Evaluation of the PFA-100® System in the Diagnosis and Therapeutic Monitoring of Patients with von Willebrand Disease

1999 ◽  
Vol 82 (07) ◽  
pp. 35-39 ◽  
Author(s):  
Augusto Federici ◽  
Anna Lecchi ◽  
Barbara Agati ◽  
Rossana Lombardi ◽  
Federica Stabile ◽  
...  
Keyword(s):  
Platelet Function ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Therapeutic Monitoring ◽  
High Shear ◽  
Before And After ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryWe have evaluated platelet function at high shear with the PFA-100® system in different subtypes of von Willebrand disease (vWD), before and after the intravenous infusions of desmopressin or a factor-VIII/von Willebrand factor (vWF) concentrate. Closure times with the PFA-100® system were determined for both the collagen/ADP and the collagen/epinephrine cartridges in 52 patients with vWD (9 type 1 “platelet normal”, 5 type 1 “platelet-discordant”, 8 type 1 “platelet-low”, 6 type 2A, 9 type 2B, 6 type 2M Vicenza, 6 type 3 and 3 acquired vWD) and 40 controls. Measurements were repeated 1 and 4 h after the i.v. infusion of desmopressin (0.3 μg/Kg) in 26 patients with types 1, type 2M Vicenza or type 2A vWD, or of a factorVIII/vWF concentrate (Alphanate HT, 60 U/Kg) in 4 patients with type 3 vWD. At all time points, vWF plasma levels and the bleeding time (Symplate II) were also determined. Baseline closure times were longer in vWD patients than in controls with both the collagen/ADP and the collagen/ epinephrine cartridges. The sensitivity of the PFA-100® system (88% and 87% with the two cartridges) was higher than that of the bleeding time (65%). Treatment with desmopressin normalized the closure times in patients with type 1 “platelet-normal” or type 2M Vicenza vWD, had no significant effects in patients with type 1 “platelet-low”, type 1 “platelet-discordant” or type 2A vWD. Infusion of a factorVIII/vWF concentrate in patients with type 3 vWD slightly shortened their prolonged closure times. In general, changes in PFA-100® were paralleled by shortenings of the bleeding times and increases in plasma vWF levels. The PFA-100® test reflects vWF-dependent platelet function under high shear stress and could be useful in the diagnosis and therapeutic monitoring of patients with vWD.

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 Therapeutic monitoring of von Willebrand disease: interest and limits of a platelet function analyser at high shear rates

1999 ◽  
Vol 106 (3) ◽  
pp. 777-783 ◽  
Author(s):  
Edith Fressinaud ◽  
Agnès Veyradier ◽  
Marianne Sigaud ◽  
Catherine Boyer-Neumann ◽  
Cécile Le Boterff ◽  
...  
Keyword(s):  
Platelet Function ◽  
Von Willebrand Disease ◽  
Therapeutic Monitoring ◽  
High Shear ◽  
Shear Rates ◽  
High Shear Rates ◽  
Von Willebrand

scholarly journals Prophylaxis in von Willebrand Disease: Coming of Age?

2016 ◽  
Vol 42 (05) ◽  
pp. 498-506 ◽  
Author(s):  
Giorgia Saccullo ◽  
Mike Makris
Keyword(s):  
Coming Of Age ◽  
Severe Disease ◽  
Standard Of Care ◽  
Von Willebrand Disease ◽  
The Past ◽  
Patients Experience ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Although in most cases von Willebrand disease (VWD) is a mild disorder, a subgroup of patients experience frequent bleeding. In contrast to severe hemophilia in which prophylaxis is the accepted standard of care, this is less frequently used in VWD. Most type 1 VWD patients can be adequately managed with episodic desmopressin and tranexamic acid. In patients with more severe disease, especially those with type 3 VWD, joint bleeds, epistaxis, menorrhagia, and gastrointestinal bleeding are problematic and usually require treatment with von Willebrand factor/factor VIII (VWF/FVIII) concentrate. While in the past these patients were managed with on-demand VWF/FVIII concentrate, several recent reports have demonstrated the value of prophylactic treatment. Despite some uncertainties about the economic impact of treatment of severe VWD, prophylaxis with VWF concentrate should now be considered as the standard of care for the more severe end of the spectrum of affected individuals. The recent introduction of recombinant VWF concentrate is likely to improve the acceptability of prophylaxis in VWD.

PFA-100 monitoring of von Willebrand factor (VWF) responses to desmopressin (DDAVP) and factor VIII/VWF concentrate substitution in von Willebrand disease type 1 and 2

2008 ◽  
Vol 100 (09) ◽  
pp. 462-468 ◽  
Author(s):  
Huub H. D. M. van Vliet ◽  
Mies C. Kappers-Klunne ◽  
Jan J. Michiels ◽  
Frank W. G. Leebeek
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Before And After ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryDose-response relationship was studied between PFA-100 closure times (PFA CTs) and factor (F)VIII-von Willebrand factor (VWF) parameters in patients with von Willebrand disease (VWD) type 1 and type 2 before and after treatment with DDAVP (n=84) or FVIII/VWF concentrate (n=38). DDAVP treatment of patients with VWD type 1 normalised the PFA CTs by increasing VWF levels to normal. Of the 14 patients with VWD type 2, PFA CTs did not normalize in eight. Haemate-P substitution in patients with VWD type 1 induced a less favourable response as compared to DDAVP, because PFA CTs did not correct in all patients. Of 12 patients with VWD type 2 treated with Haemate-P, six showed a correction of PFA CTs (<250 sec), which correlated with the normalisation of the VWF CB/ Ag ratio. In-vitro studies were performed by using whole blood of patients with VWD and adding various amounts of FVIII/VWF concentrate. Addition of Haemate-P induced an increase of the VWF CB/Ag ratio from 0.30 to 0.70 in blood of patients with VWD type 2 with correction of the PFA CTs. Immunate did not result in an increase of VWF CB/Ag ratio in blood of VWD type 2 patients, and the PFA CTs remained prolonged. We conclude that PFA-100 might be an adequate instrument not only for diagnosis but also for monitoring of DDAVP responses and FVIII/ VWF substitution of patients with VWD type 1 and 2,but this is dependent upon the type of VWD and the concentrate used.

Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients

2012 ◽  
Vol 108 (10) ◽  
pp. 662-671 ◽  
Author(s):  
Hamideh Yadegari ◽  
Julia Driesen ◽  
Anna Pavlova ◽  
Arijit Biswas ◽  
Hans-Jörg Hertfelder ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Splice Site ◽  
Von Willebrand Disease ◽  
Missense Mutations ◽  
Large Deletions ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryVon Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative defects of the von Willebrand factor (VWF). VWD is classified into three types – type 1 (partial quantitative deficiencies), type 2 (qualitative defects) and type 3 (complete deficiency of VWF). In this study we explored genotype and phenotype characteristics of patients with VWD with the aim of dissecting the distribution of mutations in different types of VWD. One hundred fourteen patients belonging to 78 families diagnosed to have VWD were studied. Mutation analysis was performed by direct sequencing of the VWF. Large deletions were investigated by multiplex ligation-dependent probe amplification (MLPA) analysis. The impact of novel candidate missense mutations and potential splice site mutations was predicted by in silico assessments. We identified mutations in 66 index patients (IPs) (84.6%). Mutation detection rate was 68%, 94% and 94% for VWD type 1, 2 and 3, respectively. In total, 68 different putative mutations were detected comprising 37 missense mutations (54.4%), 10 small deletions (14.7%), two small insertions (2.9%), seven nonsense mutations (10.3%), five splice-site mutations (7.4%), six large deletions (8.8%) and one silent mutation (1.5%). Twenty-six of these mutations were novel. Furthermore, in type 1 and type 2 VWD, the majority of identified mutations (74% vs. 88.1%) were missense substitutions while mutations in type 3 VWD mostly caused null alleles (82%). Genotyping in VWD is a helpful tool to further elucidate the pathogenesis of VWD and to establish the relationship between genotype and phenotype.

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 450-456 ◽  
Author(s):  
Pier M. Mannucci ◽  
Juan Chediak ◽  
Wahid Hanna ◽  
John Byrnes ◽  
Marlies Ledford ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
High Purity ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Invasive Procedures ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate—one virally inactivated with solvent detergent, the other with an additional heat-treatment step—were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction.

scholarly journals Von Willebrand disease: What does the future hold?

Blood ◽  
2021 ◽  
Author(s):  
Cecile V Denis ◽  
Sophie Susen ◽  
Peter J Lenting
Keyword(s):  
Von Willebrand Disease ◽  
Treatment Modalities ◽  
Adeno Associated Virus ◽  
Acquired Von Willebrand Syndrome ◽  
Dual Vector ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal to reach superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches such as gene therapy using dual-vector adeno-associated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase FVIII levels in VWD-type 3 or 2N patients will be discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired Von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) will be presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.

scholarly journals von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease

Blood ◽  
2015 ◽  
Vol 125 (19) ◽  
pp. 3006-3013 ◽  
Author(s):  
Yvonne V. Sanders ◽  
Dafna Groeneveld ◽  
Karina Meijer ◽  
Karin Fijnvandraat ◽  
Marjon H. Cnossen ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Key Points ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Severe Type ◽  
Von Willebrand Factor Propeptide

Key Points VWFpp discriminates between type 3 VWD patients and severe type 1 VWD patients with very low VWF levels. The pathophysiological mechanisms of all types of VWD can be defined by the combined ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag.

scholarly journals von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy

Blood ◽  
2013 ◽  
Vol 122 (23) ◽  
pp. 3735-3740 ◽  
Author(s):  
David Lillicrap
Keyword(s):  
Molecular Genetic ◽  
Diagnostic Algorithm ◽  
Von Willebrand Disease ◽  
Functional Assay ◽  
Binding Assays ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety.

Changes in von Willebrand factor–cleaving protease (ADAMTS13) activity after infusion of desmopressin

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 946-948 ◽  
Author(s):  
Rosemarie A. Reiter ◽  
Paul Knöbl ◽  
Katalin Varadi ◽  
Peter L. Turecek
Keyword(s):  
Von Willebrand Factor ◽  
Inverse Correlation ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Adamts13 Activity ◽  
Before And After ◽  
Physiologic Function ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand factor–cleaving protease (ADAMTS13) cleaves von Willebrand factor (VWF) and regulates its physiologic function. To investigate the relation between ADAMTS13 activity and VWF, we compared ADAMTS13 activity with the VWF-related parameters VWF antigen (VWF:Ag), VWF collagen-binding activity (VWF:CBA), VWF-propeptide, proVWF, and VWF multimeric composition in 10 healthy volunteers and 3 patients with type 1 von Willebrand disease before and after infusing 0.3 μg/kg desmopressin. The VWF-related parameters in the volunteers increased 60 minutes after start of infusion by 3.7-fold for VWF:Ag, 7.2-fold for propeptide, and 2.2-fold for VWF:CBA. Unusually large VWF multimers and traces of proVWF appeared. The ADAMTS13 activity decreased to about half the initial value. After 24 hours values returned to baseline. Patients with type 1 von Willebrand disease showed similar results. We conclude that the inverse correlation between ADAMTS13 and VWF-related parameters suggests a consumption of ADAMTS13 after the desmopressin-induced release of higher multimers of VWF.

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