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

Blood ◽  
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.

A Two Centre Experience Of Use Of a Dual Virally Inactivated FVIII/VWF Product (Wilate®) In Patients With Von Willebrand Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1112-1112 ◽  
Author(s):  
Paul A Batty ◽  
Kate Khair ◽  
Renu Riat ◽  
Yun-Han Chen ◽  
Louise Bowles ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Pathogen Transmission ◽  
Von Willebrand Disease ◽  
Primary Study ◽  
Type 3 ◽  
Von Willebrand ◽  
Conference Registration

Abstract Introduction von Willebrand disease (VWD) causes mild to severe bleeding, typically following trauma or surgical intervention. These episodes require treatment with a von Willebrand factor (VWF) containing concentrate; at present the only available concentrates are plasma derived. UK guidelines recommend using concentrates manufactured to the highest standards to reduce the risk of pathogen transmission. Methods Wilate® (Octapharma AG, Switzerland) is a dual virally inactivated FVIII/VWF concentrate available in the UK since 2007. Use of Wilate® between 2007 and 2012, including a period of product switching was evaluated in two large haemophilia centres (adult and paediatric). The primary study end-point was efficacy of concentrate usage for the treatment of bleeding and surgery. Efficacy was graded using 4 point ordinal scales that rated efficacy as; excellent, good, moderate or nil. Secondary end points were the occurrence of adverse events (immune, infective or thrombotic) and evidence of response on laboratory parameters. Results Between 01/03/07 and 01/05/12 a total of 4,565,450IU of Wilate® were used with data evaluable for 4,125,800IU (90.4%). Eighty two patients (44 male, 38 female) including 33 children (< 18yrs) and 49 adults (≥18yrs) with type 1 (n=29), type 2 (n=34), type 3 diseases (n=16) and acquired von Willebrand syndrome (AVWS) (n=3) were treated. The median age at first treatment was 22.7 yrs (range 0.01- 82.3). The mean recoveries ± SD, following first dose in adults (n=35) were FVIII:C 2.25 ± 0.65; VWF:Ag 2.4 ± 0.70 and VWF:RCo 1.91 ± 0.53. Fifty three patients (20 < 18yr, 33 ≥ 18yr) received concentrate for 93 surgical interventions (36 major, 36 minor, 21 dental procedures). This included 22 patients with type 1, 22 type 2, 7 type 3 disease and 2 with AVWS. The median loading dose prior to surgery was 2700IU (range 450-7200) corresponding to 43.1IU/kg (range 11.84-125). Surgical procedures were covered with a median of 1 treatment (range 1-13) over a median of 1 day (range 1 – 12). Thirty surgical episodes required ≥2 doses (27 major, 3 minor) with a median second dose of 1800IU (range 450-4500) corresponding to 36.4IU/kg (range 17.9-78.6). Overall efficacy was rated as excellent in 89.2% (n=83), good in 5.4% (n=5), moderate in 4.3% (n=4) and nil in 1.1% (n=1). Thirty five patients (13 < 18yr, 22 ≥ 18yr) were treated for 80 non-surgical episodes of bleeding or trauma (37 major, 43 minor). This included 10 patients with type 1, 14 type 2, 10 type 3 disease and 1 with AVWS. The median first dose given was 2475 IU (range 250-7200) corresponding to 45.7 IU/kg (range 11.8- 97.8). Bleeding episodes were treated with a median of 2 treatments (range 1-80) over a median of 2 treatment days (range 1-78). Forty-three episodes required ≥2 doses (36 major, 7 minor) with a median follow-up dose of 2700IU (range 250-8100) corresponding to 39.3IU/kg (range 11.8-95.7). Overall efficacy was rated as being excellent in 87.5% (n=70), good in 10.0% (n=8), moderate in 2.5% (n=2) and nil in 0.0% (n=0). Nine patients (1 < 18yr, 8 ≥ 18yr) were on home treatment regimens using 2,644,200 IU of Wilate® (64.1% total usage). These patients were treated using either on-demand (n=3), regular prophylaxis (n=5) or targeted prophylaxis (n=1). Two patients on prophylaxis switched to Wilate® within the study period with similar efficacy to the previous six months of treatment. Twelve patients were treated for other indications not covered by these categories. Wilate® was used to cover 3 un-complicated deliveries (1 operative and 2 vaginal deliveries). There were 8 reported adverse events (8 patients), with 4 requiring medical review although not requiring in-patient treatment. One patient had treatment failure (impaired VWF:Ag recovery) on one treatment episode, and has been successfully re-treated. Five patients were re-challenged with only one having a repeat mild reaction. Five patients switched to an alternative product at the discretion of the patient/physician. No accumulation of FVIII was seen in patients treated for ≥3 days (mean change in FVIII:C trough level (first to last) +31.89iu/dl (-124.4 - +116.6)). No thrombosis, TTI or inhibitory antibodies were reported. Conclusion Wilate® was efficacious (excellent or good efficacy in > 94%), safe and well tolerated in this heterogeneous group of 82 patients with VWD. Bleed resolution or prevention was 100% with no accumulation of FVIII seen. Disclosures: Batty: Octapharma: Research Funding, Travel and conference registration fees Other. Khair:Octapharma: Honoraria, Research Funding, Travel to conferences and regsitration fees Other. Hart:Octapharma: Consultancy, Honoraria, Research Funding, Travel and conference registration fees Other. Liesner:Octapharma: Consultancy, Honoraria, Research Funding, Travel and conference registration fees Other. Pasi:Octapharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, travel and conference fees Other.

Molecular analysis of FVIII gene in severe HA patients of Costa Rica

2010 ◽  
Vol 30 (S 01) ◽  
pp. S150-S152
Author(s):  
G. Jiménez-Cruz ◽  
M. Mendez ◽  
P. Chaverri ◽  
P. Alvarado ◽  
W. Schröder ◽  
...  
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Costa Rican ◽  
Factor Viii Gene ◽  
Intron 22 Inversion ◽  
Intron 1 ◽  
Polymerase Chain ◽  
Inversion Analysis

SummaryHaemophilia A (HA) is X-chromosome linked bleeding disorders caused by deficiency of the coagulation factor VIII (FVIII). It is caused by FVIII gene intron 22 inversion (Inv22) in approximately 45% and by intron 1 inversion (Inv1) in 5% of the patients. Both inversions occur as a result of intrachromosomal recombination between homologous regions, in intron 1 or 22 and their extragenic copy located telomeric to the FVIII gene. The aim of this study was to analyze the presence of these mutations in 25 HA Costa Rican families. Patients, methods: We studied 34 HA patients and 110 unrelated obligate members and possible carriers for the presence of Inv22or Inv1. Standard analyses of the factor VIII gene were used incl. Southern blot and long-range polymerase chain reaction for inversion analysis. Results: We found altered Inv22 restriction profiles in 21 patients and 37 carriers. It was found type 1 and type 2 of the inversion of Inv22. During the screening for Inv1 among the HA patient, who were Inv22 negative, we did not found this mutation. Discussion: Our data highlight the importance of the analysis of Inv22 for their association with development of inhibitors in the HA patients and we are continuous searching of Inv1 mutation. This knowledge represents a step for genetic counseling and prevention of the inhibitor development.

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

2021 ◽  
Vol 47 (02) ◽  
pp. 192-200
Author(s):  
James S. O'Donnell
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Risk ◽  
Von Willebrand Disease ◽  
Personalized Treatment ◽  
Treatment Plans ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractThe biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures.

Recessive von Willebrand Disease Type 2 Normandy: Variable Expression of Mild Hemophilia and VWD Type 1

2009 ◽  
Vol 121 (2-3) ◽  
pp. 119-127 ◽  
Author(s):  
Jan Jacques Michiels ◽  
Alain Gadisseur ◽  
Inge Vangenegten ◽  
Wilfried Schroyens ◽  
Zwi Berneman
Keyword(s):  
Disease Type ◽  
Von Willebrand Disease ◽  
Variable Expression ◽  
Von Willebrand

Identification of Type 2 von Willebrand Disease in Previously Diagnosed Type 1 Patients: a Reappraisal Using Phenotypes, Genotypes and Molecular Modelling

2000 ◽  
Vol 84 (12) ◽  
pp. 998-1004 ◽  
Author(s):  
Ioana Nitu-Whalley ◽  
Anne Riddell ◽  
K. Pasi ◽  
Dale Owens ◽  
M. Enayat ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Correct Diagnosis ◽  
Von Willebrand Disease ◽  
Single Amino Acid ◽  
Elisa Assay ◽  
Modelling Analysis ◽  
A1 Domain ◽  
Von Willebrand

SummaryIn order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.

Clinical cases of using coagulation factor VIII with von Willebrand factor in parturient women with type III von Willebrand disease

2020 ◽  
Author(s):  
И.В. Куртов ◽  
Е.С. Фатенкова ◽  
Н.А. Юдина ◽  
А.М. Осадчук ◽  
И.Л. Давыдкин
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Coagulation Factor Viii ◽  
Vitro Fertilization ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Болезнь Виллебранда (БВ) может представлять определенные трудности у рожениц с данной патологией. Приведены 2 клинических примера использования у женщин с БВ фактора VIII свертывания крови с фактором Виллебранда, показана эффективность и безопасность их применения. У одной пациентки было также показано использование фактора свертывания крови VIII с фактором Виллебранда во время экстракорпорального оплодотворения. Von Willebrand disease presents a certain hemostatic problem among parturients. This article shows the effectiveness and safety of using coagulation factor VIII with von Willebrand factor for the prevention of bleeding in childbirth in 2 patients with type 3 von Willebrand disease. In one patient, the use of coagulation factor VIII with von Willebrand factor during in vitro fertilization was also shown.

Desmopressin testing in children with von Willebrand syndrome in haemostaseologic centers of Saxonia, Saxonia-Anhalt and Thuringia

2009 ◽  
Vol 29 (S 01) ◽  
pp. S98-S102 ◽  
Author(s):  
B. Huhn ◽  
A. Hofmann ◽  
K. Hofmann ◽  
H. Sirb ◽  
V. Aumann ◽  
...  
Keyword(s):  
Partial Response ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Vascular Endothelium ◽  
Test Performance ◽  
Coagulation Factor ◽  
Syndrome Type ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe influence of desmopressin on hemostasis is mediated by the release of von Willebrand factor and of coagulation factor VIII from vascular endothelium. The necessity of testing desmopressin effectiveness on hemostasis is a matter of controversy and the performance of the test is not yet standardized. For this reason the desmopressin tests in 114 children with von Willebrand syndrome (type 1, n=98; type 2A, n=12; type 2M, n=2; type 2N, n=2) carried out in 7 paediatric haemostaseologic centers were retrospectively analyzed. The effectiveness of desmopressin was assessed using defined response criteria. As expected, the test performance showed a wide variation among the centers. In 99 children desmopressin was given intravenously as a short infusion at a dosage ranging from 0.25 to 0.41 μg/kg and in 15 intranasally at an absolute dose of 40 to 300 μg. The points of time for blood taking after desmopressin application ranged from 0.5 to 12 h. The absent desmopressin response in 7 patients (6%) and the partial response in 15 indicate the necessity of testing desmopressin effectiveness before the first therapeutic use. The application of desmopressin was well tolerated by the patients.

Managing Patients with von Willebrand Disease Type 1, 2 and 3 with Desmopressin and von Willebrand Factor-Factor VIII Concentrate in Surgical Settings

2009 ◽  
Vol 121 (2-3) ◽  
pp. 167-176 ◽  
Author(s):  
Jan Jacques Michiels ◽  
Huub H.D.M. van Vliet ◽  
Zwi Berneman ◽  
Wilfried Schroyens ◽  
Alain Gadisseur
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Disease Type ◽  
Von Willebrand Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand Factor Levels Do Not Increase with Age in Patients with Type 1 Von Willebrand Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4028-4028
Author(s):  
Hong I. Tarng ◽  
Lynne Taylor ◽  
Barbara A. Konkle
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Test Results ◽  
Age Related ◽  
One Year ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Over Time

Abstract A number of inherited and acquired factors modulate von Willebrand factor antigen (VWF:Ag) levels, including blood type, race, activity and stress level, thyroid hormone status, and, in women, time in menstrual cycle. In reported studies a positive correlation between VWF:Ag and/or factor VIII levels and age has been demonstrated, with an increase of 5 – 6 IU/dL per decade (Conlan MG et al, 1993; Kamphuisen PW et al, 1998). Those studies have primarily assessed VWF and factor VIII as risk factors for ischemic heart disease, cerebrovascular disease, and venous thromboembolism. None of the subjects had von Willebrand disease (VWD). Their VWF:Ag levels were in the higher normal or elevated range. The purpose of this study was to determine whether there is a relationship between age and VWF:Ag level in patients with Type 1 VWD. We collected the data from 36 patients who were diagnosed with type 1 VWD and followed at the Penn Comprehensive Hemophilia and Thrombosis Program up to a period of 13 years (See Table 1 below). For each patient, date of birth, VWF:Ag levels with corresponding test dates were collected by reviewing the medical histories and the lab results. Test results obtained during pregnancy, DDAVP testing, or during prophylaxis or therapy for bleeding control were excluded. One year was set as the observation period, so the adjacent VWF:Ag levels that were tested less than one year were excluded from the dataset. When two test results were available on a patient within a one-year period, the lower test result was used. To investigate whether there was a relationship between VWF:Ag levels and age, cross-sectional analyses (across each visit) and longitudinal analyses were performed using scatter plots, Spearman and Pearson correlations, and regression analysis. No significant increase in VWF:Ag levels with age was demonstrated. The fact that we did not find an increase in VWF:Ag levels over time in our patients could be due to the relatively small number of patients studied or could reflect a subtype of VWD, due to our selection criteria. Only patients with abnormal values were included. Some patients have a prior diagnosis of VWD and bleeding symptoms, but have normal values when tested. Since these patients are adults, this may be due, at least in part, to an age-related increase. Type 1 VWD may occur secondary to decreased VWF synthesis and/or clearance. It is possible that age-related effects on VWF levels will differ depending on the underlying factor(s) resulting in a lower VWF level. Further studies correlating a patient’s values longitudinally with the underlying pathophysiology of their disease would aid in our understanding of their bleeding risks over time. Patient # Age at Last Visit, range (mean) Females (%) Race % (Cauc/AA/Other) VWF:Ag mean 36 17–70 (34) 89 78/19/3 49%

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