von Willebrand factor clearance – biological mechanisms and clinical significance

O’Sullivan, Jamie M.; Ward, Soracha E.; Lavin, Michelle; O’Donnell, James S.

doi:10.1111/bjh.15565

Cited by 62 publications

(75 citation statements)

References 83 publications

(145 reference statements)

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“…A recent meta-analysis of 11 independent genome-wide association studies (GWASs) [56] revealed that blood group O determines low VWF independently of A and B antigens; moreover, A and B antigens may also determine higher plasma VWF. Moreover, individuals with blood group O have slightly increased VWF clearance [57], which is probably another determinant of lower VWF in subjects with this blood type and, consistently, the largest collaborative studies on VWD have found slightly increased VWF clearance in a significant proportion of type 1 VWD patients [58]. This would be an additional mechanism in the pathogenesis of this disorder.…”

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 91%

“…In this regard, VWF mutations associated with decreased VWF sialylation [59] and increased binding of VWF to LRP1 and SR-AI [60,61] have been associated with low VWF resembling the type 1 VWD phenotype, but with normal platelet and endothelial VWF [58]. Supporting these observations, large cohort studies have found a significant proportion of type 1 VWD patients with enhanced VWF clearance [39,62,63], which would be an additional mechanism of the disease.…”

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

“…Recently, O'Sullivan et al . reviewed the mechanisms and genetic loci involved in VWF clearance . Succinctly, asialoglycoprotein receptors, i.e.…”

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

“…Macrophages bind, take up and degrade VWF, playing a main role in its removal from the circulation. Recently, O'Sullivan et al reviewed the mechanisms and genetic loci involved in VWF clearance [58]. Succinctly, asialoglycoprotein receptors, i.e.…”

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

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Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Mezzano

Quiroga

2019

Journal of Thrombosis and Haemostasis

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Summary The best‐known inherited mild bleeding disorders (MBDs), i.e. type 1 von Willebrand disease (VWD), platelet function disorders (PFDs), and mild to moderate clotting factor deficiencies, are characterized clinically by mucocutaneous bleeding, and, although they are highly prevalent, still pose difficult diagnostic problems. These include establishing the pathological nature of bleeding, and the uncertainties surrounding the clinical relevance of laboratory results. Furthermore, the high frequency of bleeding symptoms in the normal population and the subjective appraisal of symptoms by patients or parents makes elucidating the pathological nature of bleeding difficult. Standardized bleeding assessment tools and semiquantitative bleeding scores (BSs) help to discriminate normal from abnormal bleeding. However, as most MBDs have similar bleeding patterns, for example, bleeding sites, frequency, and severity, BSs are of little help for diagnosing specific diseases. Global tests of primary hemostasis (bleeding time; PFA‐100/200) lack sensitivity and, like BSs, are not disease‐specific. Problems with the diagnosis of type 1 VWD and PFD include assay standardization, uncertain definition of von Willebrand factor cut‐off levels, and the lack of universal diagnostic criteria for PFD. Regarding clotting factor deficiencies, the bleeding thresholds of some coagulation factors, such as factor VII and FXI, are highly variable, and may lead to misinterpretation of the clinical relevance of mild to moderate deficiencies. Remarkably, a large proportion of MBDs remain undiagnosed even after comprehensive and repeated laboratory testing. These are tentatively considered to represent bleeding of undefined cause, with clinical features indistinguishable from those of classical MBD; the pathogenesis of this is probably multifactorial, and unveiling these mechanisms should constitute a fertile source of translational research.

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Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 91%

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

“…Recently, O'Sullivan et al . reviewed the mechanisms and genetic loci involved in VWF clearance . Succinctly, asialoglycoprotein receptors, i.e.…”

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

See 2 more Smart Citations

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Mezzano

Quiroga

2019

Journal of Thrombosis and Haemostasis

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“…Quantitative abnormalities in plasma levels of coagulation factors, including the multimeric glycoprotein von Willebrand factor (VWF) can associate with either bleeding disorders (von Willebrand disease, VWD) or increase the risk for thrombosis . Plasma levels of VWF can be modified by pathways that regulate its synthesis or secretion from endothelial cells or megakaryocytes, or clearance, which involves a series of semiselective ligand‐receptor mediated interactions involving hepatocytes, macrophages, and endothelial cells in the liver and/or spleen …”

Section: Introductionmentioning

confidence: 99%

The scavenger receptor SCARA5 is an endocytic receptor for von Willebrand factor expressed by littoral cells in the human spleen

Swystun

Ogiwara

Lai

et al. 2019

Journal of Thrombosis and Haemostasis

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Background: Scavenger receptors play a significant role in clearing aged proteins from the plasma, including the large glycoprotein coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII). A large genome-wide association study metaanalysis has identified genetic variants in the gene SCARA5, which encodes the class A scavenger receptor SCARA5, as being associated with plasma levels of VWF and FVIII.Objectives: The ability of SCARA5 to regulate the clearance of VWF-FVIII was characterized.Methods: VWF-FVIII interactions with SCARA5 were evaluated by solid phase binding assays and in vitro cell based assays. The influence of SCARA5 deficiency on VWF:Ag and half-life was assessed in a murine model. The expression pattern of SCARA5 and its colocalization with VWF was evaluated in human tissues.Results: VWF and the VWF-FVIII complex bound to human recombinant SCARA5 in a dose-and calcium-dependent manner. SCARA5 expressing HEK 293T cells bound and internalized VWF and the VWF-FVIII complex into early endosomes. In vivo, SCARA5 deficiency had a modest influence on the half-life of human VWF. mRNA analysis and immunohistochemistry determined that human SCARA5 is expressed in kidney podocytes and the red pulp, white pulp, and marginal zone of the spleen.VWF was found to colocalize with SCARA5 expressed by littoral cells lining the red pulp of the human spleen.Conclusions: SCARA5 is an adhesive and endocytic receptor for VWF. In human tissues, SCARA5 is expressed by kidney podocytes and splenic littoral endothelial cells. SCARA5 may have a modest influence on VWF clearance in humans. K E Y W O R D Sendocytosis, endothelial cells, factor VIII, GWAS, receptors scavenger, von Willebrand factor | 1385 SWYSTUN eT al.

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Low von Willebrand Factor in Children and Adolescents

Srivaths

Kouides

2021

JAMA Pediatr

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on Willebrand disease (VWD) is the most common inherited bleeding disorder, with a reported prevalence in the general population of 0.1% to 1%, 1,2 occurring in all races and ethnicities. 3 The disease is named after the Finnish internist who discovered the disorder in 1926 as a familial hemorrhagic diathesis in a 5-year-old girl from the Aland Islands, who died 10 years later of menorrhagia. 4 von Willebrand disease is classified as a quantitative or qualitative deficiency of von Willebrand factor (VWF). The quantitative deficiency includes the common partial or type 1 VWD (VWF level <30 IU/dL) and the rare severe or type 3 VWD (VWF <5 IU/dL). The qualitative deficiency, namely, type 2 VWD, is caused by structural abnormalities of the von Willebrand protein. Normal VWF levels range from 50 to 200 IU/dL, and levels that range from 30 to 50 IU/dL are considered low VWF. Whether low VWF should be considered a risk factor for bleeding or a bleeding disorder has been a decade-long debate. 5 Some studies [6][7][8] have documented increased bleeding symptoms in patients with low VWF, highlighting the clinical significance of this entity, and other studies 9-11 have provided insights into the pathogenesis of low VWF. Children and ado-lescents with VWF deficiencies often present to primary care physicians (PCPs) with symptoms such as easy bruising, mucosal bleeding, heavy menstrual bleeding (HMB), and posttraumatic and postsurgical bleeding during operations, such as tonsillectomy and adenoidectomy. 12,13 In adolescent girls with HMB in particular, the quality-of-life impact can be substantial. Consequently, it is important for physicians to be aware of this condition for early detection, appropriate specialty referrals, and continued comanagement of these patients. This narrative review of low VWF in children and adolescents clarifies the differences between type 1 VWD and low VWF; summarizes the recent findings about the clinical spectrum, pathogenesis, diagnostic evaluation, and management of the disorder; and emphasizes the role PCPs play in the care of these patients. Low VWFThe diagnosis of low VWF is made in patients with a bleeding phenotype, with VWF levels ranging from 30 to 50 IU/dL. Previous IMPORTANCE Recent studies have documented increased bleeding symptoms and related complications in patients with low von Willebrand factor (VWF), highlighting the clinical significance of this entity. Because children and adolescents with VWF deficiencies often present to primary care physicians with bleeding symptoms, physicians need to be aware of this condition for early detection.OBSERVATIONS Studies have found that children and adolescents with low VWF (VWF levels of 30-50 IU/dL) can present with clinically significant bleeding, including mucosal, menstrual, postsurgical, and posttraumatic bleeding, leading to complications such as anemia, iron deficiency, transfusion, hospitalization, and poor quality of life. Detecting and promptly managing low VWF in children and adolescents with bleeding are essential because fai...

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von Willebrand factor clearance – biological mechanisms and clinical significance

Cited by 62 publications

References 83 publications

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

The scavenger receptor SCARA5 is an endocytic receptor for von Willebrand factor expressed by littoral cells in the human spleen

Low von Willebrand Factor in Children and Adolescents

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