Key Presenting Signs and Patient Co-Variables in Early Diagnosis of Type 3 Gaucher Disease: A Global Delphi Consensus Initiative

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4886-4886 ◽  
Author(s):  
David J Kuter ◽  
Sam Salek ◽  
Atul Mehta
Keyword(s):  
Early Diagnosis ◽  
Expert Testimony ◽  
Gaucher Disease ◽  
Research Funding ◽  
Diagnostic Testing ◽  
Early Type ◽  
Travel Grant ◽  
Major Factors ◽  
Type 3

Abstract Background: Among the three phenotypes of Gaucher disease (GD), type 1 is the most prevalent in the Western hemisphere, but types 2 and 3 are increasingly seen, and occur with similar prevalence to type 1 in parts of Asia. There is a spectrum of signs and symptoms among these phenotypes, which range from fatal perinatal to asymptomatic adult disease, and this heterogeneity contributes to relatively high levels of misdiagnosis and delays in diagnosis of GD. As part of the global Gaucher earlier diagnosis consensus (GED-C) initiative, we report here the signs and patient co-variables that are regarded by expert physicians as most indicative of type 3 GD in its early stages. The overarching goal of the GED-C initiative was to generate a web-based point-scoring system for use across clinical specialties to facilitate identification of patients who may benefit from diagnostic testing for GD. Methods: In an anonymous, iterative Delphi process, a panel of expert physicians was asked to provide free-text answers to a series of open questions, including: "Which unexplained signs and co-variables may be important to consider in early type 3 GD?" An independent facilitator categorized responses from round 1 into themes, which were checked and consolidated by the two non-voting co-chairs of the initiative to generate a set of summary factors. In round 2, panel members independently rated the importance of each factor using a 5-point Likert scale (1 = not important, 5 = extremely important). Factors that were assigned an importance score of at least 3 by more than 75% of respondents were provisionally classified as major; other factors were classified as minor. In round 3, panel members rated their level of agreement with the provisional classification of factors as major using a 5-point pivoted Likert scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree). Consensus was defined as more than 67% of respondents agreeing or strongly agreeing (a score of ≥ 4) with the classification; if consensus was not reached, factors were classified as minor. Results: In total, 19 physicians with expertise in type 3 GD were recruited to the GED-C panel from 14 countries. Round 1 (100% response, n = 19) yielded 70 phrases, which were grouped into 34 themes, then consolidated as 23 factors. In round 2 (100% response, n = 19), 16 factors were provisionally classified as major. In round 3 (100% response, n = 19), consensus was reached on 10 major factors in early type 3 GD, including 9 presenting signs and 1 patient co-variable. The mean importance scores (round 2) and agreement scores (round 3) awarded to these 10 major factors are given in Table 1. Minor factors included bleeding or bruising, cardiovascular calcification, cognitive deficit, growth retardation, hyperferritinaemia, aged 18 years or younger, Jewish ancestry and a family history of Parkinson disease. Discussion: Definitive diagnostic tests for GD have been available for several years, but patient referral for testing is impeded by several issues, including a lack of knowledge among clinicians of the signs and co-variables that should arouse suspicion of GD. In type 3 GD, the problem is exacerbated by the relative rarity of the phenotype. Presenting signs and patient co-variables identified by this multidisciplinary consensus initiative will help clinicians identify those patients who may benefit from diagnostic testing for GD. Several algorithms have been devised to facilitate GD diagnosis, but non-specialists may perceive these as complex. The GED-C initiative will use the factors identified here to create a point-scoring system that clinicians of any specialty can use to obtain clear direction regarding the need to test a patient for GD. Acknowledgment: Submitted on behalf of the GED-C panel members and the European Hematology Association Scientific Working Group 'Quality of Life and Symptoms'. Administration of the GED-C initiative was funded by an unrestricted educational grant from Shire. Table 1 Mean scores of importance and agreement for 10 major factors in early diagnosis of type 3 Gaucher disease. Table 1. Mean scores of importance and agreement for 10 major factors in early diagnosis of type 3 Gaucher disease. Disclosures Kuter: Eisai: Consultancy; Genzyme: Consultancy; MedImmune: Consultancy; Rigel: Consultancy, Research Funding; CRICO: Other: Paid expert testimony; Pfizer: Consultancy; Protalex: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Consultancy, Paid expert testimony; Bristol-Myers Squibb: Research Funding; ONO: Consultancy; Shionogi: Consultancy; Shire: Consultancy; Syntimmune: Consultancy; 3SBios: Consultancy. Salek:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Shire: Consultancy; Servier: Consultancy; Sanofi: Research Funding; Agios: Consultancy. Mehta:Protalix/Pfizer: Honoraria, Other: travel grant, Research Funding; Genzyme: Honoraria, Other: travel grant, Research Funding; Actelion: Honoraria, Other: travel grant, Research Funding; Shire: Honoraria, Other: travel grant, Research Funding.

A Global Delphi Consensus Initiative for Early Diagnosis of Gaucher Disease: Key Presenting Signs and Patient Co-Variables in Type 1 Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3676-3676
Author(s):  
David J Kuter ◽  
Sam Salek ◽  
Atul Mehta
Keyword(s):  
Scoring System ◽  
Gaucher Disease ◽  
Research Funding ◽  
Diagnostic Testing ◽  
Likert Scale ◽  
Western Hemisphere ◽  
Free Text ◽  
Early Type ◽  
Major Factors

Abstract Background: Gaucher disease (GD) is associated with a broad spectrum of signs and symptoms, with phenotypes ranging from fatal perinatal to asymptomatic adult forms. Given the heterogeneous presentation and rarity of the disease, misdiagnosis is common and diagnosis is often delayed, which can lead to avoidable morbidities and potentially irreversible tissue damage. Among the three phenotypes of GD, type 1 is the most prevalent in the Western hemisphere. As part of the global Gaucher earlier diagnosis consensus (GED-C) initiative, we report here the signs and patient co-variables that are regarded by expert physicians as most indicative of type 1 GD in its early stages. The overarching goal of the GED-C initiative is to generate a web-based point-scoring system that can be used by clinicians across specialties to facilitate identification of patients who may benefit from diagnostic testing for GD. Methods: In an anonymous iterative Delphi process, a panel of expert physicians was asked to provide free-text answers to a series of open questions, including: "Which unexplained signs and co-variables may be important to consider in early type 1 GD?" An independent facilitator categorized responses from round 1 into themes, which were checked and consolidated by the two non-voting co-chairs of the initiative to generate a set of summary factors. In round 2, panel members independently rated the importance of each factor using a 5-point Likert scale (1 = not important, 5 = extremely important). Factors assigned an importance score of at least 3 by more than 75% of respondents were provisionally classified as major; other factors were classified as minor. In round 3, panel members rated their level of agreement with the provisional classification of factors as major using a 5-point pivoted Likert scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree). Consensus was defined as more than 67% of respondents agreeing or strongly agreeing (a score of ≥ 4) with the classification; if consensus was not reached, factors were classified as minor. Results: In total, 22 physicians with expertise in type 1 GD were recruited to the GED-C panel from 16 countries. Round 1 (100% response, n = 22) yielded 104 phrases, which were grouped into 38 themes, then consolidated as 21 factors. In round 2 (100% response, n = 22), 10 factors were provisionally classified as major. In round 3 (100% response, n = 22), consensus was reached on 9 major factors in early type 1 GD, including 7 presenting signs and 2 patient co-variables. The mean importance scores (round 2) and agreement scores (round 3) awarded to these 9 major factors are given in Table 1. Minor factors included asthenia, bleeding or bruising, dyslipidaemia, fatigue, gallstones, growth retardation, low bone mineral density and a family history of Parkinson disease. Table 1. Mean scores of importance and agreement for 9 major factors in rounds 2 and 3, respectively. Discussion: Definitive diagnostic tests for GD have been available for several years, but patient referral for testing is impeded by several issues, including a general lack of knowledge among clinicians of the signs and co-variables that should arouse a suspicion of GD. The presenting signs and patient co-variables identified by this multidisciplinary consensus initiative will help clinicians to identify those patients who may benefit from diagnostic testing for GD. Several algorithms have been devised with the aim of facilitating GD diagnosis, but these may be perceived as complex by the non-specialist. The next stage of the GED-C initiative will be to use the factors identified here to create a point-scoring system that clinicians of any specialty can use to obtain clear direction regarding the need to test a patient for GD. Acknowledgment: Submitted on behalf of the GED-C panel members and the European Hematology Association Scientific Working Group 'Quality of Life and Symptoms'. Administration of the GED-C initiative was funded by an unrestricted educational grant from Shire. Table 1. Table 1. Disclosures Kuter: Amgen: Consultancy; Eisai: Consultancy; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Shionogi: Consultancy; Shire: Consultancy; 3SBios: Consultancy; Bristol-Myers Squibb: Research Funding; Protalix: Research Funding; Rigel: Research Funding. Salek:Agios: Consultancy; Servier: Consultancy; Shire: Consultancy; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Mehta:Actelion: Honoraria, Other: Travel grants, Research Funding; Genzyme: Honoraria, Other: Travel grants, Research Funding; Protalix/Pfizer: Honoraria, Other: Travel grants, Research Funding; Shire: Honoraria, Other: Travel grants, Research Funding.

scholarly journals A Global Delphi Consensus Initiative for Early Diagnosis of Gaucher Disease: Barriers, Their Resolution and the Impact on Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4885-4885
Author(s):  
David J Kuter ◽  
Sam Salek ◽  
Atul Mehta
Keyword(s):  
Clinical Practice ◽  
Early Diagnosis ◽  
Expert Testimony ◽  
Gaucher Disease ◽  
Research Funding ◽  
Likert Scale ◽  
Free Text ◽  
Heterogeneous Nature ◽  
Travel Grant ◽  
The Impact

Abstract Background: Diagnosis of Gaucher disease (GD) can be difficult and diagnostic delays are common in both adult and paediatric patients. This may in part be attributable to the heterogeneous nature of early presenting signs and symptoms in GD, which may result in patients consulting various specialists before a diagnosis is reached. As part of this global Gaucher earlier diagnosis consensus (GED-C) initiative, a panel of expert physicians was asked to determine the most important barriers to diagnosis of GD. The panel was also asked about the impact of the initiative if its primary objective of facilitating earlier diagnosis was realized. Methods: In round 1 of an anonymous, multi-stage, iterative Delphi process, the panel provided free-text answers to a series of open questions, including: "In your experience, what are the greatest barriers to diagnosis in patients with early GD?" and "Assuming that this initiative achieves its goal, what difference could it make to clinical practice?" An independent facilitator grouped the responses to these questions by theme, and these were checked and consolidated as summary statements by the two non-voting co-chairs of the GED-C initiative. In round 2, panel members independently rated the importance of each statement using a 5-point Likert scale (1 = not important, 5 = extremely important). Statements awarded an importance score of at least 3 by more than 75% of respondents were reissued in round 3, in which panel members rated their level of agreement with each statement using a 5-point pivoted Likert scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree). Consensus was defined as more than 67% of respondents agreeing or strongly agreeing (a score of ≥ 4) with a statement. Results: In total, 22 experts from 16 countries were recruited to the GED-C panel. Round 1 (100% response, n = 22) yielded 47 phrases relating to barriers to diagnosis, and 30 relating to the impact of the initiative on clinical practice, which were consolidated as 9 statements describing barriers to diagnosis, and 8 summarizing the initiative's impact. In round 2 (100% response, n = 22) and round 3 (100% response, n = 22), 6 barrier statements and all 8 impact statements met the stipulated importance criteria, and consensus was then reached for all 6 barrier statements and for 7 impact statements (Table). Discussion: This initiative highlights that, as well as the heterogeneous nature of GD, clinicians' lack of awareness of GD and poor knowledge of important presenting signs probably contribute to incorrect or delayed diagnoses. The GED-C initiative aims to resolve this by providing clinicians with simple guidance regarding important factors in GD, thereby improving disease awareness and facilitating early diagnosis. This may improve understanding of the natural history of GD, patient management, and potentially patients' long-term outcomes. Acknowledgment: Submitted on behalf of the GED-C panel members and the European Hematology Association Scientific Working Group 'Quality of Life and Symptoms'. Administration of the GED-C initiative was funded by an unrestricted educational grant from Shire. Table Table. Disclosures Kuter: Bristol-Myers Squibb: Research Funding; ONO: Consultancy; Protalex: Research Funding; Eisai: Consultancy; Shionogi: Consultancy; 3SBios: Consultancy; Syntimmune: Consultancy; MedImmune: Consultancy; CRICO: Other: Paid expert testimony; Amgen: Consultancy, Paid expert testimony; Pfizer: Consultancy; Rigel: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Shire: Consultancy; Genzyme: Consultancy. Salek:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Shire: Consultancy; Servier: Consultancy; Sanofi: Research Funding; Agios: Consultancy. Mehta:Protalix/Pfizer: Honoraria, Other: travel grant, Research Funding; Genzyme: Honoraria, Other: travel grant, Research Funding; Actelion: Honoraria, Other: travel grant, Research Funding; Shire: Honoraria, Other: travel grant, Research Funding.

scholarly journals Semiautomatic VWF Multimer Densitometric Analysis: Validation of the Clinical Accuracy and Clinical Implications in Von Willebrand Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Ferdows Atiq ◽  
Johan Boender ◽  
Marjon H. Cnossen ◽  
Johanna G van der Bom ◽  
Karin Fijnvandraat ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Research Funding ◽  
Von Willebrand Disease ◽  
Densitometric Analysis ◽  
Travel Grant ◽  
Bleeding Score ◽  
Type 3 ◽  
Von Willebrand

Introduction Von Willebrand factor (VWF) multimer analysis is an essential tool in the diagnosis and classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is observer dependent, time consuming and is inaccurate in detecting subtle changes in multimer patterns. Therefore, recent studies have investigated VWF multimer quantification using semiautomatic densitometric analysis. The accuracy of VWF multimer densitometric analysis in clinical practice needs further investigation before it can be widely used. The aim of the study was to validate the accuracy of VWF multimer densitometric analysis in clinical practice. Additionally, we aimed to identify patient characteristics associated with VWF multimer densitometry outcomes in type 1 and type 2 VWD patients, and we investigated whether subtle differences in VWF multimer pattern are associated with the bleeding phenotype of VWD patients. Methods We included patients from the nationwide Willebrand in the Netherlands (WiN) study. The inclusion criteria of the WiN study were a personal hemorrhagic diathesis or family history of VWD, and historically lowest VWF antigen (VWF:Ag), VWF activity (measured with the monoclonal antibody assay: VWF:Ab) or VWF collagen binding (VWF:CB) ≤0.30 IU/mL or FVIII activity (FVIII:C) ≤0.40 IU/mL in case of type 2N VWD. At inclusion in the WiN study, blood was drawn and patients filled in an extensive questionnaire containing a self-administered Tosetto bleeding score (BS). For multimer analysis, citrated blood samples were separated on 0.9% agarose gel and visualized by Western blotting. We used IMAGEJ for densitometric analysis. The five smallest bands on densitometric images were defined as small multimers, next five bands were defined as medium multimers and the remaining bands were defined as large multimers. Medium-large VWF multimer index was calculated by dividing the patient's multimer ratio (intensity of the medium and large multimers divided by the total intensity of all multimers) by the multimer ratio of a normal control in the same western blot. If no multimers could be detected, the multimer index was set as 0. Results We included 561 VWD patients: 328 type 1, 211 type 2 and 21 type 3 patients. The median age was 44 [IQR 29-58] and 351 patients (62.7%) were female (Table 1). Figure 1 illustrates typical densitometric outcomes of a type 1 VWD patient with normal VWF multimers (A) and a type 2A patient with reduced high-molecular-weight (HMW) VWF multimers (B). Medium-large VWF multimer index was 1.06 [0.99-1.12] in type 1 and 0.53 [0.29-0.89] in type 2 and 0.00 [0.00-0.00] in type 3 VWD. Medium-large VWF multimer index was in patients visually classified as normal, reduced and absent HMW VWF multimers, respectively 1.07 [1.02-1.12], 0.84 [0.71-0.91] and 0.31 [0.20-0.44] (p<0.001, Figure 2A). With visual examination as gold standard, medium-large VWF multimer index had a very good accuracy in distinguishing normal VWF multimers from reduced HMW VWF multimers (AUC: 0.96 (0.94-0.98) p<0.001, Figure 2B). It could also accurately distinguish reduced HMW VWF multimers from absence of HMW multimers, with an AUC of 0.95 (0.92-0.97, p<0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 (0.94-0.99), p<0.001, Figure 2C and 2D). From VWF activity measurements, medium-large VWF multimer index was strongest correlated with VWF:CB (ρ=0.79, p<0.001). From the ratio of the various functional VWF measurements (divided by VWF:Ag), the strongest correlation was again found for VWF:CB/VWF:Ag ratio (ρ=0.80, p<0.001). In type 1 VWD, an increased clearance of VWF (defined as VWFpropeptide/VWF:Ag ratio ≥2.2) was independently associated with lower medium-large VWF multimer index (β=-0.10 (-0.14; -0.07), p<0.001). Also, type 1 VWD patients with a VWF gene variant had relatively lower medium-large VWF multimer index compared to type 1 patients without a VWF variant, respectively 1.03 [0.95-1.10] vs 1.08 [1.04-1.12] (p<0.001). In the total population, higher medium-large VWF multimer index was associated with a lower bleeding score: β=-4.6 (-7.2; -2.0), p=0.001, adjusted for age, sex, blood group and type of VWD. Conclusion Semiautomatic densitometric analysis of VWF multimers has an excellent accuracy in clinical practice, and may have an additional value in providing a better understanding of the clinical features such as the bleeding phenotype of VWD patients. Disclosures Atiq: CSL Behring: Research Funding; SOBI: Other: travel grant. Boender:SOBI: Current Employment; CSL Behring: Research Funding. Cnossen:Bayer: Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; Sobi: Research Funding; Takeda: Research Funding; CSL behring: Research Funding; Pfizer: Research Funding; Shire: Research Funding; Baxter: Research Funding. van der Bom:Bayer: Speakers Bureau. Fijnvandraat:SOBI: Research Funding; NovoNordisk: Consultancy; Grifols: Consultancy; Takeda: Consultancy; Roche: Consultancy; CSL Behring: Research Funding; NovoNordisk: Research Funding. Van Galen:Bayer: Research Funding; Takeda: Speakers Bureau; CSL Behring: Research Funding. Laros-Van Gorkom:Baxter: Other: Educational grant; CSL Behring: Other: Educational grant. Meijer:Bayer: Research Funding; Sanquin: Research Funding; Pfizer: Research Funding; Bayer: Speakers Bureau; Sanquin: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Aspen: Speakers Bureau; Uniqure: Consultancy. Eikenboom:CSL Behring: Research Funding; Roche: Other: Teacher on educational activities. Leebeek:Roche: Other: DSMB member for a study; SOBI: Other: Travel grant; Novo Nordisk: Consultancy; Shire/Takeda: Consultancy; Uniqure: Consultancy; Shire/Takeda: Research Funding; CSL Behring: Research Funding.

scholarly journals Bleeding in Patients with Clinically Severe Von Willebrand Disease: Interim Analysis of Athn 9: A Natural History Study for People with Severe Von Willebrand Disease (VWD)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3183-3183
Author(s):  
Angela C. Weyand ◽  
Martin Chandler ◽  
Carol Fedor ◽  
Kenneth D. Friedman ◽  
Sweta Gupta ◽  
...  
Keyword(s):  
Research Funding ◽  
Diagnostic Testing ◽  
The United States ◽  
Von Willebrand Disease ◽  
Dental Extraction ◽  
Incomplete Penetrance ◽  
Type 3 ◽  
Von Willebrand

Abstract Background:Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, occurring in ~0.1% of the population. VWD results from either a quantitative (Type 1 or 3) or qualitative (Type 2) defect in von Willebrand Factor (VWF), a multimeric plasma protein involved in platelet adhesion and aggregation at the vascular injury site. Accurate diagnosis of VWD is complex due to pre-analytical variables, a wide coefficient of variation in testing, and incomplete penetrance. Though individuals with mild VWD and bleeding symptoms are common, less is known regarding persons with VWD and a clinically severe bleeding phenotype. Aims:To characterize the bleeding phenotype and safety of treatment regimens in participants with clinically severe VWD in the United States (US). Study Design and Methods:ATHN 9 is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at 25 ATHN-affiliated sites across the US. Participants are identified by the site investigators with a projected goal to enroll 130 individuals. Patients with severe VWD defined as type 3 VWD, or a VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 30%, or persons with "clinically severe VWD" defined by VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 40% and requiring recurrent use of factor concentrates and prior enrollment in the ATHNdataset national surveillance data collection project are included. Participants with platelet-type or acquired VWD are excluded. Laboratory assessments including a standardized diagnostic battery, VWF genetic analysis (Next-gen sequencing), and inhibitor testing, performed by a central laboratory. Bleeding tendency is assessed by International Society for Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) (abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children) and the Pictorial Bleeding Assessment Chart (PBAC; heavy menstrual blood loss ≥100) if applicable. Results:Initial data on 81 participants was analyzed. Given that the enrollment occurred during the pandemic, the completion of data varied as follows: Baseline Demographics Forms 81 completed, Baseline History Forms 73 completed, and VWD Diagnostic Testing Results Forms 38 completed. Most were adult (53%), female (58%), Caucasian (82%) and non-Hispanic (82%). Approximately half (38/81, 47%) have undergone central lab diagnostic testing (Table 1) while the remaining had previous diagnostic studies. About half of the patients had Type 1, a quarter have Type 3, and the remaining had Type 2 VWD or unknown. The majority of patients (91%) had VWF:GPIbM activity <30IU/dL and (61%) had a VWF:Ag <30IU/dL. One participant had an inhibitor (1/22, 4%) to VWF. Of the participants with a baseline history form submission (73 in total), more than half (42/73, 57%) had undergone surgery, the most common being nasal cautery (11/42, 26.2%) and dental extraction (11/42, 26.2%); complicated by bleeding most commonly during or following dental extraction (2/11, 18.2%) and endoscopy/colonoscopy (2/4, 50%). Few participants (6/73, 8%) reported the presence of a target joint at enrollment, ankle being most common. The bleeding phenotype was variable with a mean ISTH BAT score of 10 (range 0-39) with the first bleeding event commonly occurring prior to age 10 years (51%), with 20% occurring prior to age 12 months (20%). The PBAC was performed on 6 of the 47 female participants in reference to their last period and was abnormal(mean 247; range 0-754). The majority (70 participants, 96%) utilized factor concentrates for prophylaxis or on-demand treatment; 27 participants (39%) were on continuous prophylaxis, while 8 (11%) were on event-based while less (10%) were on heavy menstrual bleeding (HMB) prophylaxis, and the remainder (40%) received episodic treatment. Participants used plasma derived VWF concentrate most commonly (64.3%) with the remainder using recombinant VWF or DDAVP/antifibrinolytics. Discussion: Initial evaluation of 81 participants with clinically severe VWD were diagnostically determined to be type 1 VWD with a majority having a bleeding phenotype (mean (ISTH BAT 10) and HMB (mean PBAC 247). In contrast to patients with mild disease where antifibrinolytics and desmopressin are frequently used, factor replacement was the most common treatment modality. Future analysis will focus on response to factor replacement therapy, genotype-phenotype correlation and quality of life. Disclosures Weyand: Novo Nordisk: Research Funding; Genentech: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy. Friedman: Siemens: Consultancy; Bayer: Consultancy; Alexion: Speakers Bureau; Genentech: Consultancy; Instrumentation Laboratories: Consultancy; Sanofi: Consultancy. Haley: American Thrombosis and Hemostasis Network: Research Funding. He: ATHN: Ended employment in the past 24 months. Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Wynn: Sanofi: Research Funding; Takeda: Research Funding; Genentech: Research Funding. Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. OffLabel Disclosure: Vonvendi (recombinant VWF) does not have a product indication for prophylaxis

scholarly journals Not All Patients with Mild Phenotype of Gaucher Disease (GD) Need Disease Specific Treatment As Reflected By Patients Reported Outcomes Measures

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4712-4712
Author(s):  
Shoshana Revel-Vilk ◽  
Tama Dinur ◽  
Majdolen Istaiti ◽  
Dafna Frydman ◽  
Michal Becker-Cohen ◽  
...  
Keyword(s):  
Functional Status ◽  
Gaucher Disease ◽  
Research Funding ◽  
Financial Burden ◽  
Specific Therapy ◽  
Specific Patient ◽  
Mild Phenotype ◽  
Patient Reported ◽  
Disease Specific

The introduction of disease specific therapy for patients with type 1 Gaucher disease (GD) was a revolution in the management of patients, but not without significant cost to the patient and to society. The management of mildly effected patients is still debated, and reviews about GD as well as chapters in textbooks fail to emphasize the fact that some patients may remain untreated for many years without any GD-related complications. Patient reported outcome measures (PROMs) were developed as a way to ascertain patients' views of their symptoms, their functional status, and their health-related quality-of-life (HRQoL). In this study, we evaluated the responses to a GD -specific PROM of untreated patients with GD1 and compared them to patients on GD-specific therapy. Methods: A PROM survey was developed for GD including 15 questions; six Point Verbal Response Scale regarding the last month and nine Visual Analogue Scales (VAS) from 0-10 regarding the last week (Elstein D, et al. Molecular Genetics and Metabolism 2019;126:S52). The PROM survey was proven to be accurate in encompassing disease-specific patient concerns. A Hebrew translated version of the GD-PROM was sent via mobile phone survey to 400 adult patients with type 1 GD followed in our Gaucher Unit. Clinical data and treatment status were extracted from the clinical charts. T-test and Mann-Whitney U test were used to compare normally and non-normally distributed data in independent samples, respectively. IBM SPSS version 25 was used for analysis. Results were considered to be statistically significant when two-tailed P-values were ≤0.01. Results: A total of 181 patients responded (45% response rate) of whom 65 (36%) were followed for at least 5 years in our unit without receiving GD specific therapy, i.e. enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). The median (range) age of patients, 49 (20-91) years, was not significantly different between treated and untreated patients. The percentage of patients with the N370S/N370S genotype was significantly higher in untreated patients [55/65 (85%)] compared to treated patients [67/116 (57%)]. Significantly more treated patients reported that GD had restricted their education/job (38, 34%) and fun activities (29,25%) compared to untreated patients, (4, 6.5%) and (2, 3%), respectively. Compared to untreated patients, treated patients were more worried to be an emotional burden on others [27 (23%) vs. 3 (5%)], of being financial burden on others [57 (50%) vs. 16 (25%)] and more concerned regarding the risk of bone disease [82 (74%) vs. 26 (40%)], and the risk of Parkinson disease [72 (64%) vs. 27 (42%)]. Treated patients had a significantly higher score on VAS for questions on swollen abdomen, fatigue, physical weakness, severity of bone pain and worry regarding the future over the past week compared to untreated patients (Table 1). Patients concern regarding the risk for cancer (32%) and VAS score for a question on depression were similar between groups. Conclusion:The GD-specific PROM survey shows that asymptomatic or mildly affected untreated patients with GD1 have good functional status and HRQoL, supporting our practice that not all patients with GD1 require disease-specific therapy. Still, we advise a periodic (annual or bi-annual) follow-up, preferably at a referral center. Inclusion of GD-specific PROMs in the periodic assessments is important for better understanding patients' perspectives. It is important to note that mildly affected and asymptomatic patients are mainly found among Ashkenazi Jews and from this aspect our cohort reflects patients' populations in Israel, USA, UK, etc. but less relevant to non-Jewish and particularly to Asian cohorts. With the expected increase in early diagnosis via parental and/or newborn screening the understanding that not all subjects diagnosed with GD needs disease-specific therapy is all the more important. Despite the expected differences between the more severely affected treated patients and the by definition milder untreated ones, still a high percentage of the treated patients show good HRQoL parameters, reflecting the overall success of ERT/SRT. Larger cohorts and further analysis will evaluate potential predictors for differences in PROMs within the treatment group. Disclosures Revel-Vilk: Sanofi: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Prevail Therapeutics: Consultancy; TAKEDA: Honoraria; Centogene: Other: research grant; Targeted Cell Therapies: Consultancy; Pfize: Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Bio-events: Honoraria.

scholarly journals Wish-Qol Study - Assessment of Health-Related Quality of Life (HRQoL) and Health-Economic Aspects in Patients with Von Willebrand Disease (VWD) in France: Results of the Women Cohort

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1395-1395
Author(s):  
Annie Borel-Derlon ◽  
Jenny Goudemand ◽  
Dominique Desprez ◽  
Fabienne Volot ◽  
Yves Gruel ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Von Willebrand Disease ◽  
Female Group ◽  
Bleeding Score ◽  
Type 3 ◽  
Von Willebrand

Abstract Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 1% in the general population. VWD results from a deficiency in or a dysfunction of von Willebrand factor which is a protein that is necessary for normal platelet adhesion and protection of factor VIII from proteolysis in the circulation. Nevertheless, prevalence of the most symptomatic forms such as bleeds requiring replacement treatment and /or hospitalization is about 0.01%. Although VWD affects both genders, there is a higher proportion in females than in males.VWD seems to be more symptomatic in women because of their reproductive life. Women with VWD have an increased bleeding risk in numerous situations including anemia, menorrhagia, bleeding during pregnancy, postpartum hemorrhage and impairments in their quality of life (QoL).The prevalence of menorrhagia in women with VWD is 74-92%. According to the Francecoag Network, the referral-based prevalence of moderate-to-severe VWD patients is about 1,750 cases in France. Aim: Since the disease and its treatment can affect every-day life of patients and their families, a French HRQoL Study (WiSH-QoL) exploring this impact started 22 months ago. Methods: This non-interventional 5-year study evaluates patients HRQoL and costs of care in France. At least 350 patients will be followed for 24 months in minimum 30 centers. HRQoL is assessed with the generic SF-36 and the disease-specific VWD-QoL questionnaires. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Results: Since October 2014, 245 patients have been included. We present here the first interim analysis with a focus on the female group. At the first interim analysis, data from 140 patients were documented: 91 adults with a median age of 40.0 years [18.3-78.0] and 49 children with a median age of 10.1 years [2.9-17.5]. VWD Types were already identified for 122 (87%) of these patients: 33 with VWD type 1 (27%) including 5 type 1 Vicenza; 76 type 2 (62%) and 13 type 3 (11%). The median Tosetto bleeding score reported for 124 patients (males and females) was +7 ranging from -1 to +28. From the 95 female patients, 70 were aged ≥18 years, 21 were adolescents between 8-17 years and 4 were girls below 4 years of age. Median age was 29.4 (range 4.3-78.0) years. A total of 25 women had type 1 VWD (31%), 49 had type 2 VWD (60%), and 7 had type 3 VWD (9%), for 14 patients VWD type is undetermined. The median Tosetto bleeding score of the female group was +8 ranging from -1 to +28. Out of 95 patients, 45 patients (47.4%) have received a concomitant treatment due to menorrhagia, such as iron therapy, oral contraceptive, levonorgestrel intrauterin system: 5/21 patients in the group between 8 and 17 years and 40/70 in the group ≥18 years. Out of the 60 women of childbearing potential defined as age between 15-50 years, 6 women were pregnant at time of inclusion. A total of 46 patients, aged 18 years or more have had obstetrical history prior to study inclusion. The mean number of childbirth was more than 2 i.e 2.39 range (1-8) per woman, 75% of these deliveries were natural delivery and 25% were caesarean section. Out of 108 deliveries, 28 (26%) were experienced with post-partum hemorrhages. Conclusions: With the results of the WiSH-QoL study, the first prospective study of von Willebrand disease conducted in France, especially the VWD-specific evaluation of HRQoL and treatment satisfaction a deeper insight will be gathered into the patients' daily life, their perception of well-being and their specific health care needs. With the additional domain 'pregnancy' included in the French version of the VWD-QoL questionnaire for female adult patients, it will possible to better understand how women may be affected by VWD during childbearing years. Disclosures Borel-Derlon: LFB: Other: Reference expert and national coordinator for VWD; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee; Shire - Baxalta: Research Funding. Chatelanaz:LFB Biomedicaments: Employment. Doriat-Robin:LFB Biomedicaments: Employment. von Mackensen:SOBI: Research Funding; Shire: Research Funding.

scholarly journals Epidermal Abnormalities May Distinguish Type 2 from Type 1 and Type 3 of Gaucher Disease

1996 ◽  
Vol 39 (1) ◽  
pp. 134-141 ◽  
Author(s):  
Ellen Sidransky ◽  
Manigé Fartasch ◽  
Robert E Lee ◽  
Leon A Metlay ◽  
Steve Abella ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Type 3

scholarly journals Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tim Phetthong ◽  
Thipwimol Tim-Aroon ◽  
Arthaporn Khongkraparn ◽  
Saisuda Noojarern ◽  
Chulaluck Kuptanon ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Age Of Onset ◽  
Lysosomal Storage ◽  
Pathogenic Variants ◽  
Medical Centers ◽  
Neurologic Involvement ◽  
Therapeutic Research ◽  
Type 3

Abstract Background Gaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010–2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. Results There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. Conclusions Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

scholarly journals Bone Marrow Involvement in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long Term Enzyme Replacement Therapy (median 18 years)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4862-4862
Author(s):  
Shoshana Revel-Vilk ◽  
Jeffrey Szer ◽  
Michal Becker Cohen ◽  
Ari Zimran
Keyword(s):  
Bone Marrow ◽  
Gaucher Disease ◽  
Research Funding ◽  
Low Dose ◽  
Bone Marrow Involvement ◽  
Bone Marrow Infiltration ◽  
Enzyme Replacement ◽  
Fat Fraction ◽  
Type 1 Gaucher Disease

Bone complications are the most dramatic and life-impairing outcomes of type 1 Gaucher disease (GD1), a common lysosomal storage disorder. Bone marrow infiltration by Gaucher cells substantially decreases the bone marrow fat fraction (FF), and the extent of this reduction correlates with the overall severity of skeletal manifestations in this disorder. Previous studies have demonstrated that the degree of infiltration can best be estimated by magnetic imaging resonance (MRI)-based quantitative chemical shift imaging (QCSI) and that the fat fraction (FF) score so derived can predict the risk of clinically important bone events. The aim of this study was to evaluate bone marrow involvement in GD1 patients who had received enzyme replacement therapy (ERT) for at least 5 years. Methods: Patients from SZMC Gaucher unit, ≥ 18 years, who were treated with ERT for ≥ 5 years, with a stable dose in the previous 6 months, were recruited. Patients taking another experimental drug, with past exposure to taliglucerase-alfa, presence of any medical, emotional, behavioral or psychological condition were excluded. Energy x-ray absorptiometry (DEXA) was performed at SZMC and the QSCI was performed at the Academic Medical Center in Amsterdam, Netherlands as previously described [Mass et al, Am J Radiol 2002:179:961-965]. A QCSI score of <0.30 was indicative of bone at risk. This investigator initiated clinical trial was approved IRB at SZMC and AMC and sponsored by Pfizer. Study number registration- MOH-2017-04-000351. Results: Thirty patients (13 females) at a median (range) age of 46 (19-71) years consented to participate in this study and to perform the QCSI test. GBA mutations of study patients included N370S homozygote (n=12), N370S compound heterozygote (n=17), and T431 homozygote (n=1). The median (range) duration of ERT was 18 (5-26) years. Thirteen patients were receiving imiglucerase as the primary ERT [median (range) duration, 19 (9-26) years], five patients were receiving velaglucerase alfa [median (range) duration, 11 ( 5-12) years], and 12 patients converted from imiglucerase to velaglucerase alfa [median (range) duration, 7 (6-10) years]. The majority of patients received low-dose regimen, i.e. 15 Units/kg/2 weeks (Table 1). The median (range) T score for lumbar spine from DEXA scans, available for 26 of 30 patients, was −1.3 (−2.8-0.0). The median (range) QCSI score was 0.42 (0.24-0.66). Seven patients, 23% (95% confidence interval 10%-42%), had abnormal QCSI FF scores (<0.30). Abnormal QSCI score was more common in female compared to male (Table 1) (p=0.025). Only one of these was menopausal. No differences were found in age, gender, genotype, history of splenectomy, duration and type of ERT and GD-related parameters between those with QSCI score of bone at risk to those with normal score (Table 1). In summary, these findings demonstrate that, despite prolonged treatment with imiglucerase and/or velalgucerase alfa, 23% of patients still had QCSI scores indicative of an inadequate response in bones. Nevertheless, most patients with prolonged low-dose ERT maintain a normal QCSI, indicative of a positive bone status. The higher prevalence of women in the cohort with low FF is not related to menopausal phase and remains unexplained. As no other patient-related nor GD-related parameter predicted abnormal bone marrow infiltration, a more widely available, quantitative measure of bone marrow infiltration is required for the assessment of response in bones to ERT for patients with GD1. The second phase of this study will evaluate the impact of a switch to a third ERT in those patients from this study with QCSI scores of <0.30. These patients will be offered treatment with taliglucerase alfa at equivalent doses and subsequent reassessment of any impact on clinical symptoms and QCSI scores evaluated. Disclosures Revel-Vilk: Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding. Szer:Alexion: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Centogene: Other: research grant; Shire: Consultancy, Honoraria, Research Funding; TAKEDA: Honoraria; Pfize: Honoraria, Research Funding; Bio-events: Honoraria; Targeted Cell Therapies: Consultancy; Prevail Therapeutics: Consultancy.

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