ϫ0.022 to 0.036 mm; femoral artery 0.069 mm, 95% CI Ϫ0.056 to 0.19 mm). Similar proportions of patients and controls had atherosclerotic plaques (19% and 17%, respectively). No difference was found in the plaque score between groups (adjusted difference Ϫ0.22 mm, 95% CI Ϫ0.69 to 0.26). Among vWD patients, we found no effect of treatment with vWF concentrates on intima-media thickness or plaque score. Conclusions-The results of this study indicate that vWF does not play a substantial role in human atherogenesis.

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“…1,2 This platelet-VWF is synthesized during megakaryocytopoiesis and accounts for 10% to 20% of the total VWF present in normal platelet-rich plasma. [2][3][4] Importantly, the platelet-VWF pool is distinct from plasma-VWF and is enriched in hemostatically active high molecular weight multimers (HMWM). 5,6 Consequently, high local concentrations of HMWM platelet-VWF are released from a-granules at sites of vascular injury following platelet activation.…”

Section: Introductionmentioning

confidence: 99%