Low VWF: insights into pathogenesis, diagnosis, and clinical management

O’Donnell, James S.

doi:10.1182/bloodadvances.2020002038

Cited by 29 publications

(56 citation statements)

References 73 publications

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“…In addition, further research will also be necessary to elucidate whether inter-individual variations in ABO(H) expression on platelets and/or VWF (particularly HXP and LXP) impact upon risk for cardiovascular disease (e.g. bleeding, thrombosis, TTP) 8 , 43 , or indeed susceptibility to specific types of sepsis.…”

Section: Discussionmentioning

confidence: 99%

Expresser phenotype determines ABO(H) blood group antigen loading on platelets and von Willebrand factor

O'Donghaile

Jenkins

McGrath

et al. 2020

Sci Rep

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ABO blood group is associated with cardiovascular disease, with significantly lower risk in blood group O individuals. ABO(H) blood group determinants are expressed on different glycoproteins on platelet surfaces. In addition, ABO(H) structures are also present on VWF glycans. These ABO(H) carbohydrates influence both platelet and VWF function. Previous studies have reported that approximately 5–10% of normal blood donors express abnormally high or low levels of A or B blood group antigens on their platelet surfaces (high expresser phenotype, HXP or low expresser phenotype, LXP respectively). In this study, the biological effects of the ABO Expresser phenotype were investigated. ABO(H) expression on platelets and plasma VWF was studied in a series of 541 healthy blood donors. Overall, 5.6% of our study cohort were classified as HXP, whilst 4.4% satisfied criteria for LXP. We demonstrate that genotype at the ABO blood group locus plays a critical role in modulating the platelet HXP phenotype. In particular, A1A1 genotype is a major determinant of ABO high-expresser trait. Our data further show that ABH loading on VWF is also affected by ABO expresser phenotype. Consequently, A antigen expression on VWF was significantly elevated in HXP individuals and moderately reduced in LXP subjects (P < 0.05). Collectively, these findings suggest that ABO expresser phenotype influences primary hemostasis though several different pathways. Further studies will be required to define whether inter-individual variations in ABO(H) expression on platelets and/or VWF (particularly HXP and LXP) impact upon risk for cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Expresser phenotype determines ABO(H) blood group antigen loading on platelets and von Willebrand factor

O'Donghaile

Jenkins

McGrath

et al. 2020

Sci Rep

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“…48,49 Taken together, these data clearly suggest that although mild to moderate VWF reductions in the 30 to 50 IU/dL may contribute to global bleeding risk in some individuals, they should be considered a modest risk factor for bleeding rather than a bona fide disease. 16 Based on these observations, consensus guidelines recommend that patients with partial quantitative reductions in plasma VWF levels should therefore be considered in two discrete groups (►Fig. 1).…”

Section: Low Vwfmentioning

confidence: 99%

“…Second, patients with mild to moderate reductions in plasma VWF levels (30-50 IU/dL) and a bleeding phenotype should be labeled as "low VWF." 16 Low VWF is thus a clinicopathological diagnosis rather than simply being based on laboratory VWF levels alone. 16 From a clinical perspective, the concept of low VWF as opposed to type 1 VWD is important in terms of developing personalized VWD treatment.…”

Section: Low Vwfmentioning

confidence: 99%

“…63 This is particularly relevant for patients with partial quantitative VWD including low VWF, who often have normal endogenous FVIII levels which are further increased in the context of any perioperative acute phase stress. 16…”

Section: Tranexamic Acidmentioning

confidence: 99%

“…Accumulating data over recent years has provided important advances in our understanding of VWD pathobiology. 13,[15][16][17] In particular, it has become clear that several distinct subgroups within partial quantitative VWD can now be defined. In this review, these insights into quantitative VWD pathogenesis will be considered.…”

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confidence: 99%

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Toward Personalized Treatment for Patients with Low von Willebrand Factor and Quantitative von Willebrand Disease

O’Donnell

2021

Semin Thromb Hemost

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The biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures.

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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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Low VWF: insights into pathogenesis, diagnosis, and clinical management

Cited by 29 publications

References 73 publications

Expresser phenotype determines ABO(H) blood group antigen loading on platelets and von Willebrand factor

Expresser phenotype determines ABO(H) blood group antigen loading on platelets and von Willebrand factor

Toward Personalized Treatment for Patients with Low von Willebrand Factor and Quantitative von Willebrand Disease

Low von Willebrand Factor in Children and Adolescents

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