scholarly journals Risk of Hypertension in Hemophilia Patients with a History of Inhibitors

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Anna Ter-Zakarian ◽  
Richard Barnes ◽  
Rebecca Kruse-Jarres ◽  
Doris Quon ◽  
Shannon Jackson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Research Funding ◽  
Hemophilia A ◽  
Additive Models ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Inhibitor Development ◽  
Number Of Patients ◽  
History Of ◽  
Clinical Records

Hemophilia is an X-linked bleeding disorder characterized by deficiencies of Factor VIII or IX. Hypertension in persons with hemophilia (PWH) appears to be more prevalent compared to the general population. A major complication of hemophilia remains the development of neutralizing antibodies (inhibitors) against infused clotting factor. It tends to occur within the first 50 exposure days and therefore mostly in children with severe hemophilia. Since inhibitor development is associated with high mortality and morbidity, their eradication with high dose clotting factor concentrates is critical and successful in the majority of patients. Recently a cohort study showed a positive association between presence of inhibitors in elderly patients and cardiovascular disease, although a small number of patients with inhibitors were included in that study (Sood SL, Blood Advances 2018). To date, the link between a history of inhibitors and hypertension has not been established. The primary purpose of our study was to evaluate the relationship between hypertension in PWH and a history of inhibitors, with the additional goals of investigating the association between hypertension and hemophilia type and viral status. In a retrospective review, clinical records were extracted for PWH aged 18 to 79 between 2003 and 2014 from four Hemophilia Treatment Centers in North America: Los Angeles Orthopaedic Hospital, University of California San Diego, Tulane University and University of British Columbia. We extracted demographic information on age and ethnicity, weight, height, hemophilia type and severity, inhibitor history, Hepatitis C (HCV; by serology) and Human Immunodeficiency Virus (HIV) status or reported history thereof and medication history. Primary outcomes were prevalence of hypertension stratified by inhibitor status, hemophilia type, and presence of viral coinfection. Blood pressure measurements were taken for the three clinic visits closest to the evaluation date. We fitted generalized additive models with a non-parametric spline function for age. The outcomes were hypertension (with a binary logit), systolic blood pressure (SBP) and diastolic BP (DBP). The models were adjusted for logBMI, type of hemophilia, severity, race/ethnicity, HCV and HIV. We plotted standardized curves generated by the models to compare trends in each outcome. A total of 691 PWH were included. Forty-four (6%) had a history of inhibitors, 533 had hemophilia type A (77%) and 157 had hemophilia type B (23%). HCV was positive in 419 patients (61%) and HIV in 128 patients (19%). There was no difference in the risk of hypertension between patients with or without a history of inhibitors. SBPs and DBSs were only analyzed for patients not on anti-hypertensives, and were not associated with a history of inhibitors (Fig. 1A). However, risk of hypertension was considerably higher among patients with Hemophilia B compared to patients with Hemophilia A (Fig. 1B). Hemophilia B patients were more likely to be categorized as hypertensive because both SBPs and DBPs were higher, especially in patients between 40 and 60 years of age. Finally, risk of hypertension was higher among those coinfected with both HCV and HIV (Fig. 1C). This large-scale study found no evidence that inhibitor history influenced the risk for hypertension or elevated BPs in PWH. Interestingly, Hemophilia B was associated with a higher risk of hypertension and higher BPs, similar to prior studies showing Hemophilia B had 1.87-fold higher odds of hypertension compared to Hemophilia A (von Drygalski A, Hypertension, 2013). Inhibitor development in Hemophilia B is very rare, which provides additional support that factors other than inhibitors play a role. Finally, our study showed coinfection with HIV and HCV was associated with higher hypertension risk, adding clarity to inconsistent findings on the association between hypertension and blood transmitted viral diseases in PWH. While there was no evidence that patients with a history of inhibitors have a higher risk of hypertension, our observations add to the continued efforts to elucidate the etiology of the hypertension in hemophilia and confirm that patients with Hemophilia B and/or viral infections may be at higher risk. These findings continue to inform medical care and also pave the way for additional studies to address physiological factors inherent to hemostasis and vascular pathology. Disclosures Kruse-Jarres: NovoNordisk: Other; CSLBehring and Genentech/Roche: Research Funding; Biomarin, Chugai, CSLBehring, and Genentech/Roche: Consultancy. Quon:Orthopaedic Institute for Children: Current Employment; Bayer: Honoraria; Shire/Takeda: Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Octapharma: Honoraria; Novo Nordisk: Honoraria, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Speakers Bureau; Biomarin: Honoraria, Speakers Bureau. Jackson:Octapharma, Takeda, Bayer, Roche and Pfizer: Honoraria; Bayer: Research Funding; Sanofi: Research Funding. von Drygalski:Hematherix Inc: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder; superFVa; Joint Activity and Damage Examination (JADE) Ultrasound measurement tool: Patents & Royalties; Biomarin, Bioverativ/Sanofi-Genzyme, Novo Nordisk, Pfizer, Uniqure, Takeda: Consultancy.

scholarly journals Adoption of Prophylaxis in the United States in the Era of Extended Half-Life Factor Concentrates

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2467-2467
Author(s):  
Lynn M. Malec ◽  
Gilbert C. White ◽  
Stacy E. Croteau ◽  
Dunlei Cheng ◽  
Margaret V. Ragni
Keyword(s):  
United States ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Number Of Patients

Abstract Background: Use of prophylaxis is the evidence-based strategy to prevent joint bleeds and reduce arthropathy for patients with severe hemophilia however, prophylaxis has not been universally adopted in the United States. Amongst patients with severe hemophilia enrolled in the ATHNdataset, the largest database of patients with disorders of hemostasis and thrombosis in the United States, as of 2015, 37% of patients with hemophilia A, and 45% of patients with hemophilia B do not receive prophylaxis. With the approval of extended half-life (EHL) factor products, patients and providers have options for less treatment-intense and burdensome prophylaxis. With the changing landscape of available hemophilia products, we aimed to quantify the number of patients treated at U.S. HTCs on prophylaxis utilizing the ATHNdataset with the objective determining the impact of EHL products on the proportion of patients with severe hemophilia receiving prophylaxis and to characterize use of prophylaxis according to age, race and ethnicity, geographic region, and payer. Methods: The ATHNdataset, a HIPAA compliant limited dataset sponsored by the American Thrombosis and Hemostasis Network (ATHN), was accessed as of June 30, 2018. The proportion of subjects with severe hemophilia on prophylaxis were compared to those on demand by age cohort. The proportion of subjects on prophylaxis was analyzed by race, ethnicity, insurance status, and hemophilia treatment center region. For each group receiving prophylaxis, the product (EHL versus standard half-life (SHL)), dose and frequency of treatment was analyzed. Results: ATHNdataset included 6,160 severe hemophilia patients using factor replacements, 5,234 individuals with hemophilia A and 926 individuals with hemophilia B. Overall, 76.0% (n=4,864) of patients with severe hemophilia are on prophylaxis whereas 24.0% (n=1426) are on demand; this included a total of 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B on prophylaxis. Treatment type (prophylaxis or not) had significant associations with age (p-value <0.001), ethnicity (p<0.001), race (p=0.005), hemophilia treatment center (HTC) region (p<0.001), and hemophilia type (p=0.015) (Table 1). Prophylaxis was not significantly correlated with payer (p=0.847) with a similar number of patients with Medicare/Medicaid or private insurance receiving prophylaxis. Among patients on prophylaxis, 30.8% (n=1,462) are prescribed EHL products including 27.4% of patients with hemophilia A and 50.4% with hemophilia B. In terms of dosing frequency (n=758), 73.8% of hemophilia A patients on prophylaxis receive EHL two times per week while 73.7% (n=1,906) receive SHL every other day (Table 2). Of hemophilia B patients using EHL products, 63.3% of patients receive prophylaxis once weekly, 12.7% every 10 days, and 15.0% every 2 weeks (Table 2). Discussion: The ATHNdataset highlights increased use of prophylaxis over the past 3 years in the U.S. with 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B currently receiving prophylactic therapy as compared to 63% and 55% of patients, respectively, in 2015. Further, the majority (83.7%) of patients are beginning prophylaxis according to the World Federation of Haemophilia recommendation to initiate prophylaxis by three years of age. There has been an uptake of the use of EHL factor products including a majority of patients (50.4%) with severe hemophilia B. Although not captured in the ATHNdataset, a plausible reason for the increased uptake of EHL in the hemophilia B population includes the data that 91% of patients are able to dose between weekly or less frequently. As the hemophilia treatment landscape continues to evolve, it is important to continue to understand the adoption of these new products into practice and to examine their real-world impact. Disclosures Malec: Shire: Consultancy; Bioverativ: Consultancy; Bayer: Consultancy; Bioverativ: Research Funding. White:Biomarin: Other: DSMB; Bioverativ: Other: DSMB; Bayer: Other: GRAC; Shire: Other: Physician Leadership Group; Novo Nordisk: Consultancy; Asklepios: Other: Scientific Advisory Board; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Croteau:Biomarin: Consultancy; Bioveritiv: Consultancy; Catalyst Biosciences: Consultancy; CSL-Behring: Consultancy; Genetech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Ragni:Sangamo: Research Funding; CSL Behring: Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Congenital Thrombotic Thrombocytopenia Purpura - Safer Treatment with Plasma-Derived Viral-Attenuated Clotting Factor

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3459-3459
Author(s):  
Louis M. Aledort ◽  
Lisa Boggio ◽  
Joanna A. Davis ◽  
Cynthia Gauger ◽  
Nathan L. Kobrinsky ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Clotting Factor ◽  
Allergic Reactions ◽  
Advisory Committees ◽  
Baxter Healthcare ◽  
Number Of Patients ◽  
The U.S

Abstract Congenital Thrombotic Thrombocytopenia Purpura (cTTP) has been considered a very rare disorder. Several international registries have estimated 250 patients worldwide. While the total number of patients in the U.S. is unknown, an ongoing U.S. Registry has recorded only 89 patients. (Singleton et al NORD 2014) Therapy for this disease, for prophylaxis and treatment, has been replacement of the absent ADAMTS13 with fresh frozen plasma (FFP). The major complication has been allergic reactions including anaphylaxis making this treatment unviable for some patients. Virally- inactivated FFP is not readily available in the U.S. A recombinant ADAMTS13 is in initial PK studies. There have been anecdotal reports that a plasma-derived FVIII/vWF biologic (Koate-DVI), double virally inactivated, FVIII replacement product, has been successfully used prophylactically in cTTP patients in lieu of FFP therapy to prevent episodes of TTP (Naik et al J Pediatr Hematol Oncol 2013). No other therapeutic biologic has been able to provide this benefit. Pursuant to that observation, two independent laboratories in the U.S. and Italy conducted analyses of the content of ADAMTS13 in several FVIII concentrates. The ADAMTS13 content in reconstituted concentrate of Koate-DVI was up to 9.08 + 0.70 units/ml, and was substantially higher than other FVIII products and pooled plasma. Table 1 and Table 2 We report here a cohort of 10 cTTP patients currently being managed with Koate-DVI prophylaxis. The average age of the patients is 15 years (range 7-22 years). The patients are being treated with a dose range of 25 to 40 IU/kg, at an average of once per week. This dose of Koate-DVI (containing 100 IU FVIII/ml after reconstitution) will provide approximately 2 to 4 IU/kg of ADAMTS13. Patients have been treated for variable lengths of time ranging from less than a year to over 10 years. The patients have responded very well to the Koate-DVI treatment; no severe adverse events or allergic reactions have been reported. We are prospectively comparing the frequency of new TTP episodes in this cohort with the frequency observed prior to initiation of this therapy. We report a unique experience of 10 cTTP patients being successfully managed prophylactically at home with self-infusion of Koate-DVI (Factor VIII concentrate with a long history of viral safety in the treatment of hemophilia A). These patients are receiving a convenient virally-inactivated alternative to FFP without manifesting life-threatening allergic reactions that require immunosuppression and/or hospitalization. A prospective clinical study of the safety and efficacy of Koate-DVI is planned. Table 1. Concentrate ADAMTS13 activity U/mL ADAMTS13 antigen U/mL Koate-DVI (5 lots) 9.08 ± 0.70 8.42 ± 0.12 Product A 0.12 0.13 Product B 0.22 0.61 Product C 2.30 3.87 (Peyvandi et al Am J Hematol 2013) Table 2. Concentrate ADAMTS13 Units/ml Koate-DVI 5.77 Product A 0.18 Product B 0.23 Product C 1.40 (Konkle Personal Communication 2013) Disclosures Aledort: Kedrion BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: DSMB Participation. Off Label Use: Koate-DVI is indicated for the treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor, factor VIII. This presentation discusses the use of factor VIII concentrate for ADAMTS13 deficiency.. Boggio:CSL Behring: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; Selexys: Research Funding; Bayer: Consultancy, Research Funding; OctaPharma: Consultancy, Research Funding; OPKO: Research Funding; Novo Nordisk: Consultancy, Research Funding. Kobrinsky:Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Sanofi: Speakers Bureau; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees. Rajasekhar:American Society of Hematology: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Shapiro:Baxalta: Research Funding; Shire: Speakers Bureau; BioCryst: Research Funding. Ulsh:Kedrion Biopharma: Employment.

Prevalence of Inhibitors in a Population of 3435 Hemophilia Patients in France

1992 ◽  
Vol 67 (06) ◽  
pp. 600-602 ◽  
Author(s):  
Y Sultan ◽  
Keyword(s):  
Hemophilia A ◽  
Hemophilia B ◽  
Study Group ◽  
Cooperative Study ◽  
Population Prevalence ◽  
French Study ◽  
Number Of Patients ◽  
High Incidence ◽  
Recombinant Fviii ◽  
High Responders

SummaryA cooperative study between the 37 centers of the French Hemophilia Study Group was undertaken to establish the prevalence of inhibitor patients in the French hemophilia population. The prevalence reported in the literature varies widely from 3.6% to 17.5%. Some of the studies are dealing with a small number of patients and inhibitor patients are reported either to the total number of hemophiliacs or to the severely affected ones. The French study provided information concerning 3,435 hemophiliacs and showed a prevalence of 6.2% for the overall population. Prevalence of inhibitors was found to be 7% in the population of hemophilia A patients and 12.8% in the population of severely affected ones. The prevalence of inhibitors in the population of hemophilia B patients was 2% and 4% in the population of severely affected hemophilia B patients. The cooperative study also showed that 47.5% of inhibitors are detected before 10 years of age and that 82% of inhibitor patients are high responders. Analysis of inhibitor detection in patients under the age often showed that there was a peak in the population of 2 years old children. Although not comparable to the present study the high incidence of inhibitors with ultrapurified and recombinant FVIII reported in previously untransfused patient may be borne in mind.

Inhibitor development in haemophilia according to concentrate

2015 ◽  
Vol 113 (05) ◽  
pp. 968-975 ◽  
Author(s):  
Riita Lassila ◽  
Flora Peyvandi ◽  
Gabriele Calizzani ◽  
Alex Gatt ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Calculated Data ◽  
Incidence Rates ◽  
Clotting Factor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Inhibitor Development ◽  
Haemophilia B ◽  
Number Of Patients ◽  
Recombinant Fviii ◽  
Set Up

SummaryInhibitor development represents the most serious side effect of haemophilia treatment. Any difference in risk of inhibitor formation depending on the product used might be of clinical relevance. It was this study’s objective to assess inhibitor development according to clotting factor concentrate in severe haemophilia A and B. The European Haemophilia Safety Surveillance (EUHASS) was set up as a study monitoring adverse events overall and according to concentrate. Since October 2008, inhibitors were reported at least quarterly. Number of treated patients was reported annually, specifying the number of patients completing 50 exposure days (Previously Untreated Patients, PUPs) without inhibitor development. Cumulative incidence, incidence rates and 95 % confidence intervals (CI) were calculated. Data from October 1, 2008 to December 31, 2012 were analysed for 68 centres that validated their data. Inhibitors developed in 108/417 (26 %; CI 22–30 %) PUPs with severe haemophilia A and 5/72 (7 %; CI 2–16%) PUPs with severe haemophilia B. For Previously Treated Patients (PTPs), 26 inhibitors developed in 17,667 treatment years [0.15/100 treatment years; CI 0.10–0.22) for severe haemophilia A and 1/2836 (0.04/100; (CI 0.00–0.20) for severe haemophilia B. Differences between plasma-derived and recombinant concentrates, or among the different recombinant FVIII concentrates were investigated. In conclusion, while confirming the expected rates of inhibitors in PUPs and PTPs, no class or brand related differences were observed.

scholarly journals Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2409-2409
Author(s):  
Tiffany Lin Lucas ◽  
Shveta Gupta ◽  
Joanna A. Davis ◽  
Fernando F. Corrales-Medina
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Haemophilia A ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Increased Risk ◽  
Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

Diphtheria: the patch remains

2003 ◽  
Vol 117 (10) ◽  
pp. 807-810 ◽  
Author(s):  
Raj Nandi ◽  
Mriganka De ◽  
Simon Browning ◽  
Prabhati Purkayastha ◽  
A. K. Bhattacharjee
Keyword(s):  
Early Diagnosis ◽  
Respiratory Tract ◽  
Respiratory Distress ◽  
Retrospective Analysis ◽  
Fatal Disease ◽  
Disease Characteristics ◽  
Intravenous Antibiotics ◽  
Number Of Patients ◽  
History Of ◽  
Clinical Records

This study analysed the number of patients admitted with diphtheria to a teaching hospital in the state of Assam in India over a period of five years and compared the disease characteristics and management with outcomes and incidences of diphtheria reported in the literature. It was a retrospective analysis of data elicited from clinical records of patients admitted to hospital.A total of 101 admissions were recorded during a five-year period between March 1997 to March 2002, mostly with pharyngeal diphtheria (90 per cent). The majority of patients had no history of immunization (70 per cent). Significant presenting features were a tonsillar patch, sore throat, respiratory distress and fever. All patients were treated with anti-diphtheritic serum and intravenous antibiotics. Steroids were given to 81 per cent of patients and tracheostomy was carried out in 10 per cent of cases. The mortality was 16 per cent.Diphtheria of the respiratory tract remains a potentially fatal disease commonly presenting with membranous pharyngitis. Early diagnosis and treatment with anti-diphtheritic serum and antibiotics remain the cornerstone of treatment. Inadequate immunization cover is deemed responsible for the continued menace of diphtheria.

Who Gets Inhibitors? Predicting Inhibitory Antibodies in Children with Severe Hemophilia A.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1158-1158
Author(s):  
Petra C. ter Avest ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Marijke H. van den Berg ◽  
Johanna G. van der Bom
Keyword(s):  
Family History ◽  
High Risk ◽  
Risk Score ◽  
Hemophilia A ◽  
Positive Family History ◽  
Treatment Strategies ◽  
Intensive Treatment ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
History Of

Abstract Background. Replacement therapy in severe hemophilia A patients is complicated by formation of inhibitors in around 25% of children. Identification of patients at the highest risk may help to tailor personalized treatment strategies. Objectives. To develop a scoring system that may be used to identify patients at the highest risk of inhibitor development at first treatment. Methods. We used the data from a retrospective multicentre cohort study (the Canal cohort) of patients with severe hemophilia A (factor VIII (FVIII)less than 0.01 IU/ml), born 1990–2000, followed at least until their 50th exposure day. Presence of inhibitor was defined as twice a positive inhibitor titer and a decreased FVIII recovery. Based on the coefficients of a logistic regression model, a weighted risk-score was developed. Shrinkage of regression coefficients was used to control for overfitting. The discriminative ability of the risk-score was expressed as the area under the curve (AUC) of a receiver operating characteristic curve. Results. Out of the 366 patients from the Canal cohort, 284 children were selected of whom 78 developed an inhibitor (27%). Logistic regression analysis revealed 3 independent risk factors for inhibitor development: positive family history, intensive treatment (at least 5 consecutive days) at the first FVIII exposure, and high risk FVIII gene mutations. Table 1 presents odds ratios of the uni- and multivariate analyses, and the risk score. The AUC for the risk-score was 0,724. Table 2 shows that the model is able to separate high and low risk patients from patients with an intermediate risk of 25%. Conclusions. The risk score includes positive family history of inhibitors, high risk factor VIII gene mutation and intensive treatment at first FVIII exposure. This risk score can recognize patients with a doubled risk for inhibitor development and may be used to guide inhibitor preventive treatment strategies. Table 1. Uni- and Multivariate analysis and risk-score. OR (CI), Univariate OR (CI), Multivariate p-value Risk-Score CI = confidence interval 95% Positive Family History of Inhibitors 4.0 (1.7–9.4) 3.0 (1.2–7.7) ,022 3 High risk FVIII Gene Mutation 3.6 (1.8–7.2) 3.7 (1.8–7.9) ,001 4 Intensive Treatment at 1st FVIII exposure 6.8 (3.6–12.9) 7.2 (3.4–15.1) ,000 6 Table 2. Calibration of the risk-score. Model Total n° patients Predicted n° Inhibitors Observed n° Inhibitors Positive Predictive Value Negative Predictive Value LR= Low Risk, MR= Medium Risk, HR= High risk LR:0 72 7 6 0,34 0,92 MR:3–4 153 39 38 0,25 0,69 HR: >4 59 32 34 0,58 0,80

The EPIC Study: A Clinical Trial To Assess Whether Early Low Dose Prophylaxis In The Absence Of Immunological Danger Signals Reduces Inhibitor Incidence In Previously Untreated Patients (PUPs) With Hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 576-576 ◽  
Author(s):  
Guenter Auerswald ◽  
Karin Kurnik ◽  
Jan Blatny ◽  
Armin J Reininger
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
Venous Access ◽  
Patient Specific ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Prophylactic Regimen ◽  
Inhibitor Development ◽  
Danger Signals

Abstract Background Inhibitor development is a complex, multifactorial immune response involving both patient-specific and treatment-related factors. Of the known risk factors, intensive treatment at an early age has been shown to be significant, and clinical observations have suggested that early prophylaxis (i.e. first exposure to FVIII in the absence of a bleed in the first year of age) may protect patients from inhibitor development by inducing FVIII tolerance. Aim This study aimed to assess prospectively if a once-weekly, low-dose prophylactic regimen started before 1 year of age and before the onset of a severe bleeding phenotype (i.e. joint bleed), together with the minimization of immunological danger signals, could reduce the incidence of inhibitor formation in PUPs with severe and moderately severe hemophilia A to 15% or less. Methods The EPIC study was a Phase 3b, prospective, single arm, historically-controlled, international multicenter study to assess the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A during the first 50 exposure days (EDs) of treatment with ADVATE starting with a once-weekly, low-dose (ADVATE 25 IU/kg once weekly), prophylactic regimen. If clinically indicated, it was permissible to increase the frequency of dosing to 2 or 3 times per week. In addition, infusions during the first 20 EDs had to be given 3 to 4 days before or after any vaccinations, which had to be given subcutaneously, not intramuscularly; infusions had to be avoided if the subject had high fever (above 38°C [100°F]). Main enrolment criteria were: severe and moderately severe hemophilia A (FVIII ≤2%), age <1 year, ≤3 EDs to any FVIII-containing product used for treatment of minor bleeds or for precautionary infusions following injury, adequate venous access (without need for central venous access device), no life-threatening conditions (intracranial hemorrhage, severe trauma) or requirement for surgery at the time of enrollment, no evidence of inhibitor ≥0.6 BU in Nijmegen-modified Bethesda assay at study start, no hemostatic defect other than hemophilia A, no clinically significant chronic disease other than hemophilia A,. Information about type of FVIII gene defect was obtained in 17 subjects. FVIII inhibitor tests were performed at screening, at study infusion #3, 6, 10, 15, 20, 30, 40, and 50, and at any other time point if an inhibitor was suspected. Positive inhibitor testing had to be confirmed by 2 positive inhibitor tests on samples drawn at least 1 week apart. Results A total of 22 subjects were enrolled in the study. Of 20 subjects who met all entry criteria, 19 received treatment; of these, all had severe hemophilia A (FVIII<1%). At study entry 11 of these 19 patients were never exposed to FVIII before (PUPs), while the remaining 8 patients had been treated with FVIII concentrates before. FVIII gene mutation analysis revealed intron 22 inversions in 8 out of 17 subjects, hemizygous missense mutations resulting in a stop-codon in 2 subjects, frame-shift mutations in 2 subjects, and hemizygous missense mutations in 5 subjects. A total of 8 subjects developed a confirmed inhibitor: 2 of these 8 subjects had only borderline positivity at inhibitor testing (never above 0.6 BU) with absence of any anti-FVIII antibodies (IgG, IgA, IgM and IgG subclasses) as tested by ELISA. Thus incidence of inhibitors >0.6 BU in PUPs were 27%. A total of 67 major protocol deviations (PD) were reported in 15 patients: 44 PDs of these were reported in 10 subjects and were related to the treatment regimen and therefore have contrasted with the protocol intention, which was to minimize immunological danger signals and low dose prophylactic regimen. As a result of the observed inhibitor incidence the study was terminated based on futility analysis, i.e. the probability to achieve the primary end-point of inhibitor rate reduction to ≤15%. Details on inhibitor patients will be presented. Discussion The EPIC study showed no safety issue as confirmed by the Data Safety Monitoring Board. To align treatment decisions in the presence of danger signals (which are not completely avoidable in children around 1 year of age) with a demanding study protocol was found to be challenging. Thus the hypothesis that an early low dose prophylaxis in the absence of immunological danger signals might reduce inhibitor incidence in PUPs with hemophilia A could neither be verified nor disproved within this study. Disclosures: Auerswald: Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kurnik:Baxter: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Blatny:Baxter: speaker fee Other. Reininger:Baxter Innovations GmbH: Employment.

Therapy Preference and Outcomes of Hydroxyurea for Pediatric Patients with Silent Cerebral Infarcts

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3531-3531
Author(s):  
Tullia Rushton ◽  
Inmaculada Aban ◽  
Daniel Young ◽  
Thomas H. Howard ◽  
Lee Hilliard ◽  
...  
Keyword(s):  
Randomized Trial ◽  
Sample Size ◽  
Research Funding ◽  
Retrospective Chart Review ◽  
Initial Therapy ◽  
Pediatric Radiologist ◽  
Transfusion Therapy ◽  
Exact Test ◽  
Number Of Patients ◽  
History Of

Abstract Introduction: The Silent Infarct Transfusion (SIT) Trial demonstrated that transfusion therapy over three years, as compared to no sickle cell disease (SCD) modifying therapy, reduces the risk of new CNS events, defined as an overt stroke or new or enlarged silent cerebral infarct (SCI), in patients with SCI on screening MRI. Despite the significant reduction in CNS events with transfusion therapy, patients/caregivers may choose to decline chronic transfusion therapy for secondary CNS events. Hydroxyurea is known to decrease complications of SCD, and while its impact on new CNS events in patients with a SCI has not been tested in a randomized trial, it was offered as an alternative for patients who declined transfusion therapy. We evaluated therapy preference for prevention of new CNS events among patients with SCI on screening MRI and three year outcomes of patients with SCI that elected treatment with hydroxyurea at our institution. Methods: We performed a 15-year IRB approved retrospective chart review for all patients with the diagnosis of SCI at Children's of Alabama based on their original MRI report. Ninety-two patients were identified and subsequently confirmed by an additional pediatric radiologist to have suffered a SCI and had no history of a prior overt stroke while 39 patients were excluded because of their history of overt stroke prior to the detection of a SCI. We recorded the patient/caregiver initial preference for therapy and evaluated differences in therapy selection prior to, during, and post SIT Trial. We recommend annual or biennial follow-up MRI exams to evaluate for SCI progression and recorded and reviewed all subsequent MRIs and SCD therapies for overt stroke or new or enlarged SCI. To compare outcomes of hydroxyurea for secondary CNS events to the SIT Trial, we evaluated the 27 patients with SCI that were treated with hydroxyurea (HU) for their SCI and had a subsequent MRI/MRA at least three years after their initial diagnosis of SCI. Descriptive statistics and Fisher's exact test were performed using JMP10. Sample size was calculated for a superiority trial design using a power of 85% and alpha of 5% with PASS version 14. Results: We evaluated patient/caregiver therapy preference for secondary SCI prevention among 54 patients that were not receiving a SCD modifying therapy at the time of their index SCI. We identified a significantly higher number of patients/caregivers who, after discussion with their primary SCD provider about therapeutic options, elected to initiate transfusion or enroll in the SIT Trial prior to and during SIT Trial enrollment but a higher percentage of patients/families that elected to initiate hydroxyurea after enrollment (p=0.04). Three of 36 patients (8%) elected hydroxyurea prior to and during SIT Trial enrollment as compared to 6 of 18 patients (33%) post enrollment. Among 27 participants on HU at the time of their incident SCI finding on MRI, 25 (93%) participants elected to remain on HU while only two (11%) participants elected to change to chronic transfusion therapy. The two patients that switched to transfusion also had MRA abnormalities identified at the time of their incident SCI finding. To evaluate outcomes of HU for secondary SCI prevention, 27 participants were prescribed HU for at least three years and underwent serial MRI evaluations. Three of these 27 participants developed a new SCI. Four participants had an abnormal MRA at the time of their index MRI and five patients developed an abnormal MRA on subsequent studies. The three participants that had an additional SCI had normal MRA examinations. In comparison to the SIT Trial, which identified 2.0 and 4.8 new CNS events per 100 patient years at risk for transfusion and no therapy respectively, we identified 3.7 new CNS events per 100 patient years among patients prescribed hydroxyurea. Combining our results with that of SIT Trial, a sample size of 1100 participants would be required to conduct a trial to show the superiority of transfusion over HU for secondary SCI. Conclusion: While the SIT Trial showed chronic transfusion to be superior to no therapy in preventing new CNS events in patients with SCI, patients and caregivers at our institution prefer hydroxyurea to transfusion for initial therapy to prevent secondary CNS events. A randomized trial to show superiority of transfusion over hydroxyurea for secondary stroke prevention would require a sample size too large to be practical. Disclosures Lebensburger: NHLBI: Research Funding; American Society of Hematology, Scholar Award: Research Funding.

scholarly journals Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1195-1195 ◽  
Author(s):  
Lynn M. Malec ◽  
Char M Witmer ◽  
Julie Jaffray ◽  
Peter A. Kouides ◽  
Kristina M. Haley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
Advisory Board ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
On Demand ◽  
Joint Health

Abstract Background : The hemophilia treatment landscape has evolved substantially in the last several years with the approval of extended half-life (EHL) products which reduce the burden of prophylaxis. Data reported from the American Thrombosis and Hemostasis Network (ATHN) as of June 2017 indicate that 21% of patients with moderate or severe hemophilia A, and 42% of patients with moderate or severe hemophilia B, receive prophylaxis utilizing an EHL. As new treatments become available and are adopted into practice, it is important to recognize the need for evaluation of efficacy, safety, and economic impact of their use outside of the clinical trial setting. We aimed to characterize the real world impact of EHL products by collecting detailed information on bleeding rates, joint health and quality of life amongst patients cared for at ATHN-affiliated Hemophilia Treatment Centers. We hypothesized that use of EHL products were utilized in at least 30% of patients and would lead to decreased ABRs and improved joint health. To date 67 of a planned 135 subjects have been enrolled, constituting this interim analysis. Methods:Subjects were recruited from seven U.S. Hemophilia Treatment Centers. Subjects with severe hemophilia A or B ≤ 30 years of age on prophylaxis or demand therapy were eligible for enrollment. Subjects excluded from study were those with a recent joint bleed (within the last 2 weeks) or those unwilling to complete all elements of the study. Data were collected during a one-time encounter concurrent with an appointment for clinical evaluation, including demographic information, treatment regimen, product type, frequency, location and severity of all bleeds, Hemophilia Joint Health Scores (HJHS), and Quality of life (QoL). Bleeding rates in subjects receiving prophylaxis were compared with those receiving on demand therapy by type treatment, EHL vs standard half-life (SHL), and by hemophilia type. Severity of bleeding events (mild, moderate, or severe) and HJHS were compared by prophylaxis groups. Results: A total of 67 patients were enrolled and eligible for analysis. This included 58 subjects with severe hemophilia A, and 9 subjects with severe hemophilia B. The mean age of the cohort was 15 years (median 12 years, IQR 8 - 21 years). For these patients whose race information was known, 89.1% were Caucasian, 3.3% African-American, 3.3% Asian, and 4.7% were of mixed or 'other' race. Eleven out of 61 (18.0%) subjects with known ethnicity were Hispanic. Among 59 patients whose treatment type were available, the majority were on prophylaxis (n=53; 89.8%) as compared to on demand therapy (n=6; 10.2%). The average annualized bleeding rate (ABR) was 2.8 amongst all individuals. As expected, the ABR was substantially lower in those receiving prophylaxis (ABR=1.0) as compared to on demand therapy (ABR=18.6) (p<0.001). Additionally, HJHS in those receiving prophylaxis was lower (mean HJHS= 3.9), meaning less evidence of joint damage, than in those receiving demand therapy (mean HJHS= 8.8) (p=0.162). For patients with severe hemophilia A, the ABR was lower in those individuals receiving EHL (ABR= 0.5) versus SHL (ABR= 1.5), although this did not reach statistical significance (p=0.136). All subjects with severe hemophilia B enrolled to date receive EHL products (n=9) therefore no comparison of ABR could be made between EHL and SHL products; the ABR in this group was 0.9. In patients with severe hemophilia A, there was a higher HJHS for those receiving EHL (mean HJHS= 7.0) versus those receiving SHL (mean HJHS = 2.1) (p=0.053). For patients with severe hemophilia B, all of whom received EHL, the mean HJHS was lower than in the hemophilia A cohort (mean HJHS=1.2). Conclusions: We report real-world bleeding events and joint health in patients with severe hemophilia A and B utilizing EHL and SHL products across a wide U.S. geographic distribution. As anticipated, there is substantial bleed reduction with prophylaxis versus on demand therapy. In our severe hemophilia A cohort, the ABR for patients receiving EHL products was similar to ABRs reported in clinical trials, suggesting clinical trial data may be reflective of real world use. Patients with severe hemophilia A receiving EHL for prophylaxis had a lower ABR than those receiving SHL, although the early impact is not reflected in the HJHS score. Longer follow-up will be necessary to determine the impact of EHL on HJHS. Disclosures Malec: Bioverativ: Research Funding; Bayer: Consultancy; Bioverativ: Consultancy; Shire: Consultancy. Jaffray:Octapharma: Consultancy; Bayer: Consultancy; CSL Behring: Consultancy, Research Funding. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Sidonio:Octapharma: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board; Kedrion: Research Funding; Biomarin: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board. Abshire:CSL: Consultancy; Shire: Consultancy; Novo Nordisk: Other: DSMB. White:Asklepios: Other: Scientific Advisory Board; Novo Nordisk: Consultancy; Shire: Other: Physician Leadership Group; Bayer: Other: GRAC; Bioverativ: Other: DSMB; Biomarin: Other: DSMB; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Ragni:CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Bioverativ: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

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