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Claude T Tagny, Pauline N Balôgôg, Francoise Boehlen, Dora Mbanya
In Cameroon, the Yaoundé Hemophilia Treatment Center (HTC) has so far recorded 121 cases of hemophilia and only 10 cases of von Willebrand disease (VWD). We report the case of a 16-year-old girl, living in the north of Cameroon. She presented with severe meno-metrorrhagia, which had increased drastically within the past 3 months, associated more recently by gum bleeding and epistaxis. The coagulation screen showed a prolonged bleeding time. The clinical profile of this young girl and the findings of less than 5% for von Willebrand factor (VWF):Ag and 10% for VWF Ristocetin cofactor suggests a type 3 VWD...
October 2016: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
Jose Maria Bastida Bermeja, Jose Ramon González-Porras, Cristina Jiménez, Rocio Benito, Gonzalo R Ordoñez, Maria Teresa Álvarez-Román, M Elena Fontecha, Kamila Janusz, David Castillo, Rosa María Fisac, Luis Javier García-Frade, Carlos Aguilar, María Paz Martínez, Nuria Bermejo, Sonia Herrero, Ana Balanzategui, Jose Manuel Martin-Antorán, Rafael Ramos, Maria Jose Cebeiro, Emilia Pardal, Carmen Aguilera, Belen Pérez-Gutierrez, Manuel Prieto, Susana Riesco, Maria Carmen Mendoza, Ana Benito, Ana Hortal Benito-Sendin, Víctor Jiménez-Yuste, Jesus Maria Hernández-Rivas, Ramon García-Sanz, Marcos González-Díaz, Maria Eugenia Sarasquete
Currently, molecular diagnosis of haemophilia A and B (HA and HB) highlights the excess risk-inhibitor development associated with specific mutations, and enables carrier testing of female relatives and prenatal or preimplantation genetic diagnosis. Molecular testing for HA also helps distinguish it from von Willebrand disease (VWD). Next-generation sequencing (NGS) allows simultaneous investigation of several complete genes, even though they may span very extensive regions. This study aimed to evaluate the usefulness of a molecular algorithm employing an NGS approach for sequencing the complete F8, F9 and VWF genes...
October 13, 2016: Thrombosis and Haemostasis
Alexandre Kauskot, Sonia Poirault-Chassac, Frédéric Adam, Vincent Muczynski, Gabriel Aymé, Caterina Casari, Jean-Claude Bordet, Christelle Soukaseum, Chantal Rothschild, Valérie Proulle, Audrey Pietrzyk-Nivau, Eliane Berrou, Olivier D Christophe, Jean-Philippe Rosa, Peter J Lenting, Marijke Bryckaert, Cécile V Denis, Dominique Baruch
von Willebrand disease type 2B (VWD-type 2B) is characterized by gain-of-function mutations of von Willebrand factor (vWF) that enhance its binding to platelet glycoprotein Ibα and alter the protein's multimeric structure. Patients with VWD-type 2B display variable extents of bleeding associated with macrothrombocytopenia and sometimes with thrombopathy. Here, we addressed the molecular mechanism underlying the severe macrothrombocytopenia both in a knockin murine model for VWD-type 2B by introducing the p...
October 6, 2016: JCI Insight
Jamie M O'Sullivan, Sonia Aguila, Emily McRae, Soracha E Ward, Orla Rawley, Padraic G Fallon, Teresa M Brophy, Roger J S Preston, Lauren Brady, Orla Sheils, Alain Chion, James S O'Donnell
BACKGROUND: Enhanced von Willebrand factor (VWF) clearance is important in the etiology of both type 1 and type 2 von Willebrand disease (VWD). In addition, previous studies have demonstrated that VWF glycans play a key role in regulating in vivo clearance. However, the molecular mechanisms underlying VWF clearance remain poorly understood. OBJECTIVE: To define the molecular mechanisms through which VWF N-glycan structures influence in vivo clearance. METHODS: Using a series of exoglycosidases, different pd-VWF glycoforms were generated...
October 12, 2016: Journal of Thrombosis and Haemostasis: JTH
Cécile Lavenu-Bombled, Corinne Guitton, Arnaud Dupuis, Marie-Jeanne Baas, Céline Desconclois, Marie Dreyfus, Renhao Li, Claudine Caron, Christian Gachet, Edith Fressinaud, François Lanza
Interaction between von Willebrand factor (VWF) and platelet GPIbα is required for primary haemostasis. Lack or loss-of-function in the ligand-receptor pair results in bleeding complications. Paradoxically, gain-of-function mutations in VWF or GPIbα also results in bleeding complications as observed in type 2B von Willebrand disease (VWD) and platelet-type- (PT-) VWD, respectively. A similar phenotype is observed with increased ristocetin-induced platelet agglutination and disappearance of the highest molecular weight multimers of VWF...
September 29, 2016: Thrombosis and Haemostasis
Mariya H Apostolova, Craig D Seaman, Diane M Comer, Jonathan G Yabes, Margaret V Ragni
BACKGROUND: von Willebrand factor (VWF) is a biomarker for endothelial damage. Increased VWF levels are observed in hypertension (HTN) and disorders of endothelial dysfunction, for example, atherosclerotic heart disease (ASHD) and diabetes. Whether low VWF protects against HTN is unknown. METHODS: To determine prevalence and risk factors for HTN in patients with von Willebrand disease (VWD), we conducted a cross-sectional analysis of discharge data from the National Inpatient Sample, 2009 to 2011...
September 21, 2016: Clinical and Applied Thrombosis/hemostasis
Emily Reynen, Paula James
von Willebrand disease (VWD) is a common, inherited bleeding disorder. There are three main types of VWD, which result in a quantitative or qualitative deficiency in von Willebrand factor (VWF) and in severe cases, also Factor VIII (FVIII). The severity of bleeding depends on the underlying pathophysiology. Type 1 VWD is usually mild, while types 2 or 3 VWD can be associated with moderate or significant bleeding. Managing pregnant women with VWD requires a multidisciplinary approach. Such patients are at increased risk of postpartum hemorrhage...
September 20, 2016: Seminars in Thrombosis and Hemostasis
Emmanuel J Favaloro
von Willebrand Disease (VWD) is the most common inherited bleeding disorder and also arises as an acquired defect (AVWS). VWD and AVWS are due to quantitative deficiencies and/or qualitative defects in von Willebrand factor (VWF), an adhesive plasma protein with multiple activities. Diagnosis of VWD is problematic, being subject to overdiagnosis, underdiagnosis, and misdiagnosis. This is largely due to limitations in current test procedures and an over-reliance on these imperfect test systems for clinical diagnosis...
September 13, 2016: American Journal of Hematology
Wolfgang Miesbach, Erik Berntorp
Von Willebrand disease (VWD) is the most common genetic bleeding disorder. VWD is caused by a deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates the initial adhesion of platelets at sites of vascular injury and binds and stabilises coagulation factor VIII (FVIII) in the blood. Prophylaxis of surgical bleeding in patients with VWD requires consideration of the individual situation, including the type of procedure and the bleeding rate, before decisions about treatment type, dose, duration and adjunctive therapy with antifibrinolytics or antithrombotic prophylaxis can be made...
September 13, 2016: European Journal of Haematology
Y Xu, M Deforest, J Grabell, W Hopman, P James
INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Currently, studies investigating the health-related quality of life (HR-QoL) in VWD using standardized tools are limited, particularly among patients with mild decreases in von Willebrand factor or activity. AIM: To determine HR-QoL and its predictors among patients with mild, moderate and severe forms of VWD. METHODS: Patients with clinical diagnosis of VWD were recruited from a tertiary Inherited Bleeding Disorder Clinic...
September 9, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
Laura L Swystun, Paula D James
Phenotypic assays are first-line in terms of diagnostic testing for inherited bleeding disorders. However, since the characterization of the genes that encode coagulation factors in the 1980s, significant progress has been made in translating this knowledge for diagnostic and therapeutic purposes. For the hemophilias, molecular genetic testing can be used to determine carrier status, establish a prenatal diagnosis and predict the likelihood of inhibitor development or anaphylaxis in response to infused coagulation factor concentrates...
August 17, 2016: Blood Reviews
Hamideh Yadegari, Arijit Biswas, Mohammad Suhail Akhter, Julia Driesen, Vytautas Ivaskevicius, Natascha Marquardt, Johannes Oldenburg
Disease-associated silent mutations are considered to affect the accurate pre-mRNA splicing either by influencing regulatory elements leading to exon skipping or by creating a new cryptic splice site (ss). The present study describes a new molecular pathological mechanism by which a silent mutation inhibits splicing and leads to intron retention. We identified a heterozygous silent mutation c.7464C>T in exon 44 of the von Willebrand factor (VWF) gene in a family with type 1 von Willebrand disease (VWD). In vivo and ex vivo transcript analysis revealed an aberrantly spliced transcript with intron 44 retained in the mRNA, implying disruption of the first catalytic step of splicing at 5' ss...
August 19, 2016: Blood
Tara C White-Adams, Christopher J Ng, Paula M Jacobi, Sandra L Haberichter, Jorge A Di Paola
Type 1 von Willebrand disease (VWD) is characterized by low plasma levels of von Willebrand factor (VWF) and clinical bleeding. Several mechanisms have been described that cause a decrease in plasma VWF levels in VWD, and the goal of this study was to elucidate the pathogenic origins of VWD for a group of mutations in the VWF D'D3 region traditionally associated with type 1 VWD. Varying ratios of mutant-to-wild-type VWF were expressed in two cell lines in order to study the intracellular location, multimer assembly, secretion and function of VWF...
September 2016: Thrombosis Research
Alessandra Casonato, Maria Grazia Cattini, Viviana Daidone, Elena Pontara, Antonella Bertomoro, Paolo Prandoni
Von Willebrand disease (VWD) may be caused by an impaired von Willebrand factor (VWF) synthesis, its increased clearance or abnormal function, or combinations of these factors. It may be difficult to recognize the different contributions of these anomalies. Here we demonstrate that VWD diagnostics gains from measuring platelet VWF, which can reveal a defective VWF synthesis. Measuring platelet VWF revealed that: severe type 1 VWD always coincided with significantly lower platelet and plasma VWF levels, whereas mild forms revealed low plasma VWF levels associated with low or normal platelet VWF levels, and the latter were associated with a slightly shorter VWF survival; type Vicenza (the archetype VWD caused by a reduced VWF survival) featured normal platelet VWF levels despite significantly reduced plasma VWF levels; type 2B patients could have either normal platelet VWF levels associated with abnormal multimer patterns, or reduced platelet VWF levels associated with normal multimer patterns; type 2A patients could have reduced or normal platelet VWF levels, the former associated mainly with type 2A-I, the latter with type 2A-II; plasma and platelet VWF levels were normal in type 2N, except when the defect was associated with a quantitative VWF mutation...
2016: PloS One
Augusto B Federici, Christoph Königs, Andra H James
Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Bleeding scores in VWD, focused in particular on mucosal bleeding, can be very useful in the diagnosis and validation of different types of treatment. The results of an extended prospective study with a large amount of information on clinical phenotype and implications in treatment are reviewed in this article. Treatment of mucosal and joint bleeding in severe VWD remains difficult in some patients. Due to the lack of data on the use of prophylaxis in these patients it is difficult to establish optimal treatment regimens...
August 31, 2016: Thrombosis and Haemostasis
Ergul Berber, Mehmet Ozbil, Christine Brown, Zafer Baslar, S Hande Caglayan, David Lillicrap
BACKGROUND: Abnormalities in the biosynthetic pathway or increased clearance of plasma von Willebrand factor (VWF) are likely to contribute to decreased plasma VWF levels in inherited type 1 von Willebrand disease (VWD). Recent studies demonstrated that 65% of type 1 VWD patients have candidate VWF mutations, the majority of which are missense variants. The purpose of this study was to explore the effects of three VWF missense mutations (p.M771I, p.L881R and p.P1413L) located in different functional domains of VWF, reported as candidate mutations in type 1 VWD patients in the course of the MCMDM-1VWD study...
July 25, 2016: Blood Transfusion, Trasfusione del Sangue
A Eghbali, L Melikof, H Taherahmadi, B Bagheri
INTRODUCTION: Reducing bleeding episodes is very important in haematology disorders like von Willebrand disease (VWD) and Glanzmann thrombasthenia (GT). Replacement factors are very expensive although prophylactic drugs are affordable. OBJECTIVE: To study the prophylactic effects of tranexamic acid (TXA) for reduction of bleeding episodes in patients with VWD and GT in non-invasive conditions. METHODS: A controlled, double-blind before and after single-centre trial was performed in Amir-Kabir Hospital (Arak, Iran)...
September 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
Emmanuel J Favaloro, Leonardo Pasalic, Jennifer Curnow
von Willebrand factor (VWF) is an adhesive plasma protein that primarily acts to bridge platelets to sites of vascular injury and thus prevent bleeding. von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by deficiency and/or defects of VWF, leading to low levels of plasma VWF or dysfunctional VWF. Factor VIII (FVIII) is also reduced in many patients with VWD, since VWF stabilizes and protects FVIII from degradation. Treatment of VWD primarily entails replacement of VWF, and sometimes FVIII, to protect against bleeding...
July 29, 2016: Seminars in Thrombosis and Hemostasis
Lindsay Proud, A Kim Ritchey
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting one in 1,000 people. Type 2b VWD is a less common subtype caused by a gain-of-function mutation in von Willebrand factor (VWF) that leads to the formation of large, ineffective VWF-platelet multimers in circulation. This unique pathophysiology creates diagnostic and treatment dilemmas. There is limited information on the management of type 2b VWD in the neonatal period. This report describes the management of a neonate with type 2b VWD with an emphasis on the added benefit of concomitant platelet transfusion and factor replacement therapy over factor replacement therapy alone...
July 28, 2016: Pediatric Blood & Cancer
Jan Jacques Michiels, Petr Smejkal, Miroslav Penka, Angelika Batorova, Tatiana Pricangova, Ulrich Budde, Inge Vangenechten, Alain Gadisseur
The European Clinical Laboratory and Molecular (ECLM) classification of von Willebrand disease (vWD) is based on the splitting approach which uses sensitive and specific von Willebrand factor (vWF) assays with regard to the updated molecular data on structure and function of vWF gene and protein defects. A complete set of FVIII:C and vWF ristocetine cofactor, collagen binding, and antigen, vWF multimeric analysis in low- and medium-resolution gels, and responses to desmopressin (DDAVP) of FVIII:C and vWF parameters are mandatory...
July 21, 2016: Clinical and Applied Thrombosis/hemostasis
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