Platelet morphological changes in 2 patients with von Willebrand disease type 3 caused by large homozygous deletions of the von Willebrand factor gene

Nurden, Paquita; Marca, Silvia La; Punzo, Margherita; Baronciani, Luciano; Federici, Augusto B.

doi:10.3324/haematol.2009.012658

Cited by 9 publications

(10 citation statements)

References 12 publications

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“…Traditionally, the diagnosis of type 3 VWD was predicated on the VWF:Ag levels based on sensitive immunoassays, rather than defining the diagnosis on VWF:RCo assay results, because of the limitations of that assay as described above. Recent reports suggest that platelet morphological changes [22], likelihood of alloantibody formation [21] and perhaps clinical and laboratory phenotypes, may be associated with specific VWF genetic haplotypes. The ability to measure low levels of VWF:RCo activity may provide increased sensitivity to correlate VWF structure and function in type 3 patients.…”

Section: Discussionmentioning

confidence: 99%

Improved performance characteristics of the von Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocol

Hillarp

Stadler

Haderer

et al. 2010

Journal of Thrombosis and Haemostasis

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Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocol. J Thromb Haemost 2010; 8: 2216-23.Summary. Background, objectives and methods: An accurate, sensitive and precise assay for reliable determination of the ristocetin cofactor activity of von Willebrand factor (VWF:RCo) in plasma and von Willebrand Factor (VWF)-containing concentrates has been evaluated. The assay is based on a commercially available automated protocol with modifications including a combination of adding additional ristocetin and the use of two calibration curves for the high and low measuring ranges. Results: Addition of extra ristocetin resulted in improved measurement of VWF recoveries from various VWF-containing concentrates that were underestimated using the standard automated protocol. The modifications resulted in improved assay performance over an extended measuring range (2.00-0.03 IU mL )1). Accuracy was tested using VWF deficiency plasma spiked with the 1st international standard (IS) for VWF concentrate. Seven dilutions, ranging from 1.80 to 0.05 IU mL )1, were analyzed and resulted in measured concentrations between 80% and 100% of the assigned potency of the standard. Linearity was determined from the regression plot of the same concentrate dilutions and resulted in a correlation coefficient of 0.998. The repeatability, expressed as coefficient of variation, was 2% in the normal range (0.90 IU mL . The corresponding reproducibility results were 2% and 15% at the normal and low measuring ranges, respectively. Conclusions: Analysis of patients with von Willebrand disease (VWD) indicates that the modified automated BCS Ò protocol has a superior discrimination power compared with the standard protocol. This is especially true in samples with low VWF, as in patients with type 3 VWD.

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Section: Discussionmentioning

confidence: 99%

Improved performance characteristics of the von Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocol

Hillarp

Stadler

Haderer

et al. 2010

Journal of Thrombosis and Haemostasis

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“…VWF has also been identified as a sensitive and distinct marker for early MK [4] and exposure of human MK to VWF at high shear rates in vitro was reported to accelerate platelet production [5]. More recently, abnormal VWF mutants as those found in VWD3 have been found with abnormal platelet structure [6] and those of VWD2B have been associated with reduced platelet production [7, 8]. Therefore, VWF should be considered also one of the most important markers of EC damage and platelet formation.…”

Section: Introductionmentioning

confidence: 99%

Circulating and progenitor endothelial cells are abnormal in patients with different types of von Willebrand disease and correlate with markers of angiogenesis

et al. 2011

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von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by quantitative or qualitative defects of von Willebrand factor (VWF). VWF, synthesized by endothelium and megakaryocytes (MK), circulates in plasma and is present in subendothelium and platelets. Circulating endothelial cells (CEC) and progenitor endothelial cells (EPC) have been recently proposed as markers of peripheral and bone marrow-derived angiogenesis. To evaluate the association of CEC/EPC with known inherited defects of cellular and circulating VWF, we have measured the number of CEC/EPC together with cytokines involved in angiogenesis in different VWD types. A group of 74 patients was composed by the following VWD types: VWD1 (n 5 22), VWD2A (n 5 9), VWD2B (n 5 19), VWD2M (n 5 17), and VWD3 (n 5 7). Healthy individuals (n 5 20) were used as controls. CEC (CD146 1 , CD31 1 , and CD45 2 ) and EPC (CD34 1 , CD133 1 , and CD45 2 ) were evaluated by flow cytometry. Circulating serum levels of VEGF, E-selectin, P-selectin, EPO, and TPO were determined by ELISA. CEC, VEGF, E-selectin, and EPO were higher and EPC lower in VWD patients than in controls (P < 0.01). Among the five groups of VWD patients and controls, a significant difference was found for CEC (one-way ANOVA: P 5 0.005), EPC (P 5 0.001), E-Selectin (P < 0.0001), EPO (P 5 0.021), and TPO (P 5 0.004): the latter was high in VWD3 patients. In VWD1, we found an inverse relationship between CEC and VWF:Ag levels (P 5 0.048; R 2 5 0.19). Based on these data, CEC are increased in VWD and are associated with the high levels of cytokines involved in angiogenesis (up-regulation). EPC are decreased, suggesting down-regulation of bone marrow-derived angiogenesis in VWD. Am. J. Hematol. 86:650-656, 2011. V

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“…Leebeek et al, 94 Nurden et al 97 Genetic disorders and their respective mutated genes that lead to a bleeding phenotype. Most of the disorders are categorized as rare, with the exception of VWD, the most common bleeding disorder, with prevalence of up to 1% of the general population.…”

Section: Vwf Severementioning

confidence: 99%

“…74,80,89,90 Additionally, VWD, especially type 2 and 3, has been associated with impaired megakaryopoiesis and platelet dysfunction, implicating VWF/ GPIb-V-IX interactions in a novel role during platelet production. [95][96][97] Taken together, LRO disorders comprise a heterogeneous group that has a multisystemic phenotype. In most cases, the bleeding tendency caused by these disorders has been attributed to a particular LRO; however, as we understand that cellular mechanisms are shared between cell types, it becomes clearer that >1 LRO can be affected.…”

Section: Vwf Severementioning

confidence: 99%

Orchestration of Primary Hemostasis by Platelet and Endothelial Lysosome-Related Organelles

Karampini

Bierings

Voorberg

2020

ATVB

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Megakaryocyte-derived platelets and endothelial cells store their hemostatic cargo in α- and δ-granules and Weibel-Palade bodies, respectively. These storage granules belong to the lysosome-related organelles (LROs), a heterogeneous group of organelles that are rapidly released following agonist-induced triggering of intracellular signaling pathways. Following vascular injury, endothelial Weibel-Palade bodies release their content into the vascular lumen and promote the formation of long VWF (von Willebrand factor) strings that form an adhesive platform for platelets. Binding to VWF strings as well as exposed subendothelial collagen activates platelets resulting in the release of α- and δ-granules, which are crucial events in formation of a primary hemostatic plug. Biogenesis and secretion of these LROs are pivotal for the maintenance of proper hemostasis. Several bleeding disorders have been linked to abnormal generation of LROs in megakaryocytes and endothelial cells. Recent reviews have emphasized common pathways in the biogenesis and biological properties of LROs, focusing mainly on melanosomes. Despite many similarities, LROs in platelet and endothelial cells clearly possess distinct properties that allow them to provide a highly coordinated and synergistic contribution to primary hemostasis by sequentially releasing hemostatic cargo. In this brief review, we discuss in depth the known regulators of α- and δ-granules in megakaryocytes/platelets and Weibel-Palade bodies in endothelial cells, starting from transcription factors that have been associated with granule formation to protein complexes that promote granule maturation. In addition, we provide a detailed view on the interplay between platelet and endothelial LROs in controlling hemostasis as well as their dysfunction in LRO related bleeding disorders.

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Platelet morphological changes in 2 patients with von Willebrand disease type 3 caused by large homozygous deletions of the von Willebrand factor gene

Cited by 9 publications

References 12 publications

Improved performance characteristics of the von Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocol

Improved performance characteristics of the von Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocol

Circulating and progenitor endothelial cells are abnormal in patients with different types of von Willebrand disease and correlate with markers of angiogenesis

Orchestration of Primary Hemostasis by Platelet and Endothelial Lysosome-Related Organelles

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