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PubMed2001

Management of inherited von Willebrand disease.

von Willebrand disease is a bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor. The diagnosis is based on measurements of plasma and platelet von Willebrand factor, the ability of von Willebrand factor to interact with its platelet receptor and the analysis of the multimeric composition of von Willebrand factor. Owing to the heterogeneity of von Willebrand factor defects, a correct diagnosis of types and subtypes may be sometimes difficult but is very important for an appropriate therapy. The aim of treatment is to correct the dual defects of haemostasis, i.e. abnormal coagulation, expressed by a low level of factor VIII, and abnormal platelet adhesion, expressed by a prolonged bleeding time. Desmopressin is the treatment of choice in patients with type I von Willebrand disease, who account for approximately 70% of cases, because it corrects the factor VIII/von Willebrand factor level and the prolonged bleeding time in most of these patients. In type 3 and in the majority of type 2 von Willebrand disease patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are effective and currently safe, but they do not always correct the bleeding time defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when a poor correction of the bleeding time after concentrates is associated with continued bleeding. Studies are in progress, first to better characterize patients with type I von Willebrand disease and to determine their response to desmopressin, and second, to evaluate the pharmacokinetics of factor VIII following factor VIII/von Willebrand factor concentrates and to establish the indication for concentrates.

Bleeding Time↗

PubMed2005

[Inborn and acquired von Willebrand disease].

Von Willebrand disease (VWD) is known for its marked heterogeneity which was already recognized by von Willebrand in 1926. The basis of phenotypic differentiation are quantitative and qualitative or functional differences between the different types and subtypes of VWD. Clinical relevant facts for the practitioner on diagnosis and therapy of von Willebrand disease and von Willebrand syndrome are presented.

Deamino Arginine Vasopressin↗

PubMed1998

Treatment of von Willebrand disease.

von Willebrand disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of treatment is to correct the dual defects of haemostasis, i.e., abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with type 1 von Willebrand disease, who account for approximately 80% of cases. This pharmacological compound raises endogenous factor VIII and von Willebrand factors and thereby corrects the intrinsic coagulation defect and the prolonged bleeding time in most type 1 patients. In type 3 and in the majority of type 2 patients desmopressin is not effective, and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are effective and currently safe, but the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time after concentrates is associated with continued bleeding.

Blood Transfusion↗

PubMed2001

Getting at the variable expressivity of von Willebrand disease.

Von Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by abnormalities of von Willebrand factor (VWF). VWF levels vary widely in the general population, and this variation is likely to be a major factor accounting for the incomplete penetrance and variable expressivity of VWD. In addition, variation in VWF level may play an important role in determining the risk of venous thrombosis. A large component of the variation in VWF level in the general population has been shown to be attributable to genetic factors. This review will focus on the current understanding of the genetic causes for variation in VWF level, and will highlight future directions for getting at the variable expressivity of von Willebrand disease.

ABO Blood-Group System↗

PubMed1991

Abnormal binding of factor VIII is linked with the substitution of glutamine for arginine 91 in von Willebrand factor in a variant form of von Willebrand disease.

von Willebrand factor (vWf) is a multimeric plasma glycoprotein that functions in hemostasis as the initiator of platelet adhesion to damaged blood vessels and as the carrier of Factor VIII (FVIII). Montgomery et al. (Montgomery, R.R., Hathaway, W.E., Johnson, J., Jacobsen, L., and Muntean, W. (1982) Blood 60, 201-207) reported a variant of von Willebrand disease characterized by the abnormal interaction between FVIII and a defective vWf. To identify the molecular basis of this abnormal interaction, we isolated platelet RNA from members of one of the affected families and determined the nucleotide sequence of the FVIII-binding domain encoded by the vWf mRNA. A single G to A transition at nucleotide 2561 was linked with disease expression and results in the substitution of Gln for Arg91 in mature vWf. A restriction fragment containing this mutation was introduced into a full-length vWf expression vector, and both wild type and mutant vWf were expressed in COS-7 cells. In a solid-phase binding assay, expressed vWf was captured with anti-vWf monoclonal antibody AVW1 and then incubated with 6.25-400 milliunits of recombinant FVIII. After washing, vWf-bound FVIII activity was determined with a chromogenic assay. Mutant vWf showed reduced binding of FVIII compared with wild type, suggesting that the substitution of Gln for Arg91 is the likely basis for the abnormal vWf/FVIII interaction in this von Willebrand disease variant.

Arginine↗

PubMed1998

Laboratory diagnosis of von Willebrand disease.

Von Willebrand disease is the most-common inherited bleeding disorder, including both quantitative (types 1 and 3) and qualitative (type 2) defects of von Willebrand factor. Among patients with suspected von Willebrand disease, the laboratory diagnosis requires three levels of testing: screening tests, specific assays for von Willebrand factor to establish the diagnosis, and discriminating tests to allow accurate characterization of the numerous types and subtypes of the disease. Because of their poor sensitivity, normal screening tests do not exclude the diagnosis. In most cases, specific measurements of von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity, and factor VIII levels in plasma allow differentiation of quantitative (proportionately decreased levels) and qualitative (discrepant levels) deficiencies of von Willebrand factor. Among the latter, a decreased von Willebrand factor ristocetin cofactor activity/von Willebrand factor antigen ratio is in favor of the three subtypes (2A, 2M, and 2B) defined by an abnormal interaction between von Willebrand factor and platelet glycoprotein Ib, whereas a decreased factor VIII/von Willebrand factor antigen ratio suggests subtype 2N, defined by a defective binding of von Willebrand factor to factor VIII. Several discriminating tests are available to definitively characterize each subtype. Moreover, for all variants, the link between phenotype and genotype is established using DNA analysis. In all cases, the precise characterization of type and subtype of von Willebrand disease remains essential for the choice of optimal therapeutic monitoring of each patient.

Hematologic Tests↗

PubMed1998

Comparison between von Willebrand factor (VWF) and VWF antigen II in normal individuals and patients with von Willebrand disease.

Von Willebrand disease is characterised by a quantitative (type 1) or qualitative (type 2) decrease in von Willebrand factor (vWF) a multimeric glycoprotein involved in primary haemostasis. The propeptide of von Willebrand, also named vWF antigen II (vWF:AgII), is released from platelets and endothelial cells and circulates in plasma as a glycoprotein of 100 kD. In the present study, we attempted to determine whether vWF:AgII level may provide information on the synthesis of vWF, specially in patients with von Willebrand disease (vWD). To elucidate that point, we developed an ELISA and quantify the vWF:AgII in normal individuals and in various vWD patients. The propeptide molar concentration was found to be 5 nM as compared to 31 nM for mature vWF. In normal individuals, the level of vWF:AgII was significantly decreased in females from O and A blood groups. In type 2 vWD patients the level of plasma vWF:AgII appears normal in the patients with normal level of platelet vWF. In type 2 B vWD characterised by increased affinity of mature vWF for platelet glycoprotein Ib, the vWF:AgII in contrast to the vWF antigen (vWF:Ag) was not decreased. In type 2A vWD patients the level of vWF:AgII was decreased in patients with absence of high molecular weight vWF in platelets and plasma but normal in patients with increased sensitivity to proteolysis. Finally, in type 1 vWD, some studied patients have a parallel decrease in vWF:AgII and vWF:Ag whereas in others, the vWF:Ag levels were much more affected than corresponding vWF:AgII levels, as observed in some type 2 vWD patients. Thus, in contrast to that already described, the plasma vWF:AgII level cannot discriminate type 1 from type 2 vWD patients. We conclude that the vWF:AgII measurement provides additional information on the mechanisms responsible for vWD and might also contribute to the classification of vWD patients.

Antigens↗

PubMed2004

Bleeding manifestations in males with von Willebrand disease.

von Willebrand disease (vWD) is the most common congenital bleeding disorder in the USA, affecting 1-3% of the population. Previously characterizing the bleeding symptoms in females with type 1 vWD, we evaluated 42 males with type 1 vWD, mean age 16 years (1-64), of whom 24 (57%) presented with bleeding symptoms. The most common initial symptom was postoperative bleeding (26%). The most common bleeding symptoms ever were epistaxis (53%), bruising (50%), postoperative bleeding (47%), haematomas (29%) and oral bleeding (29%). Of postoperative bleeding, ear/nose/throat (44%), dental (17%) and circumcision bleeding (22%) occurred at a median 10 years of age, despite a previous bleeding or family history in 89%. Complications included anaemia in five (12%), neurological sequelae after subdural haematoma and tonsillectomy in two (5%), transfusion-associated hepatitis C in two (5%) and degenerative joint disease after traumatic haemarthroses in one (2%). The bleeding time (BT) was prolonged in 83%, and the ristocetin cofactor (vW:RCoF) and factor VIII (FVIII:C) decreased in 64% and 43%, respectively. Haemarthroses and haematoma formation were associated with a longer activated partial thromboplastin time (APTT) (P < 0.05), and anaemia with a lower FVIII:C (P < 0.05). In 81%, a haemostatic response occurred with 1-8 deamino-d-arginine vasopressin (DDAVP), although, in 13%, surgical intervention was also required to achieve haemostasis. Postoperative bleeding could have been avoided in 89%, if a preoperative past bleeding history or family history had been obtained, and, in at least 94%, if a preoperative BT and APTT had also been performed. The failure to avoid postoperative bleeding and related complications in patients with vWD by taking a personal and family bleeding history constitutes a major public health problem.

Adolescent↗

PubMedDate not supplied

Pathogenesis and classification of von Willebrand disease.

Von Willebrand disease, the most common congenital bleeding disorder in humans, is the consequence of quantitative and/or qualitative defects of von Willebrand factor, a protein necessary for platelet adhesion and thrombus formation at sites of vascular injury. Distinct molecular defects of von Willebrand factor are responsible for the heterogeneity of von Willebrand disease subtypes. A classification in four main groups, each characterized by distinctive pathogenetic features, represents the basis for a correct therapeutic approach to bleeding episodes in these patients.

Humans↗

PubMed1990

Molecular studies of von Willebrand disease: reduced von Willebrand factor biosynthesis, storage, and release in endothelial cells derived from patients with type I von Willebrand disease.

Endothelial cells were cultured from the umbilical veins of two neonates with type I von Willebrand disease (vWD) and compared with cells cultured in parallel from normal control umbilical veins. In both cases, cultured vWD endothelial cells contained less messenger RNA (mRNA) encoding von Willebrand factor (vWF), and constitutively secreted two- to fourfold less vWF protein than their matched controls. Regulated secretion of stored vWF induced by thrombin or phorbol-12-myristate-13-acetate (PMA) was also diminished in vWD cells. Both the mRNA and protein produced by each of these type I vWD cells appeared to be of normal size. However, despite the diminished size of the vWF storage pool, electron microscopy of endothelial cells in situ showed normal appearing vWF storage organelles (Weibel-Palade bodies). These studies show that cultured umbilical vein endothelial cells can be used to explore the molecular defects in type I and perhaps other forms of vWD, and suggest that at least some forms of type I vWD are caused by diminished mRNA transcription or subsequent translation due to a defective vWF allele.

Adult↗

PubMed2005

New concepts in von Willebrand disease.

Von Willebrand factor (VWF) behaves as an extracellular adapter molecule, linking platelets to the extracellular matrix at sites of vascular injury. These interactions are crucial for hemostasis. Too little platelet adhesion causes bleeding that is typical of von Willebrand disease, whereas too much platelet adhesion may cause thrombotic thrombocytopenic purpura. Mutations in VWF or platelet glycoprotein Ib can either reduce or increase the affinity of platelet binding. Paradoxically, affinity changes in either direction cause bleeding. Crystallographic studies now suggest molecular explanations for all of these phenotypes. Clinical investigations of von Willebrand disease type 1 are defining the relationship between plasma VWF level and the risk of bleeding or thrombosis. Emerging data suggest that VWF level is a useful biomarker for the risk of either bleeding or thrombosis and could be incorporated into a comprehensive approach to treat or prevent these adverse events.

Hemorrhage↗

PubMed2006

Comparison of a new automated von Willebrand factor activity assay with an aggregation von Willebrand ristocetin cofactor activity assay for the diagnosis of von Willebrand disease.

von Willebrand disease (VWD) is caused by quantitative and/or qualitative defects of von Willebrand factor (VWF). The HemosIL von Willebrand Factor Activity assay, a new automated immunological test to measure VWF activity, was implemented on STAC and compared with the von Willebrand ristocetin cofactor activity (VWF:RCo) aggregation method. Imprecision and dilution studies were also performed. Within-run imprecision was 17.2% and between-run imprecision was 8.3% (coefficients of variation). Dilution studies showed a linearity between 12.5 and 100%. Passing and Bablok regression comparing the HemosIL von Willebrand Factor Activity assay and the aggregation method yielded a slope of 1.25 (95% confidence interval: 1.11-1.38) and intercept of -1.40 (95% confidence interval: -8.07 to 0.00). The correlation coefficient was 0.84 (95% confidence interval: 0.78-0.89). With a cut-off value of 50% for VWF activity, the assay has a sensitivity of 94.1% and a specificity of 92.8%, compared with the VWF:RCo aggregation assay with a cut-off value of 60% producing a sensitivity of 100.0% (specificity 87.6%). With a cut-off value of 60%, the HemosIL von Willebrand Factor Activity assay on STAC is a reliable assay for VWD. VWF:RCo or other functional testing is still required to confirm the diagnosis and for further classification of VWD.

Female↗

PubMed1995

Estimation of the carbohydrate moiety of von Willebrand factor in the plasma of patients with subtypes 2a and 2b of von Willebrand disease.

Von Willebrand disease (vWD) results from quantitative (types 1 and 3) or qualitative (type 2) deficiency of von Willebrand factor (vWF). This glycoprotein present in plasma is involved in platelet adhesion at the site of vascular injury and serves as the carrier of antihaemophilic A factor (FVIII). Whereas recent studies have identified mutations in patients suffering from type 2 vWD, the integrity of the carbohydrate moiety of vWF in these patients is still matter of debate. In order to analyse in the plasma milieu the carbohydrate content of plasma vWF from various well-characterized type 2 vWD patients, we developed a colorimetric assay in microtiter plate based on the use of peroxidase-conjugated lectins specific for either alpha 2-6 sialic acid or beta 1-4 galactose. Removal of sialic acid from purified plasma vWF induced significant changes in the reactivity of both lectins. The analysis of various normal plasmas showed no influence of the blood groups and allowed us to compare various vWD patients. The reactivity of lectins for plasma vWFs from two type 2A and six type 2B vWD patients harbouring different mutations was not statistically different from that of a pool of normal plasmas. We conclude that the alpha 2-6 sialic acid and beta 1-4 galactose content of plasma vWF is not altered in these patients affected with types 2A and 2B vWD.

Carbohydrates↗

PubMed2006

Comparative analysis and classification of von Willebrand factor/factor VIII concentrates: impact on treatment of patients with von Willebrand disease.

von Willebrand disease (vWD) is a bleeding disorder that results from defects in the quality or quantity of von Willebrand factor (vWF), a glycoprotein essential for normal thrombus formation. vWF circulates in plasma as multimers in sizes ranging up to 20,000 kd. The high molecular weight vWF (HMWvWF) multimers are most essential for primary hemostasis, whereas the lower molecular weight multimers are less functionally active. For many patients, the treatment of choice is factor replacement with a vWF/FVIII concentrate, preferably one with a high content of HMWvWF multimers. Given that the commercially available vWF/FVIII concentrates seem to differ substantially in their biochemical properties as well as in their clinical efficacy, we did a comparative study with 12 vWF/FVIII concentrates to investigate content and activities of FVIII and vWF, as well as the content of HMWvWF multimers. The content of HMWvWF multimers varied considerably among the 12 concentrates. The specific vWF activities, as assessed by ristocetin cofactor activity (vWF:RCo) and collagen-binding activity (vWF:CB), correlated well with the HMWvWF content of the products. Of the products tested, Haemate P/Humate-P had the highest content of HMWvWF multimers (with a multimer pattern closest to that of normal human plasma), the highest specific vWF activities, and the highest values of vWF:RCo and vWF:CB per unit of FVIII:coagulant (C). The goal of bleeding prophylaxis and treatment in type 2, severe type 1, and type 3 vWD patients is to normalize vWF activities (vWF:RCo and vWF:CB) and FVIII:C preferentially by vWF/FVIII concentrates containing the high vWF multimers and a high vWF:RCo/FVIII ratio to achieve normal primary and secondary hemostasis. Based on the present study of a comparative analysis of currently available vWF/FVIII concentrates, a classification of vWF/FVIII products is proposed.

Chemistry, Clinical↗

PubMed2005

Determinants of bleeding severity in von Willebrand disease.

von Willebrand disease (VWD) is one of the most common bleeding disorders. It is caused by abnormalities in the von Willebrand factor (VWF) protein, and is characterized by incomplete penetrance and variable expressivity. VWF levels vary widely in the population. The best-characterized human genetic modifier of VWF is the ABO blood group. Patients with VWD show considerable variation in bleeding tendency even within the same family, independently of VWF levels. It is possible that several modifier genes influence the phenotype. Variants of genes that encode for platelet receptors as well as those that encode for clotting factor levels have been proposed as modifiers. It is hoped that new clinical-genetic studies will shed light on these issues and help practitioners to determine the population at risk for bleeding.

Animals↗

PubMed1996

Molecular basis of von Willebrand disease.

von Willebrand disease (vWD), the most common congenital bleeding disorder in man, is related to quantitative and/or qualitative abnormalities of von Willebrand factor (vWF), a protein necessary for platelet-vessel wall interactions and for carrying factor VIII. Distinct abnormalities of vWF are responsible for the three main types of vWD. Types 1 and 3 are defined by a quantitative defect of vWF whereas type 2, comprising subtypes 2A, 2B, 2M and 2N, refers to patients with a qualitative defect of vWF. Recent progress in the molecular biology of vWF has led to the identification of the molecular basis of vWD in a significant number of patients. Type 2A is characterized by a decreased platelet-dependent function of vWF and includes subtypes IIA and IIC. In all the cases of subtype IIA, aa substitutions have been identified in the A2 domain of vWF which contains a proteolytic site. In the rare subtype IIC, some aa substitutions or insertion have been found within the propeptide of vWF. In type 2B, defined by an increased affinity of vWF for platelet GPIb, various aa substitutions or insertions have been localized within the A1 domain containing binding sites for GPIb, collagen, heparin and sulfatides. In type 2N, characterized by a defective binding of vWF to factor VIII, several aa substitutions have been identified within the factor VIII-binding domain in the N-terminal part of vWF. The identification of gene defects is difficult in types 1 and 3 of vWD. Whereas various abnormalities (gross, partial or point deletions, point insertions, nonsense mutations) have been shown to be at the origin of the quantitative vWF defect in type 3, the molecular basis of type 1 is still unknown in most cases. A data base of gene defects in vWD has been recently established. Its updating may contribute to consider a future classification of vWD based on the nature of the gene defect. Furthermore, the characterization of mutations in vWD presents a more fundamental interest in providing further insight into the structure-function relationship and the synthesis of vWF.

Amino Acid Sequence↗

PubMed2001

Advances in the treatment of von Willebrand disease.

Von Willebrand disease (VWD) is the most commonly inherited bleeding disorder, caused by inheritance of a quantitative or qualitative abnormality of von Willebrand factor (VWF). While the majority of patients with VWD are successfully treated with adjunctive therapies or with the synthetic vasopressin analog desmopressin acetate (DDAVP), a subset of patients requires replacement therapy. In the past, cryoprecipitate was the mainstay of therapy; however, it was associated with seroconversion to hepatitis B (HBV), hepatitis C (HCV), and the human immunodeficiency virus (HIV) in treated individuals. With the advent of virucidal methodology and, more recently, nucleic acid testing (NAT) of plasma fractions, the plasma-derived concentrates containing VWF are now considered the therapeutic standard of care.

Blood Component Transfusion↗

PubMed2002

A Reliable von Willebrand factor: ristocetin cofactor enzyme-linked immunosorbent assay to differentiate between type 1 and type 2 von Willebrand disease.

von Willebrand disease (vWD) is the most common hereditary bleeding disorder due to either a qualitative or a quantitative defect in von Willebrand factor (vWF). vWF is a multimeric plasma protein that plays an important role in (1) primary hemostasis, by sustaining indirect platelet adhesion especially at high shear rates, and in (2) secondary hemostasis, by protecting factor VIIIc (FVIIIc) from degradation. A correct diagnosis of vWD is based on the accurate identification of one of the six different subtypes (type 1, 2A, 2B, 2M, 2N, 3). To do this, different laboratory tests are available. One aspect of the identification is the discrimination between type 1 and type 2 (2A, 2B, and 2M) vWD. In type 1 vWD, both vWF levels (vWF:Ag) and vWF activity (vWF:RCof) are decreased; in type 2, the vWF:Ag level is normal or decreased and vWF:RCof is decreased. Thus, ratios of vWF:Ag to vWF:RiCof above 1 allow identifation of type 2 vWD patients. The currently used vWF:RCof test is an agglutination test in which patients' plasma is added to washed fixed control platelets in the presence of ristocetin and the extent of agglutination is measured. This test suffers from high interlaboratory and intralaboratory variability. We have recently shown that the same vWF:RCof can also be measured in an enzyme-linked immunosorbent assay (ELISA) with a low interassay and intraassay variability and can be used to identify patients suffering from vWD. We here show that our test allows the discrimination between type 1 and type 2 vWD patients.

Agglutination Tests↗