Von Willebrand disease type 1: a diagnosis in search of a disease

Von Willebrand disease (VWD) type 1 is reported to be common but frequently is difficult to diagnose. Many people have nonspecific mild bleeding symptoms, von Willebrand factor (VWF) levels display low heritability, and low VWF levels (15% to 50% of normal) are weak risk factors for bleeding. Therefore, bleeding and low VWF levels often associate by chance. Even with stringent diagnostic criteria based on a triad of bleeding symptoms, a low VWF level, and a positive family history, the prevalence of “false-positive” VWD type 1 is comparable to the published prevalence of the disease. Consequently, many patients diagnosed with VWD type 1 do not have a specific hemorrhagic disease at all, which limits the utility of the diagnosis. This unfortunate reality is a consequence of trying to force patients into binary categories of “diseased” or “healthy” that are incompatible with the continuous biologic context in which VWF functions. The problem may be avoided by substituting an empirical epidemiologic approach like that applied to other modest risk factors for disease such as elevated cholesterol and high blood pressure. Such a risk management strategy could be generalized to include other hemorrhagic and thrombotic risk factors.

Download Full-text

Low von Willebrand factor: sometimes a risk factor and sometimes a disease

Hematology ◽

10.1182/asheducation-2009.1.106 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 106-112 ◽

Cited By ~ 52

Author(s):

J. Evan Sadler

Keyword(s):

Risk Factors ◽

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Diagnostic Feature ◽

Multiple Risk Factors ◽

Von Willebrand ◽

The Relationship ◽

Willebrand Factor ◽

Pathophysiologic Mechanisms

Abstract A sufficiently low level of von Willebrand factor (VWF) predisposes to bleeding that can be quite serious, and low VWF is a diagnostic feature of von Willebrand disease (VWD) type 1, which is characterized by partial quantitative deficiency of VWF. Recent groundbreaking studies of patients with VWD type 1 have delineated several pathophysiologic mechanisms that determine the plasma concentration of VWF, but the relationship between VWF level and the likelihood of bleeding remains less well understood. In part, this problem reflects the broad range of VWF levels in the population, so that the distinction between “normal” and “low” is arbitrary. The risk of bleeding certainly increases as the VWF level decreases, but the relationship is not very strong until the VWF level is very low. Furthermore, mild bleeding symptoms are common in apparently healthy populations and have many causes other than defects in VWF, which can make it impossible to attribute bleeding to any single factor, such as low VWF. These difficulties might be resolved by an epidemiologic approach to VWF and other risk factors for bleeding, analogous to how physicians manage multiple risk factors for cardiovascular disease or venous thromboembolism.

Download Full-text

Characterisation of Type 2N von Willebrand Disease Using Phenotypic and Molecular Techniques

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650401 ◽

1996 ◽

Vol 75 (06) ◽

pp. 959-964 ◽

Cited By ~ 27

Author(s):

I M Nesbitt ◽

A C Goodeve ◽

A M Guilliatt ◽

M Makris ◽

F E Preston ◽

...

Keyword(s):

Direct Sequencing ◽

Von Willebrand Disease ◽

Molecular Techniques ◽

Haemophilia A ◽

Binding Region ◽

Gene Encoding ◽

Covalently Linked ◽

Von Willebrand ◽

Willebrand Factor

Summaryvon Willebrand factor (vWF) is a multimeric glycoprotein found in plasma non covalently linked to factor VIII (FVIII). Type 2N von Willebrand disease (vWD) is caused by a mutation in the vWF gene that results in vWF with a normal multimeric pattern, but with reduced binding to FVIII.We have utilised methods for the phenotypic and genotypic detection of type 2N vWD. The binding of FVIII to vWF in 69 patients, 36 with type 1 vWD, 32 with mild haemophilia A and one possible haemophilia A carrier with low FVIII levels was studied. Of these, six were found to have reduced binding (five type 1 vWD, one possible haemophilia A carrier), DNA was extracted from these patients and exons 18-23 of the vWF gene encoding the FVIII binding region of vWF were analysed. After direct sequencing and chemical cleavage mismatch detection, a Thr28Met mutation was detected in two unrelated individuals, one of whom appears to be a compound heterozygote for the mutation and a null allele. No mutations were found in the region of the vWF gene encoding the FVIII binding region of vWF in the other four patients

Download Full-text

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

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1722864 ◽

2021 ◽

Vol 47 (02) ◽

pp. 192-200

Author(s):

James S. O'Donnell

Keyword(s):

Von Willebrand Factor ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Personalized Treatment ◽

Treatment Plans ◽

Type 3 ◽

Von Willebrand ◽

Willebrand Factor

AbstractThe 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.

Download Full-text

Polymorphism in the promoter region of von Willebrand factor gene and von Willebrand disease type 1

Genetics and Molecular Biology ◽

10.1590/s1415-47572003000400001 ◽

2003 ◽

Vol 26 (4) ◽

pp. 397-401 ◽

Cited By ~ 3

Author(s):

Daniel Simon ◽

Eliane Bandinelli ◽

Israel Roisenberg

Keyword(s):

Von Willebrand Factor ◽

Promoter Region ◽

Disease Type ◽

Von Willebrand Disease ◽

Factor Gene ◽

Von Willebrand ◽

Willebrand Factor

Download Full-text

An apparently silent nucleotide substitution (c.7056C>T) in the von Willebrand factor gene is responsible for type 1 von Willebrand disease

Haematologica ◽

10.3324/haematol.2010.036848 ◽

2011 ◽

Vol 96 (6) ◽

pp. 881-887 ◽

Cited By ~ 12

Author(s):

V. Daidone ◽

L. Gallinaro ◽

M. Grazia Cattini ◽

E. Pontara ◽

A. Bertomoro ◽

...

Keyword(s):

Von Willebrand Factor ◽

Nucleotide Substitution ◽

Von Willebrand Disease ◽

Factor Gene ◽

Von Willebrand ◽

Willebrand Factor

Download Full-text

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

Blood Advances ◽

10.1182/bloodadvances.2020002038 ◽

2020 ◽

Vol 4 (13) ◽

pp. 3191-3199 ◽

Cited By ~ 1

Author(s):

James S. O’Donnell

Keyword(s):

Clinical Management ◽

Molecular Mechanisms ◽

Optimal Choice ◽

Von Willebrand Disease ◽

Limited Information ◽

Von Willebrand ◽

The Relationship ◽

Willebrand Factor ◽

Choice Of Therapy

Abstract von Willebrand disease (VWD) constitutes the most common inherited human bleeding disorder. Partial quantitative von Willebrand factor (VWF) deficiency is responsible for the majority of VWD cases. International guidelines recommend that patients with mild to moderate reductions in plasma VWF antigen (VWF:Ag) levels (typically in the range of 30-50 IU/dL) should be diagnosed with low VWF. Over the past decade, a series of large cohort studies have provided significant insights into the biological mechanisms involved in type 1 VWD (plasma VWF:Ag levels <30 IU/dL). In striking contrast, however, the pathogenesis underpinning low VWF has remained poorly understood. Consequently, low VWF patients continue to present significant clinical challenges with respect to genetic counseling, diagnosis, and management. For example, there is limited information regarding the relationship between plasma VWF:Ag levels and bleeding phenotype in subjects with low VWF. In addition, it is not clear whether patients with low VWF need treatment. For those patients with low VWF in whom treatment is deemed necessary, the optimal choice of therapy remains unknown. However, a number of recent studies have provided important novel insights into these clinical conundrums and the molecular mechanisms responsible for the reduced levels observed in low VWF patients. These emerging clinical and scientific findings are considered in this review, with particular focus on pathogenesis, diagnosis, and clinical management of low VWF.

Download Full-text

Critical independent regions in the VWF propeptide and mature VWF that enable normal VWF storage

Blood ◽

10.1182/blood-2002-07-2281 ◽

2003 ◽

Vol 101 (4) ◽

pp. 1384-1391 ◽

Cited By ~ 32

Author(s):

Sandra L. Haberichter ◽

Paula Jacobi ◽

Robert R. Montgomery

Keyword(s):

Endothelial Cells ◽

Species Differences ◽

Intracellular Localization ◽

Von Willebrand Disease ◽

Healthy Individuals ◽

Furin Cleavage ◽

Storage Granules ◽

Von Willebrand ◽

Willebrand Factor

Von Willebrand factor (VWF) is synthesized in endothelial cells, where it is stored in Weibel-Palade bodies. Administration of 1-desamino-8-D-arginine-vasopressin (DDAVP) to patients with type 1 von Willebrand disease and to healthy individuals causes a rapid increase in plasma VWF levels. This increase is the result of stimulated release of VWF from Weibel-Palade bodies in certain beds of endothelial cells. The VWF propeptide (VWFpp) targets VWF to storage granules through a noncovalent association. The nature of the VWFpp/VWF interaction was investigated by using cross-species differences in VWF storage. While canine VWFpp traffics to storage granules and facilitates the multimerization of human VWF, it does not direct human VWF to storage granules. Since storage takes place after furin cleavage, this defect appears to be due to the defective interaction of canine VWFpp and human VWF. To determine the regions within VWFpp and VWF important for this VWFpp/VWF association and costorage, a series of human-canine chimeric VWFpp and propeptide-deleted VWF (Δpro) constructs were produced and expressed in AtT-20 cells. The intracellular localization of coexpressed proteins was examined by confocal microscopy. Two amino acids, 416 in VWFpp and 869 in the mature VWF molecule, were identified as being critical for the association and granular storage of VWF.

Download Full-text

Major haemorrhage related to surgery in patients with type 1 and possible type 1 von Willebrand disease

Thrombosis and Haemostasis ◽

10.1160/th-07-12-0757 ◽

2008 ◽

Vol 100 (05) ◽

pp. 797-802 ◽

Cited By ~ 13

Author(s):

Alicia Blanco ◽

Roberto Chuit ◽

Susana Meschengieser ◽

Ana Kempfer ◽

Cristina Farías ◽

...

Keyword(s):

Family History ◽

Surgical Procedures ◽

Tooth Extraction ◽

Positive Family History ◽

Major Haemorrhage ◽

Von Willebrand Disease ◽

Bleeding Complications ◽

Laboratory Test Results ◽

Von Willebrand

SummaryPatients with von Willebrand disease (VWD) frequently bleed under a challenge. The aim of our study was to identify predictive markers of perioperative major haemorrhage in type 1 (VWF:RCo = 15–30 IU dl-1) and possible type 1 (VWF:RCo = 31–49 IU dl-1)VWD patients. We recorded perioperative bleeding complications previous to diagnosis and laboratory parameters in 311 patients with 498 surgical procedures. The patients were grouped according to the absence (A) or presence (B) of perioperative major haemorrhages. Eighty-one patients (26%) and 87 surgical procedures (17.5%) presented major haemorrhages associated with surgeries. There was no difference between the percentage of type 1 and possible type 1 VWD patients who had major haemorrhages (32.6% and 24.8% respectively; p=ns). No difference in the prevalence of O blood group, age, gender, positive family history and laboratory test results (FVIII and VWF) was observed, independent of the haemorrhagic tendency. Bleeding after tooth extraction was the most frequent clinical feature observed in patients with perioperative major haemorrhages. The bleeding score and the number of bleeding sites (≥3) were not predictors of major haemorrhage associated with surgery. Caesarean section and adenotonsillectomy showed the highest frequency of major haemorrhages (24.6% and 22.3%, respectively). In conclusion, type 1 and possible type 1VWD patients showed similar incidence of perioperative major haemorrhages. Laboratory tests and positive family history did not prove to be effective at predicting major haemorrhages in patients that had either type 1 or possible type 1 VWD. The history of bleeding after tooth extraction could define risk factors of major haemorrhage.

Download Full-text