FAKTOR PATOGENESIS DAN DIAGNOSIS PENYAKIT von Willebrand

von Willebrand disease (vWD) is an autosomal inherited bleeding disorder caused by a deficiency or abnormality of von Willebrandfactor (vWF). vWF is a large multimeric glycoprotein that mediates platelet adhesion at the site of vessel injury. It also protects factorVIII from proteolytic degradation in the circulation. vWD has a prevalence of about 1% in the general population but less than 10%have bleeding symptoms. Bleeding symptoms are usually mucocutaneous and post surgical with varying severity. This disorder canresult from either a quantitative (types 1 and 3) or qualitative (type 2) defect in vWF. Type 2 vWD has been further classified into fourdistinct subtypes; 2A, 2B, 2M and 2N. The diagnosis of vWD requires attention to personal and family history of excessive bleeding andconfirmation by laboratory evaluation. A mild chronic thrombocytopenia is often seen in type 2B vWD. Patients with mild vWD oftenhave both a normal bleeding time and normal APTT. Specific tests for vWD diagnosis involve vWF antigen level, vWF activity (ristocetincofactor), and factor VIII activity. Once a diagnosis is established, additional tests that aid in classifying the type of vWD includeristocetin-induced platelet aggregation and vWF multimer analysis.

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Estimation of the Carbohydrate Moiety of von Willebrand Factor in the Plasma of Patients with Subtypes 2a and 2b of von Willebrand Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649900 ◽

1995 ◽

Vol 74 (04) ◽

pp. 1180-1184

Author(s):

Christophe de Romeuf ◽

Bruno Samor ◽

Claudine Mazurier

Keyword(s):

Sialic Acid ◽

Von Willebrand Factor ◽

Platelet Adhesion ◽

Colorimetric Assay ◽

Microtiter Plate ◽

Von Willebrand Disease ◽

Carbohydrate Moiety ◽

Von Willebrand ◽

Willebrand Factor

SummaryVon 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 α 2-6 sialic acid or β 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 α 2-6 sialic acid and β 1-4 galactose content of plasma vWF is not altered in these patients affected with types 2A and 2B vWD.

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The Course of von Willebrand Factor and Factor VIII Activity in Patients with von Willebrand Disease during Pregnancy

Acta Haematologica ◽

10.1159/000496820 ◽

2019 ◽

Vol 142 (2) ◽

pp. 71-78 ◽

Cited By ~ 1

Author(s):

Christiane Delbrück ◽

Wolfgang Miesbach

Keyword(s):

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Factor Viii Activity ◽

Third Trimester ◽

Coagulation Parameters ◽

The Third ◽

Von Willebrand ◽

Willebrand Factor

Introduction: Women with von Willebrand disease (VWD) are at a higher risk of bleeding, which might affect the health of mother and child during pregnancy and the intra- and postpartum periods. This retrospective cohort study evaluates changes in the coagulation parameters von Willebrand factor antigen (VWF:Ag), von Willebrand ristocetin cofactor (VWF:RCo), and Factor VIII activity (FVIII:C) during pregnancy in patients with VWD. In total, 44 pregnancies of 38 patients were assessed (VWD type 1 n = 32, type 2A n = 3, type 2B n = 1, type 2 subtype unidentified n = 2). The patients’ median age at childbirth was 32 years (range 22–40). Results: A significant increase in coagulation parameters was found in patients with VWD type 1 (VWF:Ag, VWF:RCo, and FVIII:C p = 0.000). In the third trimester, VWF:Ag and FVIII:C normalized in all patients with VWD type 1; in 3 patients VWF:RCo remained below the normal range. Patients with VWD type 2 showed a significant increase of VWF:Ag (p = 0.003) and FVIII:C (p = 0.011), and a non-significant increase of VWF:RCo (p = 0.097). In 4 of 9 pregnancies of patients with VWD type 2, all surveyed coagulation parameters normalized until the third trimester. Conclusion: For the majority of the observed patients, the von Willebrand parameters increased during pregnancy.

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Biologic Response and Adverse Events To Stimate In Patients With Von Willebrand Disease

Blood ◽

10.1182/blood.v122.21.2365.2365 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2365-2365

Author(s):

Xiangqian Song ◽

Leonard A. Valentino ◽

Mindy L. Simpson ◽

Lisa Boggio

Keyword(s):

Adverse Events ◽

Factor Viii ◽

Biological Response ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Excessive Bleeding ◽

Initial Adhesion ◽

Von Willebrand

Abstract von Willebrand factor (VWF) is a large multimeric glycoprotein secreted from platelet α-granules and Weibel-Palade bodies of endothelial cells. VWF mediates the initial adhesion of platelets at sites of vascular injury and binds to and stabilizes blood coagulation factor VIII in the circulation to protect it from inactivation and clearance. von Willebrand disease (VWD) is the most common hereditary bleeding disorder and results from the deficiency or dysfunction of VWF leading to mucocutaneous bleeding, including epistaxis, menorrhagia, and excessive bleeding after trauma or surgery. Bleeding in patients with VWD is treated with infusion of plasma-derived VWF containing FVIII concentrates or 1-desamino-8-D-arginine vasopressin (DDAVP, desmopression). DDAVP is an analog of vasopressin antidiuretic hormone which can stimulate the exocytosis of VWF from storage sites and increase VWF and FVIII levels. DDAVP can be administrated by intravenous and intranasal routes. There are several reports of the safety and efficacy of intravenous DDAVP, but few with concentrated intranasal DDAVP (Stimate®). Here we report on the efficacy and safety of Stimate® in patients with VWD Methods Hospital records for 72 patients with VWD who received Stimate® from 1998 to 2012 were reviewed. The primary endpoint was the patients’ biological response to Stimate®, defined as at least a 3 fold increase compared to baseline of both ristocetin cofactor activity (VWF:RCo), factor VIII procoagulant activity (FVIII:C), or both VWF:RCo and FVIII:C are over 100% after Stimate®. Individuals not meeting the response criteria were deemed to be nonresponse. The adverse events were analyzed between different VWD types, response, age, gender, and race. Result Of those 72 VWD patients, 45 have type 1 (62%), 7 have type 2 (10%), and in 20 cases the subtype was unclear (28%). Responsive to Stimate® was observed in 43 (95.6%) of type 1, 4 (57.1%) of type 2, and 19 (95%) in which the diagnosis was unclear. In total, 16 patients (22.2%) had adverse events: 1 – allegoric response, 8 - mild headache, 4 - mild hyponatremia, and 4 - blood pressure (BP) reduced more than 20 mmHg. Conclusion Patients with VWD 1 have higher response rates to Stimate® than patients with VWD 2 in our test. The Stimate® is effective and safe for treatment of VWD. Disclosures: Valentino: Baxter, Bayer, Biogen Idec, GTC Biotherapeutics, Inspiration Biopharmaceuticals, Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees.

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Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD)

Blood ◽

10.1182/blood-2006-05-020784 ◽

2006 ◽

Vol 109 (1) ◽

pp. 112-121 ◽

Cited By ~ 241

Author(s):

Anne Goodeve ◽

Jeroen Eikenboom ◽

Giancarlo Castaman ◽

Francesco Rodeghiero ◽

Augusto B. Federici ◽

...

Keyword(s):

Gene Mutations ◽

Von Willebrand Disease ◽

Clinical Markers ◽

High Prevalence ◽

True Type ◽

History Of ◽

Von Willebrand ◽

Willebrand Factor

Abstract Type 1 von Willebrand disease (VWD) is characterized by a personal and family history of bleeding coincident with reduced levels of normal plasma von Willebrand factor (VWF). The molecular basis of the disorder is poorly understood. The aims of this study were to determine phenotype and genotype and their relationship in patients historically diagnosed with type 1 VWD. Families were recruited in 9 European countries based on previous type 1 VWD diagnosis. Bleeding symptoms were recorded, plasma phenotype analyzed, and VWF mutation analysis performed in all index cases (ICs). Phenotypic and molecular analysis stratified patients into those with or without phenotypes suggestive of qualitative VWF defects (abnormal multimers) and with or without mutations. A total of 105 of 150 ICs (70%) had mutations identified. A subgroup with abnormal multimers (38% of ICs, 57 of 150) showed a high prevalence of VWF gene mutations (95% of ICs, 54 of 57), whereas in those with qualitatively normal VWF, fewer mutations were identified (55% of ICs, 51 of 93). About one third of the type 1 VWD cases recruited could be reconsidered as type 2. The remaining group could be considered “true” type 1 VWD, although mutations were found in only 55%.

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Heavy Menstrual Bleeding in Adolescent: Normal or a Sign of an Underlying Disease?

Seminars in Reproductive Medicine ◽

10.1055/s-0041-1739309 ◽

2021 ◽

Author(s):

Kaisu Luiro ◽

Elina Holopainen

Keyword(s):

Intrauterine Device ◽

Pubertal Development ◽

Abnormal Uterine Bleeding ◽

Underlying Disease ◽

Von Willebrand Disease ◽

Menstrual Bleeding ◽

Excessive Bleeding ◽

Common Etiology ◽

History Of ◽

Von Willebrand

AbstractHeavy, and often irregular, menstrual bleeding (HMB) is a common gynecologic complaint among adolescents. During the first few post-menarcheal years, anovulatory cycles related to immaturity of the hypothalamic–pituitary–ovarian axis are the most common etiology for abnormal uterine bleeding and should be considered as a part of normal pubertal development rather than a disease. If an already regular menstrual cycle becomes irregular, secondary causes of anovulation should be ruled out. Inherited and acquired bleeding disorders, such as von Willebrand disease, and quantitative and qualitative abnormalities of platelets are relatively common findings in adolescents with HMB from menarche. History of excessive bleeding or a diagnosed bleeding disorder in the family supports this etiology, warranting specialized laboratory testing. First-line treatment of HMB among adolescents is medical management with hormonal therapy or nonhormonal options. Levonorgestrel-releasing intrauterine device is an effective tool also for all adolescents with menstrual needs.

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Von Willebrand Disease Combined with Factor V Deficiency: Variant Bari

10.1055/s-0039-1682594 ◽

1977 ◽

Author(s):

N. Ciavarella ◽

F.A. Scaraggi ◽

M. Petronelli ◽

M. Coviello ◽

A. Oreste ◽

...

Keyword(s):

Bleeding Time ◽

Von Willebrand Disease ◽

The Other ◽

Hemorrhagic Diathesis ◽

Factor V ◽

Factor V Deficiency ◽

New Variant ◽

History Of ◽

Von Willebrand ◽

Combined Deficiency

We report a new variant of the von Willebrand’disease combined with a deficiency of Factor V. A 35 yr. old woman presented a history of severe hemorrhagic diathesis with prolonged epistaxis, gum bleeding and menometrorrhagias, one of which caused hysterectomy. PT 24"/15", aPTT 70"/33", F.V 8%; Template Ivy Bleeding Time (BT) 15'-10'; VIIIC 7%, VIIIRAG 76%, VIIIWF 48%; Platelet Retention (PR) 95%; Ristocetin-Induced Platelet Aggregation (RIPA) > 2.0 mg/ml; Electrophoretic mobility was normal. Other plasmatio and platelet assays were normal. The propositus has two female children. One presented: BT 5'30" - 6'30"; F.V 137%; VIIIC 54%, VIIIRAG 66%, VIIIWF 56%. The other. BT 5'-8"; F.V 107%; VIIIC 29%, VIIIRAG 30%, VIIIWF 37%. One of her two sisters has F.V 53%. The other was normal. One of her two brothers has VIIIC 84%, VIIIRAG 65%, VIIIWF 52%. The other was normal. As her father died of a severe hemorrhagic episode, we studied her three aunts. One has VIIIC 44%. Another has BT 7'30" and F.V “borderline. The third has F.V “borderline. In all the subjects presented PR was normal, while in all but two RIPA was reduced. This new variant may represent a genetical link between the von Willebrand’disease and a combined deficiency of F.VIII and F.V.

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Response to DDAVP in children with von Willebrand disease type 2

Hämostaseologie ◽

10.1055/s-0037-1617014 ◽

2009 ◽

Vol 29 (02) ◽

pp. 143-148 ◽

Cited By ~ 3

Author(s):

U. Budde ◽

K. Beutel ◽

W.-A. Hassenpflug ◽

H. Hauch ◽

T. Obser ◽

...

Keyword(s):

Disease Type ◽

Von Willebrand Disease ◽

Molecular Defect ◽

Variable Response ◽

Functional Parameters ◽

Functional Defect ◽

Biologic Response ◽

High Level ◽

Von Willebrand

SummaryWe have prospectively evaluated the biologic response to desmopressin (DDAVP) in 28 children with type 2 von Willebrand disease (VWD) in correlation with the phenotype and the molecular defect of VWF. The diagnosis of VWD type 2 was mainly based on VWF functional parameters and/or an aberrant VWF multimer pattern. Seventeen different mutations were identified (6 of them novel). No response with respect to the functional parameters VWF:RCo and/or VWF:CB was seen in patients with severe abnormality of the VWF multimer pattern. One patient with VWD type 2A phenotype IIC Miami did not respond with respect to VWF:CB, but showed a good response of VWF:Ag and FVIII:C as expected. Interestingly he showed a persistently high level of VWF:Ag and FVIII:C up to 4 hours after DDAVP infusion. Patients with minor alterations of multimer structure and particular mutations responded well to DDAVP, whereas patients with normal multimer structure but a defect in platelet dependent functional parameters did not respond with VWF:RCo. Conclusion: Children with VWD type 2 show a variable response to desmopressin depending on the mutation that correlates with the functional defect and the presence or absence as well as the half-life of large VWF multimers. Our data emphasize the usefulness of DDAVP testing even in patients with VWD type 2, possibly with the exception of VWD type 2B.

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Screening for haemorrhagic disorders in paediatric patients by means of a questionnaire

Hämostaseologie ◽

10.1055/s-0037-1621503 ◽

2009 ◽

Vol 29 (S 01) ◽

pp. S87-S89 ◽

Cited By ~ 4

Author(s):

I. Music ◽

M. Novak ◽

B. Acham-Roschitz ◽

W. Muntean

Keyword(s):

Predictive Value ◽

Laboratory Diagnosis ◽

Von Willebrand Disease ◽

Control Group ◽

Older Children ◽

Mild Disease ◽

History Of ◽

Von Willebrand ◽

Specific Symptoms ◽

Infants And Young Children

SummaryAim: In children, screening for haemorrhagic disorders is further complicated by the fact that infants and young children with mild disease in many cases most likely will not have a significant history of easy bruising or bleeding making the efficacy of a questionnaire even more questionable. Patients, methods: We compared the questionnaires of a group of 88 children in whom a haemorrhagic disorder was ruled out by rigorous laboratory investigation to a group of 38 children with mild von Willebrand disease (VWD). Questionnaires about child, mother and father were obtained prior to the laboratory diagnosis on the occasion of routine preoperative screening. Results: 23/38 children with mild VWD showed at least one positive question in the questionnaire, while 21/88 without laboratory signs showed at least one positive question. There was a trend to more specific symptoms in older children. Three or more positive questions were found only in VWD patients, but only in a few of the control group. The question about menstrual bleeding in mothers did not differ significantly. Sensitivity of the questionnaire for a hemostatic disorder was 0.60, while specifity was 0.76. The negative predictive value was 0.82, but the positive predictive value was only 0.52. Conclusions: Our small study shows, that a questionnaire yields good results to exclude a haemostatic disorder, but is not a sensitive tool to identify such a disorder.

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Von Willebrand disease and Weibel-Palade bodies

Hämostaseologie ◽

10.1055/s-0037-1619048 ◽

2010 ◽

Vol 30 (03) ◽

pp. 150-155 ◽

Cited By ~ 9

Author(s):

J. W. Wang ◽

J. Eikenboom

Keyword(s):

Platelet Adhesion ◽

Coagulation Factor ◽

Von Willebrand Disease ◽

Inflammatory Factors ◽

Limited Data ◽

Storage Organelle ◽

And Function ◽

Von Willebrand ◽

Willebrand Factor

SummaryVon Willebrand factor (VWF) is a pivotal haemostatic protein mediating platelet adhesion to injured endothelium and carrying coagulation factor VIII (FVIII) in the circulation to protect it from premature clearance. Apart from the roles in haemostasis, VWF drives the formation of the endothelial cell specific Weibel-Palade bodies (WPBs), which serve as a regulated storage of VWF and other thrombotic and inflammatory factors. Defects in VWF could lead to the bleeding disorder von Willebrand disease (VWD).Extensive studies have shown that several mutations identified in VWD patients cause an intracellular retention of VWF. However, the effects of such mutations on the formation and function of its storage organelle are largely unknown. This review gives an overview on the role of VWF in WPB biogenesis and summarizes the limited data on the WPBs formed by VWD-causing mutant VWF.

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