vWD Type Research Articles

The Impact of Bleeding Disorders on the Socioeconomic Status of Adult Patients.

The impact of inherited bleeding disorders on the socioeconomic status (SES) of affected individuals is not clear. The SES of adult patients with congenital bleeding disorders (PWBD) from a centre in Germany (age 42.3 ± 15.0 years) was compared to that of a gender- and age-matched control group of patients with thrombophilia or a thrombotic event (PWT). Patients completed a questionnaire including aspects of SES, impact of the disease on their lives, and health-related quality of life (HRQoL). Forty-five patients were enrolled in each group; 71 % of PBWD had a severe form of the bleeding disorder (FVIII/IX activity < 1 % or VWD type 3), and 60 % of all PWBD were treated on-demand. PWBD had a lower monthly income (p = 0.029) and a worse occupational status (p = 0.047) than PWT, but there was no difference regarding the project-specific SES index. PWBD also reported a worse HRQoL in the physical summary component score of the SF-36 (p < 0.001). More PWBD (69.8 %) reported a high impact of the disease on their lives than PWT (33.3 %, p < 0.001). In summary, PWBD had a worse occupational status, monthly income, health behaviour, HRQoL, and impact of the disease on their lives compared to PWT, but not a significantly different SES in general.

Protein kinase C signaling dysfunction in von Willebrand disease (p.V1316M) type 2B platelets

Abstractvon Willebrand disease (VWD) type 2B is characterized by gain-of-function mutations in von Willebrand factor (VWF), enhancing its binding affinity for the platelet receptor glycoprotein (GP)Ibα. VWD type 2B patients display a bleeding tendency associated with loss of high-molecular-weight VWF multimers and variable thrombocytopenia. We recently demonstrated that a marked defect in agonist-induced activation of the small GTPase, Rap1, and integrin αIIbβ3 in VWD (p.V1316M) type 2B platelets also contributes to the bleeding tendency. Here, we investigated the molecular mechanisms underlying impaired platelet Rap1 signaling in this disease. Two distinct pathways contribute to Rap1 activation in platelets: rapid activation mediated by the calcium-sensing guanine nucleotide exchange factor CalDAG–GEF-I (CDGI) and sustained activation that is dependent on signaling by protein kinase C (PKC) and the adenosine 5′-diphosphate receptor P2Y12. To investigate which Rap1 signaling pathway is affected, we expressed VWF/p.V1316M by hydrodynamic gene transfer in wild-type and Caldaggef1−/− mice. Using αIIbβ3 integrin activation as a read-out, we demonstrate that platelet dysfunction in VWD (p.V1316M) type 2B affects PKC-mediated, but not CDGI-mediated, activation of Rap1. Consistently, we observed decreased PKC substrate phosphorylation and impaired granule release in stimulated VWD type 2B platelets. Interestingly, the defect in PKC signaling was caused by a significant increase in baseline PKC substrate phosphorylation in circulating VWD (p.V1316M) type 2B platelets, suggesting that the VWF–GPIbα interaction leads to preactivation and exhaustion of the PKC pathway. Consistent with PKC preactivation, VWD (p.V1316M) type 2B mice also exhibited marked shedding of platelet GPIbα. In summary, our studies identify altered PKC signaling as the underlying cause of platelet hypofunction in p.V1316M-associated VWD type 2B.

A 12.3-kb Duplication Within the VWF Gene in Pigs Affected by Von Willebrand Disease Type 3.

Von Willebrand Disease (VWD) type 3 is a serious and sometimes fatal hereditary bleeding disorder. In pigs, the disease has been known for decades, and affected animals are used as models for the human disease. Due to the recessive mode of inheritance of VWD type 3, severe bleeding is typically seen in homozygous individuals. We sequenced the complete porcine VWF (Von Willebrand Factor) complementary DNA (cDNA) and detected a tandem duplication of exons 17 and 18, causing a frameshift and a premature termination codon (p.Val814LeufsTer3) in the affected pig. Subsequent next generation sequencing on genomic DNA proved the existence of a 12.3-kb tandem duplication associated with VWD. This duplication putatively originates from porcine Short Interspersed Nuclear Elements (SINEs) located within VWF introns 16 and 18 with high identity. The premature termination truncates the VWF open reading frame by a large part, resulting in an almost entire loss of the mature peptide. It is therefore supposed to account for the severe VWD type 3. Our results further indicate the presence of strong, nonsense-mediated decay in VWF messenger RNA (mRNA) containing the duplication, which was supported by the almost complete absence of the complete VWF protein in immunohistochemistry analysis of the VWD-affected pig. In the past, differentiation of wild-type and heterozygous pigs in this VWD colony had to rely on clinical examinations and additional laboratory methods. The present study provides the basis to distinguish both genotypes by performing a rapid and simple genetic analysis.

Liver transplantation in hemophilia A and von Willebrand disease type 3: perioperative management and post-transplant outcome.

infection with the hepatitis C virus (HCV) causes significant morbidity and mortality in patients with hemophilia. Finally, patients are considered for a liver transplantation (LT) due to cirrhosis and/or hepatocellular carcinoma (HCC). we report the cases of congenital coagulopathy and HCV infection that underwent LT in our institution. There were three patients with hemophilia A and one patient with von Willebrand disease (vWD) type 3. The coagulopathy outcome, perioperative management, factor and blood product usage and post-transplant survival were assessed. The deficient factor was initially administered in a direct bolus one hour before surgery with a target level of 100 IU/dl, which was sustained until stable hemostasis was reached. All three patients with hemophilia A were cured of their coagulopathy following transplantation. Factor VIII (FVIII) was 93 IU/dl at eleven years, 59 IU/dl at 13 months and 109 IU/dl at nine months post-transplant, in each case. The mean perioperative usage of FVIII concentrates was 175 IU/kg; concentrates were infused for an average of 36 hours post-transplant. The natural course of the bleeding symptoms of the patient with type-3 vWD was attenuated, with no detectable hemostatic levels of von Willebrand factor antigen (vWF:Ag) after transplantation. after transplantation, hemophilia A cure and improved bleeding phenotype of type-3 vWD reduced morbidity and mortality. However, potential graft reinfection with HCV and relapsing HCC cast a shadow over these optimum results.

Von Willebrand disease type 1 in Doberman Pinscher dogs: genotyping and prevalence of the mutation in the Buenos Aires region, Argentina.

von Willebrand disease (vWD) is the most common inherited coagulopathy in dogs, particularly in Doberman Pinschers. We developed a pyrosequencing-based assay to estimate the frequency of the c.7437G>A mutation associated with vWD type 1 in the Doberman Pinscher population of Buenos Aires, Argentina. We found a 0.41 frequency for the mutated allele, which varied significantly within families (family 1 = 0.43, family 2 = 0.58, unrelated animals = 0.35). The use of a popular founder male carrier of mutant allele A increased vWD incidence within a family and in the general population. The mode of inheritance was confirmed as autosomal dominant with incomplete penetrance. No differences were found between sexes and coat colors. Pyrosequencing was a good complement to clinical and coagulation tests for vWD type 1 diagnosis and a useful alternative for detecting the c.7437G>A mutation.

Use of mirena (levonorgestrel-releasing intrauterine system) in menorraghia in a young female with von Willebrand disease (vWD) Type 3 - A case report

von Willebrand disease (vWD) is a bleeding disorder that is predominantly attributable to reduced levels of von Willebrand factor (vWF) activity. vWD prevalence is 1% in the population and vWD Type 3 is very rare. vWD Type 3 is inherited as autosomal recessive manner and accounts for less than 5% of all cases. Individuals with vWD type 3 can have a severe internal and joint bleeding. However, type 3 and type 2 variants are extremely difficult to manage and there is no guarantee that haemostasis will be achieved even when plasma concentrations have apparently been corrected into the normal range. We report a female child aged 10 years presented to us with heavy menstrual bleeding for three days which continued for another seven days. This episode was after recent onset of menarche and was diagnosed as having vWD Type 3. It was considered as a life threatening bleeding. Immediate and long term management of this patient with a major bleed was a daunting task. She was treated with Intermediate purity factor viii/ factor viii (cryoprecipitate), activated factor vii, Blood and antifibrinolytics. Long term endometrial suppression was the key to hinder excessive bleeding during menstruation (which could be life threatening) as she would need prophylaxis during each episode. Selecting the correct method which suits her best was not without difficulty. Intrauterine use of Mirena (levonogestrel-releasing intrauterine system-LNG-IUS) Was a better option and there are very few reports if at all of its use in a similar situation. We have used it as a novel method to suppress excessive menstrual bleeding (long term) in this patient with von Willebrand disease type 3.

Autosomal recessive inherited bleeding disorders in Pakistan: a cross-sectional study from selected regions

BackgroundAutosomal recessive bleeding disorders (ARBDs) include deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand Disease (vWD) type 3, Glanzmann’s thrombasthenia (GT) and Bernard–Soulier syndrome. Patients with primary bleeding disorders from all the major provincial capitals of Pakistan were screened for ARBDs. Prothrombin (PT), activated partial thromboplastin time (APTT), bleeding time (BT) and fibrinogen levels were measured. Cases with isolated prolonged APTT were tested for factors VIII and IX using factor assays This was followed by FXI:C level assessment in cases with normal FVIII and FIX levels. vWD was screened in patients with low FVIII levels. Factors II, V and X were tested in patients with simultaneous prolongation of PT and APTT. Peripheral blood film examination and platelet aggregation studies were performed to assess platelet disorders. Urea clot solubility testing was done to detect Factor XIII levels where platelet function tests were normal. Descriptive analysis was done using SPSS version 16.ResultsOf the 429 suspected bleeding disorder patients, 148 (35%) were diagnosed with hemophilia A and 211 (49.1%) patients had ARBDs. 70 patients (16.3%) remained undiagnosed. Out of 211 patients with ARBD; 95 (33.8%) had vWD type 3. Fibrinogen deficiency was found in 34 patients (12%), GT in 27 (9.6%), factor XIII deficiency in 13 (4.6%), factor VII deficiency in 12 (4.3%), factor V deficiency in 9 (3.2%). Eight patients (2.8%) had vitamin K-dependent clotting factor deficiency, Bernard–Soulier syndrome was diagnosed in seven patients (2.5%), factor X deficiency in 2 (0.7%), factor II deficiency in 2 (0.7%), factor XI deficiency and combined factor V and VIII deficiency in 1 (0.4%) patient each.ConclusionvWD type 3 was the most common ARBD found in our sample of patients in Pakistan, followed by fibrinogen deficiency and GT in respective order.

Perioperative Management of Von Willebrand Disease, a Systematic Review and Meta-Analysis

Background: von Willebrand disease (vWD) is the most common inherited bleeding disorder characterized by quantitative or qualitative defect of von Willebrand factor (vWF) production. Patients with vWD are at high risk of bleeding during surgery. We aimed to evaluate the efficacy and safety of factor VIII (FVIII)/vWF concentrates and DDAVP for bleeding prevention in vWD patients who undergo surgery or an invasive procedure.Methods:The electronic searches were performed in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases. The articles published from inception to January 2016 were eligible for inclusion in this review. Studies will be included if they are observational studies or clinical trials of pediatric or adult patients who were laboratory confirmed vWD (type 1 or type 2 or type 3). We excluded case report or case series with less than 5 patients, acquired vWD and incomplete outcome reports. The primary outcome was the efficacy of hemostatic control as defined by studies. We calculated pooled incidence of the patient who achieve good or excellent hemostatic control with corresponding 95% confidence interval using single proportion meta-analysis. The secondary outcomes were adverse outcomes from FVIII/vWF and DDAVP.Results: After screening, there were 54 studies included in the meta-analysis. Forty-five studies investigated the efficacy of vWF/FVIII. Pooled analysis revealed that 98.4% (95% CI; 97.8-99.1%, I2=45.5%) of FVIII/vWF treated patients achieved excellent or good hemostasis. Subgroup analysis according to type of surgery revealed that excellent or good hemostasis was 99.4% (95%CI; 98.4-100%, I2=0%) in major surgery and 99.0% (95%CI; 98.2-99.9%, I2=0%) in minor surgery, Table 1. Adverse effects were observed in 0.2% (95% CI; 0-0.4, I2=85.1%) patients who received FVIII/vWF. The reported adverse effects from FVIII/vWF concentrates included phlebitis, shortness of breath, chest tightness, urticaria, pruritus, chill, malaise, fever, paresthesia, transient elevation of liver function test, nausea, vomiting, dizziness, headache and parvovirus B 19 seroconversion. Thromboembolism occurred in 0.17% of patients who received vWF/FIII. There were 26 studies investigating DDAVP during surgery. Hemostasis was excellent or good in 98.0% (95%CI; 97.0-99.0%, I2=26.3%. In dental procedure, 99.0% of patients receiving DDAVP (95%CI; 97.6-100%, I2=0%) achieved excellent or good hemostasis. Subgroup analysis showed that good/excellent hemostasis was found in 96.9% of pediatric patients (95%CI; 95.1-98.7%, I2=58.8%) and 96.9% (95%CI; 92.7-100%, I2= 0%) in adult patients, Table 2. Adverse effects from DDAVP were reported in 1.2% (95%CI; 0.4-2.1%, I2=95%). Hyponatremia of any level was observed in 16.1% (95%CI; 8.9-22.4%, I2=94.1%). The other reported adverse effects were headache, fatigue, rash, seizure (from hyponatremia), flushing, dizziness, peripheral edema, nausea and vomiting. No thromboembolic event was found in DDAVP treated patients.Conclusions: Both FVIII/vWF concentrates and DDAVP are effective and safe for bleeding prevention during surgery or an invasive procedure in vWD patients. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diagnostic Differentiation of von Willebrand Disease Types 1 and 2 by von Willebrand Factor Multimer Analysis and DDAVP Challenge Test.

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. The ECLM classification distinguishes recessive types 1 and 3 vWD from recessive vWD 2C due to mutations in the D1 and D2 domains and vWD 2N due to mutations in the D'-FVIII-binding domain of vWF. The ECLM classification differentiates between mild vWD type 1 with variable penetrance of bleedings from symptomatic dominant type 1 vWD secretion defect and/or clearance defect with normal vWF multimers versus vWD 1M and 2M with normal or smeary vWF multimers in low- and medium-resolution gels. High-quality multimeric analysis of vWF in medium-resolution gels based on a DDAVP challenge test clearly delineates and distinguishes each of the dominant type 2 vWDs 1/2E, 2M, 2B, 2A, and 2D caused by vWF gene mutations in the D3 multimerization domain, loss or gain-of-function mutations in the glycoprotein Ib receptor A1 domain, gene mutations in the A2 proteolytic domain, and the C-terminal dimerization domain, respectively.

Report on von Willebrand Disease in Malaysia

BACKGROUND:Von Willebrand disease (vWD) is an inherited hemostatic disorder that affects the hemostasis pathway. The worldwide prevalence of vWD is estimated to be 1% of the general population but only 0.002% in Malaysia.AIM:Our present paper has been written to disclose the statistical counts on the number of vWD cases reported from 2011 to 2013.MATERIAL AND METHODS:This article is based on sociodemographic data, diagnoses and laboratory findings of vWD in Malaysia. A total of 92 patients were reported to have vWD in Malaysia from 2011 to 2013.RESULTS:Sociodemographic-analysis revealed that 60% were females, 63% were of the Malay ethnicity, 41.3% were in the 19-44 year old age group and 15.2% were from Sabah, with the East region having the highest registered number of vWD cases. In Malaysia, most patients are predominately affected by vWD type 1 (77.2%). Factor 8, von Willebrand factor: Antigen and vWF: Collagen-Binding was the strongest determinants in the laboratory profiles of vWD.CONCLUSION:This report has been done with great interest to provide an immense contribution from Malaysia, by revealing the statistical counts on vWD from 2011-2013.

Autosomal Recessive Inherited Bleeding Disorders in Pakistan, a Cross Sectional Study from Selected Regions

INTRODUCTION: Incidence of autosomal recessive disorders is rare, includes deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand disease type 3, Glanzmann Thrombasthenia and Bernard Soulier syndrome.OBJECTIVE: Spectrum of autosomal recessive bleeding disorders (ARBDs] among Pakistani patients.PATIENTS AND METHODS: This cross-sectional study was carried out at Karachi, Lahore, Islamabad and Peshawar. PT,aPTT, BT, and fibrinogen levels done. Patients with prolonged APTT were tested for factors VIII and IX. If FVIII was low, von Willebrand factor: antigen (vWF: Ag) and von Willebrand factor: ristocetin cofactor (vWF: RCo) were performed. When PT and aPTT both were prolonged, FII, FV, and FX were tested. Peripheral film and platelet aggregation studies were done for platelet disorders. Urea clot solubility test was done at the end.RESULTS: Out of429 patients, 148 were diagnosed with Hemophilia A, remaining 281 patients had ARBDs. 95 (33.8%) had VWD type 3. Fibrinogen deficiency was found in 34 (12%), Glanzmann Thrombasthenia in 27 (9.6%), factor XIII in 13 (4.6%), factor VII in 12 (4.3%), factor V in 9 (3.2%), 8 (2.8%) in vitamin K dependent clotting factors, , Bernard Soulier in 7 patient (2.5%),factor X in 2 (0.7%), factor II in 2 (0.7%), factor XI and combined factor V and VIII in 1 (0.4%)patients each. 70 patients (16.3%) remained undiagnosed.CONCLUSION: VWD type 3 is the most common deficiency followed by fibrinogen deficiency. Glanzmann thrombasthenia was the third most common ARBD. DisclosuresNo relevant conflicts of interest to declare.

Types and Sub Types of Von Willebrand Disease Classified on the Basis of Multimer Analysis

Introduction: Von Willebrand disease is a common genetically inherited bleeding disorder. Types of VWD classified on the basis of coagulation factor assays but it cannot characterize further subtypes or verdict the quality and quantity of VWF. Multimer analysis facilitates the classification and prerequisite parameter to accurate diagnosis of VWD.Objective: To characterize the type and subtypes of VWD type I and II on the basis of laboratory data and analysis of VWF multimer structure.Setting: NIBD Karachi, University of Bonn Germany, Children Hospital & Chughtai Lab Lahore, PAEC Islamabad and HMC Peshawar.Material And Method: VWF Ag, Ricof, FVIII, Glycoprotein Ib and multimer analysis of VWD plasma on 1.6% medium resolution SDS-agarose gel electrophoresis was carried out, and then VWF multimer were transferred on nitrocellulose membrane. Incubated nitrocellulose membrane with using polyclonal rabbit anti-human VWF antibody and Goat anti-rabbit IgG HRP conjugate then protein detected by immune reaction after evaluation of the membrane under luminescence.Results: We studied 57 index patients, 2(3.5%) type I, 4(7.01%) type II, 3(5.26%) unclassified and 48(15.78%) were type III vWD. In type I,II, unclassified and III mean vWF Ag was 52.28, 35.15, 54.5 , 5.7 IU/dl, vWF RCo: 19.5, 18, 38.8, 7.22 IU/dl, vWF Ag/ RCof: 0.655, 0.393, 0.74, 0.55, FVIII 69, 25.7, 61.7, 7.22 IU/dl and GpIb: 27.25, 19.8, 39.8, 4.1. Significant loss of large multimers in type II while multimers were subtle in 2 cases, normal pattern in type I and entirely absence of multimers pattern in case of type III observed.Conclusion: Types and subtypes of VWD classified on the basis of concentration and distribution of vWF multimer by functional and immunological assays but single test is not enough for appropriate diagnosis. We need molecular genetics for von Willebrand disease for further diagnosis. DisclosuresOldenburg:SOBI: Consultancy.

Effect of the Novel Biodegradable N, O-Carboxymethylchitosan and Oligo-Chitosan on the Platelet Thrombogenicity Cascade in von Willebrand Disease

IntroductionVon Willebrand disease (vWD) is the second least common hemostatic disorder in Malaysia, and it has a low prevalence. This study examined the underlying platelet thrombogenicity cascades in the presence of different formulations of chitosan-derivatives in vWD patients. This paper aimed to determine the significant influence of chitosan biomaterial in stimulating the platelet thrombogenicity cascades that involve the von Willebrand factor, Factor 8, Thromboxane A2, P2Y12 and Glycoprotein IIb/IIIa in vWD. Materials and methodsVariable chitosan formulations of N,O-Carboxymethylchitosan (NO-CMC) and Oligo-Chitosan (O-C) were tested. Fourteen vWD subjects voluntarily participated in this study after signing informed consent forms. The patient’s demographic profiles, family history, type of vWD, clinical symptoms and laboratory profiles were recorded and analyzed. Enzyme-linked immunosorbent assay, flow cytometry and Western blot tests were used to determine the level of the chitosan-adhered-platelet-mechanisms. ResultsThe study revealed that most patients were predominantly affected by vWD type I. The O-C group of chitosan’s scaffold pores is sufficient to allow for nutrients and cells. The O-C-stimulated-mediators are capable of initiating the platelet actions and were detected to expedite the blood coagulation processes. The oligo-group of chitosans was capable of amplifying and triggering more platelet activator’s pathways via the studied mediators. The present findings suggest that the ability of each type of chitosan to coagulate blood varies depending on its chemical composition. ConclusionThe oligo group of chitosans is potentially capable of triggering platelet thrombogenicity cascades by activating platelets in vWD patients to form a platelet plug for hemostasis process.

Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease

AbstractVon Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF.

Clinical and laboratory diagnosis of VWD.

VWD is the most common inherited bleeding disorder and is due to a deficiency and/or abnormality of VWF. VWD is inherited in an autosomal-dominant or autosomal-recessive pattern, but women are apparently more symptomatic. Three main criteria are required for correct diagnoses of VWD: (1) positive bleeding history since childhood, (2) reduced VWF activity in plasma, and (3) history of bleeding in the family. The bleeding score, together with baseline VWF levels and family history, have been proposed as more evidence-based criteria for VWD. Measurements of a reduced VWF activity in plasma are essential for the diagnosis of VWD; assays for the evaluation of the interactions between VWF and platelet glycoprotein Ib receptor with or without ristocetin, as well as VWF collagen binding, are currently in use. However, other tests such as VWF antigen, factor VIII, ristocetin-induced platelet agglutination, multimeric analysis, VWF propeptide, VWF/FVIII binding assay, and assessment of biological response to desmopressin are necessary to characterize VWD types. Levels of VWF activities <30 U/dL have been associated with a bleeding phenotype and the presence of mutations in the VWF gene.

English

INTRODUCTION: VWD is named after Erik Adolf Von Willebrand, a Finnish pediatrician who first described the disease in 1926. Von Willebrand disease is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of Von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. There are three forms of VWD: VWD Type-I, Type-II, Type-III. Within the three inherited types of VWD there are various sub-types.1 VWD Type-1 is the most common type of the disorder2 and those that have it are typically asymptomatic or may experience mild symptoms such as nose bleeds although it may be severe in some cases. There are various factors that affect the presentation and severity of symptoms of VWD such as blood type.3

Von Willebrand Disease

Von Willebrand Disease

Von Willebrand Disease

1. Stacy Cooper, MD 2. Clifford Takemoto, MD 1. Charlotte Bloomberg Children’s Center, Johns Hopkins Hospital Baltimore, MD 1. 1. Nichols W, 2. Hultin MB, 3. James AH, 4. et al Von Willebrand Disease (VWD): Evidence-Based Diagnosis and Management Guidelines, The National Heart, Lung, and Blood Institute (NHLBI) Expert Panel Report (USA) . Nichols W, Hultin MB, James AH, et al. Haemophilia. 2008;14(2):171–232 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] 2. 1. O’Brien SH Bleeding Scores: Are They Really Useful? O’Brien SH. Am Soc Hematol Educ Program. 2012;2012(1):152–156 [OpenUrl][5] 3. 1. Montgomery G, 2. Cox JG 1. Orkin SH, 2. Nathan DG, 3. Ginsburg D, 4. Look AT, 5. Fisher DE, 6. Lux SE, 7. Lantigua CJ Von Willebrand Disease . Montgomery G, Cox JG. In: Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE, Lantigua CJ. Nathan and Oski’s Hematology of Infancy and Childhood. 7th ed. Philadelphia, PA: Saunders; 2009:1487–1524 Von Willebrand disease (vWD) is an inherited bleeding diathesis. It is caused by quantitative or qualitative defects in von Willebrand factor (vWF), which functions to bind platelets to damaged endothelium and to stabilize factor VIII (FVIII). A range of mutations have been identified in this protein, encompassing the spectrum of single missense mutations to large deletions. Because of variation in the diagnostic criteria for vWD, debate exists regarding the prevalence; however, some studies estimate it to be as high as 1% to 2% of the population when including children and adults. There are 3 major categories of vWD, classified as partial deficiency of vWF (type 1), functional defects (type 2), and complete deficiency of vWF (type 3). Type 2 can be further subcategorized based on the 4 subtypes of specific qualitative defects of the multimers (types 2A, 2B, 2M, and 2N). The different types of vWD vary in severity. Type 1 is the most common, an autosomal dominant disorder that comprises approximately 75% of vWD patients, and is usually confined to mild bleeding. Type 2 may demonstrate either dominant or recessive inheritance, and type 3 is autosomal recessive, with … [1]: {openurl}?query=rft.jtitle%253DHaemophilia%2B%253A%2B%2Bthe%2Bofficial%2Bjournal%2Bof%2Bthe%2BWorld%2BFederation%2Bof%2BHemophilia%26rft.stitle%253DHaemophilia%26rft.aulast%253DNichols%26rft.auinit1%253DW.%2BL.%26rft.volume%253D14%26rft.issue%253D2%26rft.spage%253D171%26rft.epage%253D232%26rft.atitle%253Dvon%2BWillebrand%2Bdisease%2B%2528VWD%2529%253A%2Bevidence-based%2Bdiagnosis%2Band%2Bmanagement%2Bguidelines%252C%2Bthe%2BNational%2BHeart%252C%2BLung%252C%2Band%2BBlood%2BInstitute%2B%2528NHLBI%2529%2BExpert%2BPanel%2Breport%2B%2528USA%2529.%26rft_id%253Dinfo%253Adoi%252F10.1111%252Fj.1365-2516.2007.01643.x%26rft_id%253Dinfo%253Apmid%252F18315614%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1111/j.1365-2516.2007.01643.x&link_type=DOI [3]: /lookup/external-ref?access_num=18315614&link_type=MED&atom=%2Fpedsinreview%2F35%2F3%2F136.atom [4]: /lookup/external-ref?access_num=000253626100001&link_type=ISI [5]: {openurl}?query=rft.jtitle%253DAm%2BSoc%2BHematol%2BEduc%2BProgram%26rft.volume%253D2012%26rft.spage%253D152%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx

Von Willebrand Disease in Pregnancy

ABSTRACT Von Willebrand disease (vWD) is the most common inherited bleeding disorder. It is due to deficiency of von Willebrand factor (vWF) which may be either quantitative or qualitative. There are 3 types of vWD out of which Type III is the rarest but the most severe. We report a 27 years second gravida diagnosed with vWD in her index pregnancy. Though her antenatal period was uneventful, she developed complications in the perioperative period following a caesarean section. However, with a multidisciplinary team effort, the maternal and fetal outcome were favourable. How to cite this article Bagga R, Jangid A, Gainder S, Malhotra P, Varma S, Ahluwalia J, Arora A. Von Willebrand Disease in Pregnancy. J Postgrad Med Edu Res 2014;48(3):157-158.

The various states of von Willebrand factor and their function in physiology and pathophysiology

The specific interactions of von Willebrand factor (VWF) with the vessel wall, platelets or other interfaces strongly depend on (a shear-induced) VWF activation. Shear flow has been shown to induce a conformational transition of VWF, but is modulated by its thermodynamic state (state-function relationship). The state in turn is determined by physical (e.g. vessel geometry), physico-chemical (e.g. pH) and molecular-biological (e.g. mutants, binding) factors. Combining established results with recent insights, we reconstruct VWF biology and its state-function relationship from endothelial cell release to final degradation in the human vasculature. After VWF secretion, endothelial-anchored and shear activated VWF multimers can rapidly interact with surrounding colloids, typically with platelets. Simultaneously, this VWF activation enables ADAMTS13 to cleave VWF multimers thereby limiting VWF binding capacity. The subsequent cell-surface dissociation leads to a VWF recoiling to a globular conformation, shielding from further degradation by ADAMTS13. High local concentrations of these soluble VWF multimers, transported to the downstream vasculature, are capable for an immediate reactivation and re-polymerisation initiating colloid-binding or VWF-colloid aggregation at the site of inflamed endothelium, vessel injuries or pathological high-shear areas. Focusing on these functional steps in the lifecycle of VWF, its qualitative and quantitative deficiencies in the different VWD types will facilitate more precise diagnostics and reliable risk stratification for prophylactic therapies. The underlying biophysical principles are of general character, which broadens prospective studies on the physiological and pathophysiological impact of VWF and VWF-associated diseases and beares hope for a more universal understanding of an entire class of phenomena.