Effectiveness of emicizumab in preventing life‐threatening bleeding complications in type 3 von Willebrand disease with inhibitors: A paediatric report

Haemophilia ◽  
2020 ◽  
Author(s):  
Maria Giuseppina Cefalo ◽  
Francesca Ronco ◽  
Giovina Di Felice ◽  
Martina Rinelli ◽  
Vincenzo Oriana ◽  
...  
Keyword(s):  
Von Willebrand Disease ◽  
Bleeding Complications ◽  
Life Threatening ◽  
Type 3 ◽  
Von Willebrand

Type 3 Von Willebrand Disease with Alloantibodies and Its Challenging Management During Episode of Bleeding

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1405-1405
Author(s):  
Anupam Verma ◽  
Hassan Yaish ◽  
George M. Rodgers
Keyword(s):  
Factor Viii ◽  
Clinical Course ◽  
Conflicts Of Interest ◽  
Von Willebrand Disease ◽  
Recombinant Factor Viii ◽  
Severe Bleeding ◽  
Post Infusion ◽  
Life Threatening ◽  
Type 3 ◽  
Von Willebrand

Abstract Abstract 1405 Type 3 Von Willebrand Disease (VWD) is the most severe and least common of the three VWD types. The incidence varies by ethnicity ranging from 0.1–5.3 cases/million. 8.5% of patients develop alloantibodies to Von Willebrand Factor (VWF), becoming non-responsive to treatment or prone to life threatening reactions. Predisposing factors include extent of previous exposure to VWF and mutations causing a null-allele gene. Variability of the clinical course is attributed to different antigenic specificities and potency of the antibodies. Management of these patients during events of bleeding is challenging. We report 2 cases of girls with type 3 VWD. The first was diagnosed at birth and had her initial VWF transfusion as a neonate. The second was diagnosed at 4 years of age. Both were frequently treated with VWF and developed alloantibodies. The clinical course, severity and circumstances leading to the diagnosis were different in both cases. Life threatening anaphylactic reactions like hypotension, bronchospasm and tongue edema was noticed in the first. The second showed poor factor recovery and response to treatment with urticaria. She continued to tolerate therapy but failed tolerance induction. Peak antibody level was 84 BU compared to 3 BU in the first. Novel VWF gene mutations were detected in both. Recently the first patient was managed for profuse bleeding post extensive dental procedure. Recombinant Factor VIII infusion was administered every 3 hours with monitoring of aPTT and Factor VIII levels. Based on peak and post 3 hour levels of Factor VIII, we concluded the half life of Factor VIII could be as short as 2 hours in patients with type 3 VWD. Post infusion peak level might approach 200% in some instances. Due to persistent bleeding despite adequate correction of Factor VIII and aPTT, platelet transfusion was cautiously administered which proved to be not only effective in controlling bleed but was also safe and not associated with any anaphylactic reaction. In conclusion, patients with type 3 VWD and alloantibodies can be successfully managed with aggressive frequent therapy with recombinant Factor VIII infusions. Platelet transfusions during episodes of severe bleeding can also be safe and effective.Administration of Factor VIII by continuous infusion could be an option if high post infusion peaks are to be avoided. Disclosures: No relevant conflicts of interest to declare.

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

Evaluation of the Abnormal Platelet Function in von Willebrand Disease by the Blood Filtration Test

1996 ◽  
Vol 76 (03) ◽  
pp. 460-468 ◽  
Author(s):  
Francesco I Pareti ◽  
Marco Cattaneo ◽  
Luca Carpinelli ◽  
Maddalena L Zighetti ◽  
Caterina Bressi ◽  
...  
Keyword(s):  
Platelet Function ◽  
Relevant Information ◽  
Von Willebrand Disease ◽  
Type I ◽  
Cumulative Number ◽  
Primary Hemostasis ◽  
Normal Platelet ◽  
Filter Test ◽  
Type 3 ◽  
Von Willebrand

SummaryWe have evaluated platelet function in different subtypes of von Willebrand disease (vWD) by pushing blood through the capillarysized channels of a glass filter. Patients, including those with type IIB vWD, showed lower than normal platelet retention and increased cumulative number of blood drops passing through the filter as a function of time. In contrast, shear-induced platelet aggregation, measured in the cone-and-plate viscometer, was paradoxically increased in type IIB patients. Treatment with l-desamino-8-D-arginine vasopressin (DDAVP) tended to normalize the filter test in patients with type I-platelet normal and type I-platelet low vWD, but infusion of a factor VUI/von Willebrand factor (vWF) concentrate lacking the largest vWF multimers was without effect in type 3 patients. Experiments with specific monoclonal antibodies demonstrated that the A1 and A3 domains of vWF, as well as the glycoproteins Ibα and Ilb-IIIa on platelets, are required for platelet retention in the filter. Thus, the test may reflect vWF function with regard to both platelet adhesion and aggregation under high shear stress, and provide relevant information on mechanisms involved in primary hemostasis.

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.

scholarly journals A common 253-kb deletion involving VWF and TMEM16B in German and Italian patients with severe von Willebrand disease type 3

2007 ◽  
Vol 5 (4) ◽  
pp. 722-728 ◽  
Author(s):  
R. SCHNEPPENHEIM ◽  
G. CASTAMAN ◽  
A. B. FEDERICI ◽  
W. KREUZ ◽  
R. MARSCHALEK ◽  
...  
Keyword(s):  
Disease Type ◽  
Von Willebrand Disease ◽  
Type 3 ◽  
Von Willebrand

scholarly journals Phage Display Broadly Identifies Inhibitor-reactive Regions in von Willebrand Factor

2021 ◽  
Author(s):  
Andrew Yee ◽  
Manhong Dai ◽  
Stacy E. Croteau ◽  
Jordan A. Shavit ◽  
Steven W. Pipe ◽  
...  
Keyword(s):  
Phage Display ◽  
Von Willebrand Factor ◽  
Gene Deletion ◽  
Von Willebrand Disease ◽  
Response To Treatment ◽  
Phage Library ◽  
Incomplete Removal ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryBackgroundCorrection of von Willebrand factor (VWF) deficiency with replacement products containing VWF can lead to the development of anti-VWF alloantibodies (i.e., VWF inhibitors) in patients with severe von Willebrand disease (VWD).ObjectiveLocate inhibitor-reactive regions within VWF using phage display.MethodsWe screened a phage library displaying random, overlapping fragments covering the full length VWF protein sequence for binding to a commercial anti-VWF antibody or to immunoglobulins from three type 3 VWD patients who developed VWF inhibitors in response to treatment with plasma-derived VWF. Immunoreactive phage clones were identified and quantified by next generation DNA sequencing (NGS).ResultsNGS markedly increased the number of phage analyzed for locating immunoreactive regions within VWF following a single round of selection and identified regions not recognized in previous reports using standard phage display methods. Extending this approach to characterize VWF inhibitors from three type 3 VWD patients (including two siblings homozygous for the same VWF gene deletion) revealed patterns of immunoreactivity distinct from the commercial antibody and between unrelated patients, though with notable areas of overlap. Alloantibody reactivity against the VWF propeptide is consistent with incomplete removal of the propeptide from plasma-derived VWF replacement products.ConclusionThese results demonstrate the utility of phage display and NGS to characterize diverse anti-VWF antibody reactivities.

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