scholarly journals Rare Occurrence of Inhibitors in Von Willebrand Disease: A Case Report

2022 ◽  
Vol 8 ◽  
Bipin P. Kulkarni ◽  
Kirti Ghargi ◽  
Chandrakala Shanmukhaiah ◽  
Shrimati D. Shetty

Introduction: Type 3 Von Willebrand Disease (VWD) is the least common but the most severe form of a disease, with a prevalence of about 0. 5 to 1 per million in Western countries. The prevalence of type 3 VWD in the developing countries, with a high degree of consanguinity, is about 6 per million. Moreover, due to underdiagnosis of the milder cases, the prevalence of type 3 VWD is about 50% of the cases. Rarely, some patients develop the Von Willebrand Factor (VWF) inhibitors, which may subsequently develop severe anaphylactic reactions on further exposure to the VWF containing factor replacement therapy. The prevalence of inhibitor development in patients with type 3 VWD has been shown to be in the range of 5.8 to 9.5%. In the absence of a gold standard assay for the quantitation of VWF inhibitors, a correct diagnosis and management of these patients are often challenging.Objectives: The objective of this study is to standardize the Bethesda assay for the VWF inhibitors and to estimate the VWD inhibitor titer in two cases of congenital type 3 VWD, which developed the VWF inhibitors.Results and Conclusions: We could successfully standardize the Bethesda assay for the quantitation of VWF inhibitors in two patients with congenital type 3 VWD with inhibitors.

2021 ◽  
Vol 47 (02) ◽  
pp. 192-200
James S. O'Donnell

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.

2021 ◽  
Andrew Yee ◽  
Manhong Dai ◽  
Stacy E. Croteau ◽  
Jordan A. Shavit ◽  
Steven W. Pipe ◽  

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.

2013 ◽  
Vol 5 (1) ◽  
pp. e2013051 ◽  
Alberto Tosetto

Quantification of the bleeding severity by use of bleeding assessment tools (BAT) and bleeding score (BS) has been consistently shown to improve the clinical diagnosis of von Willebrand disease (VWD) while helping researchers establish phenotype/genotype correlations.  Subjects with a BS equal or higher than 3 may be consider having a bleeding tendency, and should be referred for a laboratory investigation, particularly for VWD. In the diagnosis of type 1 VWD, the use of the BS has been shown to be highly specific (>95%) with reported sensitivities ranging from 40 to 100%. The BS is related to all available measurements of von Willebrand factor activity, including the PFA-100 closure time. Therefore, in clinical practice the use of BAT should always be the first step to standardize the assessment of patients with suspected VWD. The use of the recent ISTH consensus BAT is suggested to harmonize the collection of bleeding symptoms in patients with a suspected or confirmed hemostatic disorder, particularly VWD. The ISTH BAT is also coupled with a Web-based repository of bleeding symptoms, therefore providing an integrated framework for collaboration in the field of clinical evaluation of VWD and mild bleeding disorders.

И.В. Куртов ◽  
Е.С. Фатенкова ◽  
Н.А. Юдина ◽  
А.М. Осадчук ◽  
И.Л. Давыдкин

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.

2021 ◽  
Vol 14 (8) ◽  
pp. e241613
Vaishnavi Divya Nagarajan ◽  
Asha Shenoi ◽  
Lucy Burgess ◽  
Vlad C Radulescu

An 18-year-old man with a history of type 3 von Willebrand disease (VWD) presented with a spontaneous pyohaemothorax. Type 3 VWD may present with both mucocutaneous and deep-seated bleeds, such as visceral haemorrhages, intracranial bleeds and haemarthrosis. There have been very few cases described in children of spontaneous pyohaemothorax. Management of this patient was challenging due to risks of bleeding following surgical drainage, requiring constant replacement with von Willebrand factor concentrate, while monitoring factor VIII levels to balance the risks of thrombosis.

2020 ◽  
Vol 31 (1) ◽  
pp. 77-79
Barbara Faganel Kotnik ◽  
Karin Strandberg ◽  
Maruša Debeljak ◽  
Lidija Kitanovski ◽  
Janez Jazbec ◽  

2000 ◽  
Vol 84 (08) ◽  
pp. 195-203 ◽  
Andrew Stewart ◽  
Fraser Witherow ◽  
Susan Grieve ◽  
Pamela Dawson ◽  
Keith Fox ◽  

SummaryIntra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin ≥70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses ≥300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001; r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1013-1013
Adrien Mohl ◽  
Tamás Masszi ◽  
Eszter Nagy ◽  
Tobias Obser ◽  
Florian Oyen ◽  

Abstract Background: Type 3 is the most severe form of von Willebrand disease (VWD) caused by the virtual absence of von Willebrand factor (VWF) in affected patients. The prevalence of type 3 VWD in Hungary is 2.6 per million. Capitalizing on a nationwide National Bleeding Disorder Registry, we designed a study to characterize the genetic background of the entire Hungarian type 3 VWD population. The current report focuses on the molecular characterization of a novel large deletion. Methods: 24 patients from 23 unrelated families were studied by direct sequencing of the 52 exons of the VWF gene. The breakpoints of a large deletion were characterized by standard gene mapping. Breakpoint-specific PCR was used to confirm the presence of the deletion, and to screen for identical deletions in other populations from Germany, Russia, and Poland. Results: A large partial deletion (delExon1-3) of the 5′-region of the VWF gene was detected in 10 alleles (19 percent of all type 3 mutations). Five patients from 4 unrelated families were homozygous, and 2 patients were heterozygous for the deletion. Consanguinity was known in one of the families. In comparison, 2435 delC in exon 18, a common cause of type 3 VWD in some European populations, was found on 6 alleles (12 percent; one patient homozygous). The large deletion resulted in the loss of a 35 kb fragment, incorporating exons 1, 2 and 3. The 5′ breakpoint is located in the 5′ untranslated region, while the 3′ breakpoint is in intron 3 of VWF. No other known gene is lost with the deletion. Clinically, all homozygous patients had serious bleeding episodes from infancy requiring frequent VWF substitutions. However, bleeding became much milder in all patients with no significant spontaneous bleeding after the age of 3-5 years. No inhibitor to VWF was detected. delExon1-3 was not detected in any of the other screened populations. Conclusion: We report a large novel deletion including exons 1, 2 and 3 of VWF commonly causing type 3 VWD in the Hungarian population. This mutation, which is most probably due to a founder effect, seems to be unique to Hungarian patients with a high allele frequency. Together, delExon1-3 and 2435delC make up 31 % of genetic defects in Hungarian patients with VWD type 3. This offers a rational approach to molecular testing of respective families in Hungary.

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 2059-2066 ◽  
Reinhard Schneppenheim ◽  
Ulrich Budde ◽  
Tobias Obser ◽  
Jacqueline Brassard ◽  
Kerstin Mainusch ◽  

Abstract Dimerization defects of von Willebrand factor (vWF) protomers underlie von Willebrand disease (vWD) type 2A, subtype IID (vWD 2A/IID), and corresponding mutations have been identified at the 3′ end of the vWF gene in exon 52. This study identified and expressed 2 additional mutations in this region, a homozygous defect in a patient with vWD type 3 (C2754W) and a heterozygous frameshift mutation (8566delC) in a patient with vWD type 2A, subtype IIE. Both mutations involve cysteine residues that we propose are possibly essential for dimerization. To prove this hypothesis, transient recombinant expression of each of the 2 mutations introduced in the carboxy-terminal vWF fragment II and in the complete vWF complementary DNA, respectively, were carried out in COS-7 cells and compared with expression of vWD 2A/IID mutation C2773R and the wild-type (WT) sequence in COS-7 cells. Recombinant WT vWF fragment II assembled correctly into a dimer, whereas recombinant mutant fragments were monomeric. Homozygous expression of recombinant mutant full-length vWF resulted in additional dimers, probably through disulfide bonding at the amino-terminal multimerization site, whereas recombinant WT vWF correctly assembled into multimers. Coexpression of recombinant mutant and recombinant WT vWF reproduced the multimer patterns observed in heterozygous individuals. Our results suggest that a common defect of vWF biosynthesis—lack of vWF dimerization—may cause diverse types and subtypes of vWD. We also confirmed previous studies that found that disulfide bonding at the vWF amino-terminal is independent of dimerization at the vWF carboxy-terminal.

Sign in / Sign up

Export Citation Format

Share Document