67 results on '"Kessler CM"'
Search Results
2. Real world impact of emicizumab & immunosuppression on Acquired Hemophilia A: A Multicenter US Cohort.
- Author
-
Poston JN, Bryan C, von Drygalski A M.D, Al Banaa K, Zhou JY, Parnes A, Chen EC, Khan O, Ellsworth P, Cafuir L, Walsh C, Escobar MA, Wu JF, Malec LM, Kessler CM, Janbain M, and Kruse-Jarres R
- Abstract
Acquired Hemophilia A (AHA) is an autoimmune bleeding disorder from anti-factor VIII (FVIII) antibodies with high morbidity and mortality due to bleeding and complications from immunosuppression (IST). To address the real-world implications of the FVIII mimetic antibody, emicizumab, and the role of IST, we retrospectively collected deidentified data on 62 AHA patients treated with off label emicizumab for a median of 10 weeks at 12 US hemophilia treatment centers. Most patients (95.2%) had acute bleeding at diagnosis with 62.9% having partial or no control of bleeds despite use of hemostatic agents at the time emicizumab was started. The main reason for initiating emicizumab was outpatient bleeding prophylaxis. After initiation of emicizumab, 87.1% had no additional bleeds. There were 6 breakthrough bleeds (2 spontaneous) in 5 patients and no fatal bleeding events on maintenance emicizumab. The mean breakthrough bleed rate per patient-week was 0.02 (95% CI 0.0 - 0.03) during the first 12 weeks of emicizumab for the 55 patients with at least 12 weeks of follow up. Of these patients, 92.7% received IST with 74.5% given rituximab-based regimens. Complete resolution of inhibitor and normalization of FVIII levels occurred in 56% overall and 63% of the patients treated with rituximab. Overall, the median time to discontinue emicizumab and IST was 18 weeks. Two patients had thrombotic events on emicizumab, but no adverse events were attributed to emicizumab and there were no infections due to IST. Emicizumab provides effective outpatient bleeding prophylaxis for AHA, and concurrent IST may further mitigate bleeding., (Copyright © 2024 American Society of Hematology.)
- Published
- 2024
- Full Text
- View/download PDF
3. Risk of myeloproliferative neoplasms among U.S. Veterans from Korean, Vietnam, and Persian Gulf War eras.
- Author
-
Tiu A, McKinnell Z, Liu S, Gill P, Antonio M, Shancer Z, Srinivasa N, Diao G, Subrahmanyam R, Kessler CM, and Jain M
- Abstract
The Promise to Address Comprehensive Toxics (PACT) Act expanded U.S. Veterans' health care and benefits for conditions linked to service-connected exposures (e.g., Burn Pits, Agent Orange). However, myeloproliferative neoplasms (MPN) are not recognized as presumptive conditions for Veterans exposed to these toxic substances. This study evaluated the development of MPN among U.S. Veterans from the Korean, Vietnam, and Persian Gulf War eras. This retrospective cohort study included 65 425 Korean War era Veterans; 211 927 Vietnam War era Veterans; and 214 007 Persian Gulf War era Veterans from January 1, 2006, to January 26, 2023. Veterans with MPN, thrombosis, bleeding, and cardiovascular risk factors were identified through ICD-9 and -10 codes. Veterans from the Persian Gulf War era had the highest risk of developing MPN compared with Veterans from the Korean and Vietnam War eras, hazard ratio (HR) 4.92, 95% confidence interval (CI) 4.20-5.75 and HR 2.49, 95% CI 2.20-2.82, both p < .0001, respectively. Vietnam War era Veterans also had a higher risk of MPN development compared with Korean War era Veterans, HR 1.97, 95% CI 1.77-2.21, p < .0001. Persian Gulf War era Veterans were diagnosed with MPN at an earlier age, had higher risks of thrombosis and bleeding, and had lower survival rates compared with Korean War and Vietnam War era Veterans. This study reinforces evidence that environmental and occupational hazards increase the risk of clonal myeloid disorders and related complications, impacting overall survival with MPN. Limitations include the inability to confirm clonality and fully verify deployment and exposure status., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)
- Published
- 2024
- Full Text
- View/download PDF
4. PFA-100 System: A New Method for Assessment of Platelet Dysfunction.
- Author
-
Mammen EF, Comp PC, Gosselin R, Greenberg C, Hoots WK, Kessler CM, Larkin EC, Liles D, and Nugent DJ
- Subjects
- Humans, Female, Male, Adult, Middle Aged, Platelet Aggregation, Platelet Function Tests methods, Platelet Function Tests instrumentation, Blood Platelet Disorders diagnosis, Blood Platelet Disorders blood, Blood Platelets metabolism
- Abstract
This is a celebratory reprint of a historical paper published in STH in 1998. The original Abstract follows.The PFA-100 system is a platelet function analyzer designed to measure platelet-related primary hemostasis. The instrument uses two disposable cartridges: a collagen/epinephrine (CEPI) and a collagen/ADP (CADP) cartridge. Previous experience has shown that CEPI cartridges detect qualitative platelet defects, including acetylsalicylic acid (ASA)-induced abnormalities, while CADP cartridges detect only thrombocytopathies and not ASA use. In this seven-center trial, 206 healthy subjects and 176 persons with various platelet-related defects, including 127 ASA users, were studied. The platelet function status was determined by a platelet function test panel. Comparisons were made as to how well the defects were identified by the PFA-100 system and by platelet aggregometry. The reference intervals for both cartridges, testing the 206 healthy subjects, were similar to values described in smaller studies in the literature (mean closure time [CT] of 132 seconds for CEPI and 93 seconds for CADP). The use of different lot numbers of cartridges or duplicate versus singleton testing revealed no differences. Compared with the platelet function status, the PFA-100 system had a clinical sensitivity of 94.9% and a specificity of 88.8%. For aggregometry, a sensitivity of 94.3% and a specificity of 88.3% were obtained. These values are based on all 382 specimens. A separate analysis of sensitivity by type of platelet defect, ASA use versus congenital thrombocytopathies, revealed for the PFA-100 system a 94.5% sensitivity in identifying ASA users and a 95.9% sensitivity in identifying the other defects. For aggregometry, the values were 100% for ASA users and 79.6% for congenital defects. Analysis of concordance between the PFA-100 system and aggregometry revealed no difference in clinical sensitivity and specificity between the systems (p > 0.9999). The overall agreement was 87.5%, with a Kappa index of 0.751. The two tests are thus equivalent in their ability to identify normal and abnormal platelet defects. Testing 126 subjects who took 325 mg ASA revealed that the PFA-100 system (CEPI) was able to detect 71.7% of ASA-induced defects with a positive predictive value of 97.8%. The overall clinical accuracy of the system, calculated from the area under the receiver operating characteristic curve, was 0.977. The data suggest that the PFA-100 system is highly accurate in discriminating normal from abnormal platelet function. The ease of operation of the instrument makes it a useful tool to use in screening patients for platelet-related hemostasis defects., Competing Interests: None declared., (Thieme. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
5. Emicizumab: the hemophilia A game-changer.
- Author
-
Alcedo Andrade PE, Mannucci PM, and Kessler CM
- Subjects
- Humans, Hemorrhage etiology, Factor VIII therapeutic use, Factor VIII immunology, Hemophilia A drug therapy, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Bispecific therapeutic use, Antibodies, Bispecific adverse effects
- Abstract
In hemophilia, the unmet needs regarding adherence to prophylaxis and lack of effective long-term prophylaxis regimens, especially in patients with inhibitors, led to the production of emicizumab, the first non-factor medicine for subcutaneous administration in patients with severe and moderate hemophilia A with or without factor VIII inhibitors. This review describes the research steps behind the development of this game-changing medication as well as its success in the prophylaxis of bleeding episodes, as witnessed by the results of pivotal clinical trials but also by real-life use in the frame of a still expanding global market. We also discuss potential and actual adverse events and the nuances related to clinical use, such as laboratory monitoring, development of neutralizing antidrug antibodies, risk of thrombosis/hypercoagulability and role in the management of surgical operations. The potential of emicizumab to prevent bleeding in other congenital and acquired coagulation disorders is also outlined.
- Published
- 2024
- Full Text
- View/download PDF
6. The Pitfalls of Global Hemostasis Assays in Myeloproliferative Neoplasms and Future Challenges.
- Author
-
Tiu A, Chiasakul T, and Kessler CM
- Subjects
- Humans, Thrombin, Cross-Sectional Studies, Hemostasis, Biomarkers, Janus Kinase 2, Myeloproliferative Disorders complications, Myeloproliferative Disorders diagnosis, Polycythemia Vera complications, Thrombosis etiology, Thrombosis complications, Thrombocythemia, Essential, Thrombophilia complications
- Abstract
Venous and arterial thromboembolism are major complications of myeloproliferative neoplasms (MPNs), comprising polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Global hemostasis assays, including thrombin generation assay (TGA), rotational thromboelastometry (ROTEM), and thromboelastography (TEG), have been proposed as biomarkers to assess the hypercoagulability and thrombotic risk stratification in MPNs. We performed a systematic literature review on the parameters of TGA, ROTEM, and TEG and their association with thrombotic events and treatment strategies in MPNs. Thirty-two studies (all cross-sectional) were included, which collectively enrolled 1,062 controls and 1,608 MPN patients. Among the 13 studies that reported arterial or venous thrombosis, the overall thrombosis rate was 13.8% with 6 splanchnic thromboses reported. Out of the 27 TGA studies, there was substantial heterogeneity in plasma preparation and trigger reagents employed in laboratory assays. There was a trend toward increased peak height among all MPN cohorts versus controls and higher endogenous thrombin potential (ETP) between ET patients versus controls. There was an overall trend toward lower ETP between PV and PMF patients versus. controls. There were no substantial differences in ETP between JAK2-positive versus JAK2-negative MPNs, prior history versus negative history of thrombotic events, and among different treatment strategies. Of the three ROTEM studies, there was a trend toward higher maximum clot firmness and shorter clot formation times for all MPNs versus controls. The three TEG studies had mixed results. We conclude that the ability of parameters from global hemostasis assays to predict for hypercoagulability events in MPN patients is inconsistent and inconclusive. Further prospective longitudinal studies are needed to validate these biomarker tools so that thrombotic potential could be utilized as a primary endpoint of such studies., Competing Interests: C.M.K. participated in clinical research trials sponsored by Incyte; and also participated in advisory boards with both Incyte and PharmaEssentia.All other authors have nothing to disclose., (Thieme. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
7. Association of patient, treatment and disease characteristics with patient-reported outcomes: Results of the ECHO Registry.
- Author
-
Hay CRM, Makris M, Shima M, Nagao A, Jiménez-Yuste V, Skinner M, Kessler CM, and von Mackensen S
- Subjects
- Humans, United States, Treatment Outcome, Quality of Life, Prospective Studies, Registries, Pain, Surveys and Questionnaires, Patient Reported Outcome Measures, Hemophilia A drug therapy
- Abstract
Introduction: Patient-reported outcomes (PROs) in people living with haemophilia A (PLWHA) are often under-reported. Investigating PROs from a single study with a diverse population of PLWHA is valuable, irrespective of FVIII product or regimen., Aim: To report available data from the Expanding Communications on Haemophilia A Outcomes (ECHO) registry investigating the associations of patient, treatment and disease characteristics with PROs and clinical outcomes in PLWHA., Methods: ECHO (NCT02396862), a prospective, multinational, observational registry, enrolled participants aged ≥16 years with moderate or severe haemophilia A using any product or treatment regimen. Data collection, including a variety of PRO questionnaires, was planned at baseline and annually for ≥2 years. Associations between PRO scores and patient, treatment and disease characteristics were determined by statistical analyses., Results: ECHO was terminated early owing to logistical constraints. Baseline data were available from 269 PLWHA from Europe, the United States and Japan. Most participants received prophylactic treatment (76.2%), with those using extended-half-life products (10.0%) reporting higher treatment satisfaction. Older age and body weight >30 kg/m
2 (>BMI) were associated with poorer joint health. Older age was associated with poorer physical functioning and work productivity. Health-related quality of life and pain interference also deteriorated with age and >BMI; >BMI also increased pain severity scores., Conclusion: ECHO captured a variety of disease characteristics, treatment patterns, PROs and clinical outcomes obtained in real-world practice with ≤1 year's follow-up. Older age, poorer joint health and >BMI adversely affected multiple aspects of participant well-being., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)- Published
- 2024
- Full Text
- View/download PDF
8. Clinical efficacy of simoctocog alfa versus extended half-life recombinant FVIII concentrates in hemophilia A patients undergoing personalized prophylaxis using a matching-adjusted indirect comparison method.
- Author
-
Kessler CM, Corrales-Medina FF, Mannucci PM, Jiménez-Yuste V, and Tarantino MD
- Subjects
- Humans, Half-Life, Hemorrhage etiology, Hemorrhage prevention & control, Hemorrhage drug therapy, Recombinant Proteins, Treatment Outcome, Factor VIII adverse effects, Factor VIII therapeutic use, Hemophilia A drug therapy
- Abstract
Objectives: We aimed to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) versus three extended half-life (EHL) recombinant FVIII (rFVIII) concentrates., Methods: Treatment effects were compared using matching-adjusted indirect comparisons after matching individual patient-level baseline characteristics for simoctocog alfa (pharmacokinetic [PK]-guided personalized prophylaxis) against published aggregate personalized prophylaxis data for efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol., Results: A higher percentage (p < .001) of patients with zero bleeds was found with simoctocog alfa compared with efmoroctocog alfa (75% vs. 45%), damoctocog alfa pegol (77% vs. 38%), and rurioctocog alfa pegol (target trough level 1%-3%; 78% vs. 42%). Similar efficacy was found comparing simoctocog alfa against rurioctocog alfa pegol 8%-12% (77% vs. 62%). The mean total annualized bleeding rate was lower (p < .001) with simoctocog alfa than damoctocog alfa pegol (1.5 vs. 4.9). Consistent with approved dosing, the mean FVIII weekly dose was higher (p < .001) for simoctocog alfa than efmoroctocog alfa, damoctocog alfa pegol, or rurioctocog alfa pegol 1%-3%, but lower (p < .001) than rurioctocog alfa pegol 8%-12%., Conclusions: Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to higher zero bleed rates compared with personalized EHL rFVIII concentrate regimens, albeit with higher weekly doses, and a lower percentage of patients treated twice weekly or less., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
9. Bleeding events in people with congenital haemophilia A without factor VIII inhibitors receiving prophylactic factor VIII treatment: A systematic literature review.
- Author
-
Mannucci PM, Kessler CM, Germini F, Nissen F, Ofori-Asenso R, Brocchieri C, Bendinelli S, and Iorio A
- Subjects
- Humans, Factor VIII therapeutic use, Hemorrhage etiology, Hemorrhage prevention & control, Hemorrhage drug therapy, Hemarthrosis drug therapy, Hemophilia A complications, Hemophilia A drug therapy, Hemostatics therapeutic use
- Abstract
Background: Evidence on bleeding rates in people with congenital haemophilia A (PwcHA) without inhibitors on factor VIII (FVIII) replacement products is inconsistent., Aim: This systematic literature review assessed bleeding outcomes in PwcHA using FVIII-containing products as prophylactic treatment., Methods: A search was conducted using the bibliographic databases Medline, Embase and Cochrane Central Register of Controlled Trials on the Ovid platform. The search involved a bibliographic review of clinical trial studies, routine clinical care studies and registries and a search of ClinicalTrials.gov, EU Clinical Trials Register and conference abstracts., Results: The search yielded 5548 citations. A total of 58 publications were included for analysis. In 48 interventional studies, the pooled estimated mean (95% confidence interval [CI]) annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) and proportion of participants with zero bleeding events were 3.4 (3.0-3.7), 2.0 (1.6-2.5), and 38.5% (33.1-43.9), respectively. In 10 observational studies, the pooled estimated mean (95% CI) ABR, AJBR and proportion of participants with zero bleeding events were 4.8 (4.0-5.5), 2.6 (2.1-3.2), and 21.8% (19.9-47.5), respectively. A large variation in mean effect size for ABR, AJBR and zero bleeding event data across cohorts and cohort types was observed. Funnel plots indicated potential reporting bias for publications incorporating ABR and AJBR data across both interventional and observational studies., Conclusion: This meta-analysis shows that PwcHA without inhibitors still have bleeds despite FVIII prophylaxis. Improved standardization on capturing and reporting bleeding outcomes is needed so that effective comparisons between treatments can be made., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
10. Corrigendum to 'Efficacy of emicizumab is maintained throughout dosing intervals for bleed prophylaxis' [Research and Practice in Thrombosis and Haemostasis, Volume 7, Issue 2, February 2023, 100077].
- Author
-
Pipe SW, Trzaskoma B, Minhas M, Lehle M, Ko RH, Gao L, Mahlangu J, Kempton CL, Kessler CM, and Kruse-Jarres R
- Abstract
[This corrects the article DOI: 10.1016/j.rpth.2023.100077.]., (© 2023 The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
11. Efficacy of emicizumab is maintained throughout dosing intervals for bleed prophylaxis.
- Author
-
Pipe SW, Trzaskoma B, Minhas M, Lehle M, Ko RH, Gao L, Mahlangu J, Kempton CL, Kessler CM, and Kruse-Jarres R
- Abstract
Background: Across the HAVEN clinical trial program, the efficacy of emicizumab has been demonstrated in children, adolescents, and adults with hemophilia A, with or without factor VIII inhibitors. After the 4-week loading dose period, emicizumab concentrations are expected to remain at levels that provide bleed protection throughout the entire dosing interval, regardless of the chosen maintenance dosing regimen, ie, weekly, every 2 weeks, or every 4 weeks., Objectives: The objective of this study was to examine the timing of treated bleeds within the dosing intervals for emicizumab administered during the HAVEN 1 to 4 studies., Methods: In this post hoc analysis, we pooled data from all the participants of the HAVEN 1 to 4 studies and analyzed the timing of treated bleeds in relation to the emicizumab dose., Results: A total of 392 participants were included in this analysis, with a median (range) age of 28.0 years (1.1-77.0 years). Target joints were identified in 237 of 392 (60.5%) participants before the study entry. Overall, 211 of 392 (53.8%) participants experienced 907 treated bleeding events. The total mean (SD) annualized bleeding rate across the 4 studies was 1.6 (5.9). There was no evidence that bleeding events clustered on any 1 particular day in any dosing schedule from HAVEN 1 to 4 ( P > .05 for all 3 treatment regimens)., Conclusion: Data from the HAVEN 1 to 4 trials show consistent bleed prevention within the dosing interval, regardless of the dosing regimen chosen. These findings provide further evidence of the sustained efficacy of emicizumab across all approved dosing regimens to reduce bleeding in people with hemophilia A., (© 2023 The Authors.)
- Published
- 2023
- Full Text
- View/download PDF
12. First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B.
- Author
-
Harmatz P, Prada CE, Burton BK, Lau H, Kessler CM, Cao L, Falaleeva M, Villegas AG, Zeitler J, Meyer K, Miller W, Wong Po Foo C, Vaidya S, Swenson W, Shiue LH, Rouy D, and Muenzer J
- Subjects
- Humans, Zinc Finger Nucleases
- Abstract
Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood., Competing Interests: Declaration of interest Marina Falaleeva, Andres G. Villegas, Jennifer Zeitler, Kathleen Meyer, Wendy Swenson, and Lisa Shiue are employees and stockholders of Sangamo Therapeutics, Inc. Didier Rouy is a former employee of Sangamo Therapeutics, Inc. Liching Cao is an employee of Sangamo Therapeutics, Inc. and has a patent pending (16/534,483; WO 2020/05947; US 2020/0071743) for enzymatic assays supporting MPS studies. Cheryl Wong Po Foo is a former employee of Sangamo Therapeutics, Inc., and a current employee of Astellas Gene Therapies. Sagar Vaidya is a former employee of Sangamo Therapeutics, Inc., and has a patent pending for “Method for the treatment of mucopolysaccharidosis type II” and is a current employee of Travere Therapeutics. Weston Miller is a former employee of Sangamo Therapeutics, Inc., owns stock in Sangamo Therapeutics, Inc., and is a full-time employee of Astellas Gene Therapies. Paul Harmatz has received writing support, clinical trial support, and/or consulting fees from Sangamo Therapeutics, Inc., BioMarin Pharmaceutical Inc., Takeda/Shire, REGENXBIO, Denali Therapeutics Inc., Inventiva Pharma, QED Therapeutics, Ascendis Pharma, Orphazyme, Ultragenyx Pharmaceutical, Amicus, Aeglea BioTheraeutics, Homology, JCR Pharmaceuticals, Ltd, Paradigm, Audentes Therapeutics, and Chiesi; has received registry support from Genzyme, BioMarin Pharmaceutical Inc., and Shire (Takeda). Barbara Burton has served as a consultant for Biomarin, Shire (Takeda), Denali Therapeutics Inc., Genzyme, Ultragenyx, Moderna, Aeglea, Horizon, Alexion, Inventiva, Applied Therapeutics, SIO, and JCR Pharmaceuticals Co., Ltd. She has received clinical trial funding from Biomarin, Shire (Takeda), Ultragenyx, Sangamo Therapeutics, Inc., and Homology Medicines. Carlos Prada has served as a consultant for Sanofi-Genzyme and Shire (Takeda). Heather Lau is an employee of Ultragenyx Pharmaceutical, Inc., and reports grants and non-financial support from Sangamo Therapeutics, Inc.(.), during the conduct of the study. Outside the submitted work, Dr. Lau reports personal fees from Actelion, Ltd.; grants and personal fees from Amicus Therapeutics; grants and personal fees from Biomarin Pharmaceutical, Inc.; personal fees from Chiesi; grants from Denali Therapeutics, Inc.; grants from Mallinckrodt Pharmaceuticals; grants and personal fees from Orphazyme; grants from Intrabio, Ltd.; grants, personal fees, and non-financial support from Sanofi; grants, personal fees, and non-financial support from Takeda; grants, personal fees, non-financial support, and other from Ultragenyx Pharmaceutical, Inc.; grants from Pfizer, Inc.; grants and personal fees from Prevail Therapeutics, Inc.; grants, personal fees, and non-financial support from Aspa Therapeutics; grants from Protalix BioTherapeutics; personal fees and other from National Gaucher Foundation; personal fees from Taysha Therapeutics; personal fees and other from Muscular Disease Association; personal fees and other from National Fabry Disease Foundation; personal fees and other from MPS Society; grants, personal fees, and other from Adult Polyglucosan Body Disorder Disease Foundation; personal fees and other from National Fabry Disease Foundation; and grants, personal fees and other from National Tay Sachs and Allied Disease Foundation. Craig Kessler has served as an advisory board participant with an honorarium from Sangamo Therapeutics, Inc., and his university has received support from Sangamo Therapeutics, Inc., for clinical gene therapy research. He has also served as chair, DSMB for a FVIII gene therapy trial with Bayer. Joseph Muenzer has served as a principal investigator for Takeda clinical trials, received travel and speaking fees to speak at Takeda meetings, and served on Takeda advisory boards. He has participated in advisory boards and consulted for Genzyme, Bluebird Bio, Inc., Denali Therapeutics, Inc., and served as a consultant for REGENXBIO., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
13. Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1-3.
- Author
-
Callaghan MU, Asikanius E, Lehle M, Oldenburg J, Mahlangu J, Uguen M, Chebon S, Kruse-Jarres R, Jiménez-Yuste V, Shima M, Trask P, Kempton CL, Kessler CM, Levy GG, and Peyvandi F
- Abstract
Background: Bleeding in people with hemophilia A can be life threatening, and intra-articular bleeds can result in joint damage. Most clinical studies focus on treated bleeds, while bleeds not treated with coagulation factor(s) (untreated bleeds) are underreported., Objectives: We assessed the incidence of untreated bleeds during a noninterventional study (NIS) wherein people with hemophilia A, with or without factor VIII (FVIII) inhibitors, were managed according to standard practice., Patients/methods: Using the Bleed and Medication Questionnaire, we prospectively collected data from three cohorts: Cohort A, adults/adolescents (age ≥12 years) with FVIII inhibitors; Cohort B, children (aged <12 years) with FVIII inhibitors; Cohort C, adults/adolescents without FVIII inhibitors. Untreated bleeds were analyzed for site, frequency, and etiology of bleeding and compared with those during emicizumab prophylaxis in the same individuals after transferring to a Phase III HAVEN trial., Results: In the 221 participants enrolled in the NIS (Cohort A, n = 103; Cohort B, n = 24; Cohort C, n = 94), the incidence of untreated bleeds was approximately 40% of all bleeds in people with FVIII inhibitors and 26.2% in adolescents/adults without inhibitors. Approximately 70% of treated bleeds and approximately 54% of untreated bleeds in adults/adolescents were in joints. Untreated joint bleeds were less common (7.1%) in children. Overall, intra-individual comparisons showed reduced treated/untreated bleeds following transition from standard to emicizumab prophylaxis., Conclusion: A significant proportion of bleeding events are untreated in people with hemophilia A. There is a need to further understand why bleeds remain untreated and to capture such events in clinical studies., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
- Published
- 2022
- Full Text
- View/download PDF
14. A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia.
- Author
-
Mascarenhas J, Kosiorek HE, Prchal JT, Rambaldi A, Berenzon D, Yacoub A, Harrison CN, McMullin MF, Vannucchi AM, Ewing J, O'Connell CL, Kiladjian JJ, Mead AJ, Winton EF, Leibowitz DS, De Stefano V, Arcasoy MO, Kessler CM, Catchatourian R, Rondelli D, Silver RT, Bacigalupo A, Nagler A, Kremyanskaya M, Levine MF, Arango Ossa JE, McGovern E, Sandy L, Salama ME, Najfeld V, Tripodi J, Farnoud N, Penson AV, Weinberg RS, Price L, Goldberg JD, Barbui T, Marchioli R, Tognoni G, Rampal RK, Mesa RA, Dueck AC, and Hoffman R
- Subjects
- Disease Progression, Humans, Hydroxyurea adverse effects, Interferon-alpha adverse effects, Polycythemia Vera drug therapy, Polycythemia Vera genetics, Thrombocythemia, Essential drug therapy, Thrombocythemia, Essential genetics, Thrombosis chemically induced, Thrombosis prevention & control
- Abstract
The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856., (© 2022 by The American Society of Hematology.)
- Published
- 2022
- Full Text
- View/download PDF
15. Development of factor IX inhibitor in an adult with severe haemophilia B following COVID-19 vaccination: A case report.
- Author
-
Chiasakul T and Kessler CM
- Subjects
- Adult, COVID-19 Vaccines adverse effects, Factor IX therapeutic use, Humans, Vaccination, COVID-19 prevention & control, Hemophilia A, Hemophilia B complications, Hemophilia B drug therapy
- Published
- 2022
- Full Text
- View/download PDF
16. GARDE: a standards-based clinical decision support platform for identifying population health management cohorts.
- Author
-
Bradshaw RL, Kawamoto K, Kaphingst KA, Kohlmann WK, Hess R, Flynn MC, Nanjo CJ, Warner PB, Shi J, Morgan K, Kimball K, Ranade-Kharkar P, Ginsburg O, Goodman M, Chambers R, Mann D, Narus SP, Gonzalez J, Loomis S, Chan P, Monahan R, Borsato EP, Shields DE, Martin DK, Kessler CM, and Del Fiol G
- Subjects
- Delivery of Health Care, Electronic Health Records, Humans, Information Storage and Retrieval, Decision Support Systems, Clinical, Population Health Management
- Abstract
Population health management (PHM) is an important approach to promote wellness and deliver health care to targeted individuals who meet criteria for preventive measures or treatment. A critical component for any PHM program is a data analytics platform that can target those eligible individuals., Objective: The aim of this study was to design and implement a scalable standards-based clinical decision support (CDS) approach to identify patient cohorts for PHM and maximize opportunities for multi-site dissemination., Materials and Methods: An architecture was established to support bidirectional data exchanges between heterogeneous electronic health record (EHR) data sources, PHM systems, and CDS components. HL7 Fast Healthcare Interoperability Resources and CDS Hooks were used to facilitate interoperability and dissemination. The approach was validated by deploying the platform at multiple sites to identify patients who meet the criteria for genetic evaluation of familial cancer., Results: The Genetic Cancer Risk Detector (GARDE) platform was created and is comprised of four components: (1) an open-source CDS Hooks server for computing patient eligibility for PHM cohorts, (2) an open-source Population Coordinator that processes GARDE requests and communicates results to a PHM system, (3) an EHR Patient Data Repository, and (4) EHR PHM Tools to manage patients and perform outreach functions. Site-specific deployments were performed on onsite virtual machines and cloud-based Amazon Web Services., Discussion: GARDE's component architecture establishes generalizable standards-based methods for computing PHM cohorts. Replicating deployments using one of the established deployment methods requires minimal local customization. Most of the deployment effort was related to obtaining site-specific information technology governance approvals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
17. Immune thrombocytopenia in the elderly: immunosenescent and clinical diversity.
- Author
-
Cunningham JM and Kessler CM
- Subjects
- Aged, Autoimmunity, Humans, Immunosenescence, Purpura, Thrombocytopenic, Idiopathic diagnosis, Thrombocytopenia
- Published
- 2022
- Full Text
- View/download PDF
18. New strategies for the treatment of immune thrombocytopenia.
- Author
-
Kessler CM
- Subjects
- Humans, Purpura, Thrombocytopenic, Idiopathic diagnosis, Purpura, Thrombocytopenic, Idiopathic drug therapy, Thrombocytopenia
- Published
- 2022
19. Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.
- Author
-
Goldenberg NA, Kittelson JM, Abshire TC, Bonaca M, Casella JF, Dale RA, Halperin JL, Hamblin F, Kessler CM, Manco-Johnson MJ, Sidonio RF, Spyropoulos AC, Steg PG, Turpie AGG, and Schulman S
- Subjects
- Adolescent, Age Factors, Anticoagulants adverse effects, Child, Child, Preschool, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Incidence, Infant, Infant, Newborn, Kaplan-Meier Estimate, Male, Recurrence, Therapeutics, Time Factors, Venous Thromboembolism etiology, Young Adult, Anticoagulants administration & dosage, Hemorrhage chemically induced, Venous Thromboembolism drug therapy
- Abstract
Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown., Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age., Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021., Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism., Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve)., Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively)., Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk., Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.
- Published
- 2022
- Full Text
- View/download PDF
20. First report of COVID-19 vaccine induced flare of compensated congenital thrombotic thrombocytopenic purpura.
- Author
-
Dykes KC and Kessler CM
- Subjects
- ADAMTS13 Protein, COVID-19 Vaccines, Humans, Plasma Exchange, SARS-CoV-2, COVID-19, Purpura, Thrombotic Thrombocytopenic therapy
- Published
- 2022
- Full Text
- View/download PDF
21. Recognition of thrombotic risk of thrombocytosis in iron deficiency
- Author
-
Al-Samkari H, Kessler CM, and Auerbach M
- Subjects
- Animals, Rats, Anemia, Iron-Deficiency complications, Anemia, Iron-Deficiency diagnosis, Anemia, Iron-Deficiency epidemiology, Thrombocytosis complications, Thrombocytosis diagnosis, Thrombocytosis epidemiology, Thrombosis epidemiology, Thrombosis etiology
- Published
- 2021
- Full Text
- View/download PDF
22. Highlights in COVID-19 from the 62nd American Society of Hematology Annual Meeting.
- Author
-
Kessler CM
- Subjects
- Anticoagulants therapeutic use, COVID-19 diagnosis, Hematology, Humans, Immunization, Passive, Neoplasms therapy, Platelet Aggregation Inhibitors therapeutic use, Risk Factors, SARS-CoV-2 isolation & purification, Severity of Illness Index, Societies, Medical, Treatment Outcome, Venous Thromboembolism drug therapy, COVID-19 Serotherapy, COVID-19 complications, COVID-19 therapy, Neoplasms complications, Venous Thromboembolism etiology
- Published
- 2021
23. Challenges and key lessons from the design and implementation of an international haemophilia registry supported by a pharmaceutical company.
- Author
-
Hay CRM, Shima M, Makris M, Jiménez-Yuste V, Oldenburg J, Fischer K, Iorio A, Skinner MW, Santagostino E, von Mackensen S, and Kessler CM
- Subjects
- Female, Humans, Male, Pharmaceutical Preparations, Registries, Hemophilia A epidemiology
- Abstract
Introduction: Real-world data are lacking regarding the relationship between prospectively collected patient-reported outcomes (PROs), clinical outcomes and treatment in people with haemophilia (PWH). The Expanding Communications on Hemophilia A Outcomes (ECHO) registry was designed to address this data gap, but a range of difficulties led to early study closure., Aim: To describe the challenges faced and lessons learned from implementing a multinational haemophilia registry., Methods: The Expanding Communications on Hemophilia A Outcomes was planned as a five-year observational cohort study to collect data from 2000 patients in nine countries. Based on direct observations, feedback from patients enrolled in ECHO, challenges of the study design and input from study-sponsor representatives, the ECHO Steering Committee systematically identified the challenges faced and developed recommendations for overcoming or avoiding them in future studies., Results: The study closed after two years because few countries were activated and patient recruitment was low. This was related to multiple challenges including delayed implementation, stringent pharmacovigilance requirements, objections of investigators and patients to the burden of multiple PROs, data collection issues, lack of resources at study sites, little engagement of patients and competing clinical trials, which further limited recruitment. At study closure, 269 patients had been enrolled in four of nine participating countries., Conclusions: Researchers planning studies similar to ECHO may want to consider the barriers identified in this global registry of PWH and suggestions to mitigate these limitations, such as greater patient involvement in design and analysis, clearer assessment and understanding of local infrastructure and potential changes to the administration of the study., (© 2020 John Wiley & Sons Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
24. Acquired Coagulopathy With Immune Checkpoint Inhibitors: An Underrecognized Association Between Inflammation and Coagulation.
- Author
-
Joseph JJ, Rajan A, Gulley JL, Ito S, and Kessler CM
- Abstract
Introduction: Immune-related adverse events affecting virtually every organ system have been described in individuals receiving immune checkpoint inhibitors. The spectrum of hematologic adverse effects is diverse and includes autoimmune cytopenias, hemolysis, or inhibition of coagulation factors. The interplay of inflammation and the coagulation cascade is complex, and immune checkpoint inhibitors can induce coagulopathy by disrupting the intricate link between these pathways., Methods: We report acquired coagulopathy in two patients treated with the programmed death-ligand 1 antibodies, atezolizumab and avelumab, respectively. Clinical findings and results of extensive laboratory workup are reported. We hypothesize that cytokine release is a potential pathologic mechanism responsible for acquired coagulopathy., Results: Symptoms included fever, fatigue, and disorientation in one patient and fever, myalgias, and skin rash in the other. Laboratory features included an abnormal coagulation profile; low fibrinogen levels; and elevated D-dimer, ferritin, and triglycerides. Treatment consisted of intravenous glucocorticoids in both cases and the use of fresh frozen plasma, cryoprecipitate, and clotting factor support in one patient., Conclusions: Recognition of acquired coagulopathy as a complication of immunotherapy and its aggressive management are crucial to reduce morbidity and mortality associated with this condition.
- Published
- 2020
- Full Text
- View/download PDF
25. Highlights in nonmalignant hematology from the 2019 American Society of Hematology meeting.
- Author
-
Kessler CM
- Subjects
- Congresses as Topic, Humans, United States, Hematologic Diseases, Hematology, Societies, Medical
- Published
- 2020
26. Re-personalization and stratification of hemophilia care in an evolving treatment landscape.
- Author
-
Hart DP, Kessler CM, and Aledort L
- Subjects
- Humans, Hemophilia A therapy, Precision Medicine methods
- Abstract
Hemophilia therapeutics are evolving rapidly. Comprehensive care must also evolve to embrace this change. Online tools and guidelines are widely available to optimize prophylaxis with conventional clotting factor concentrates using an individual's predicted pharmacokinetic profile. Novel hemostatic agents (e.g. biphenotypic antibody) are also becoming widely available, with other agents with differing mechanisms of action in final stages of trial. Contemporary issues including challenges of prophylaxis; bleed treatment; laboratory monitoring and inhibitor risk/surveillance are summarized in this narrative review, focusing on how a re-personalization of education and treatment will be necessary to meet these challenges of the rapidly changing therapeutic landscape.
- Published
- 2019
- Full Text
- View/download PDF
27. Clinical evaluation of bleeds and response to haemostatic treatment in patients with acquired haemophilia: A global expert consensus statement.
- Author
-
Tiede A, Giangrande P, Teitel J, Amano K, Benson G, Nemes L, Jiménez-Yuste V, d'Oiron R, Benchikh El Fegoun S, and Kessler CM
- Subjects
- Delphi Technique, Female, Hemostatics therapeutic use, Humans, Male, Surveys and Questionnaires, Treatment Outcome, Consensus, Expert Testimony, Hemophilia A complications, Hemorrhage complications, Hemorrhage drug therapy, Hemostatics pharmacology, Internationality
- Abstract
Background: Acquired haemophilia (AH) is a rare bleeding disorder with significant morbidity and mortality. Most patients initially present to physicians without experience of the disease, delaying diagnosis and potentially worsening outcomes. Existing guidance in AH is limited to clinical opinion of few experts and does not address monitoring bleeds in specific anatomical locations., Aim: Derive consensus from a large sample of experts around the world in monitoring bleeding patients with AH., Methods: Using the Delphi methodology, a structured survey, designed to derive consensus on how to monitor bleeding patients with AH, was developed by a steering committee for completion by a group of haematologists with an interest in AH. Consensus was defined as ≥75% agreement with a given survey statement. After three rounds of survey refinement, a final list of consensus statements was compiled., Results: Thirty-six global specialists in AH participated. The participants spanned 20 countries and had treated a median of 12.0 (range, 1-50) patients with AH within the preceding 5 years. Consensus was achieved in all items after three survey rounds. In addition to statements on general management of bleeding patients, consensus statements in the following areas were presented: urinary tract, gastrointestinal tract, muscles, skin, joints, nose, pharynx, mouth, intracranial and postpartum., Conclusions: Here, we present consensus statements derived from a broad sample of global specialists to address monitoring of location-specific bleeds and evaluating efficacy of bleeding treatment in patients with AH. These statements could be applied in practice by treating physicians and validated by individual population surveys., (© 2019 The Authors. Haemophilia published by John Wiley & Sons Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
28. Bleeding after treatment with rivaroxaban or apixaban.
- Author
-
Kessler CM
- Published
- 2019
29. A new strategy for uncontrollable bleeding after treatment with rivaroxaban or apixaban: Q&A.
- Author
-
Kessler CM and Goldstein JN
- Published
- 2019
30. Long-term risk of recurrence in patients with a first unprovoked venous thromboembolism managed according to d-dimer results; A cohort study.
- Author
-
Kearon C, Parpia S, Spencer FA, Schulman S, Stevens SM, Shah V, Bauer KA, Douketis JD, Lentz SR, Kessler CM, Connors JM, Ginsberg JS, Spadafora L, and Julian JA
- Subjects
- Adult, Aged, Biomarkers blood, Clinical Decision-Making, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Recurrence, Risk Assessment, Risk Factors, Sex Factors, Time Factors, Treatment Outcome, Venous Thromboembolism blood, Venous Thromboembolism diagnosis, Anticoagulants administration & dosage, Fibrin Fibrinogen Degradation Products analysis, Venous Thromboembolism drug therapy
- Abstract
Essentials Long-term recurrence risk after a first unprovoked VTE with negative d-dimer levels is uncertain. Anticoagulation was stopped if d-dimer was negative, and was continued if d-dimer was positive. Five years after stopping anticoagulants, recurrent VTE was 30% in men and 17% in women. Negative d-dimers do not justify stopping anticoagulants in most men but appear to in most women., Background: The long-term risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative d-dimer results is uncertain., Objectives: To determine this risk, including in subgroups based on sex., Patients and Methods: ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if d-dimer was negative on therapy and 1 month after stopping therapy. Other patients remained on anticoagulant therapy. We previously reported findings after a mean of 2.2 years. The current report includes 3 years of additional follow-up in 293 of these patients., Results: During a median follow-up of 5.0 years, recurrent VTE after stopping therapy in response to negative d-dimer testing was 5.1% (95% confidence interval [CI], 3.6-6.5) per patient-year overall, 7.5% (95% CI, 5.5-10.0) in men, 3.8% (95% CI, 2.0-6.6) in women with VTE not associated with estrogens, and 0.4% (95% CI, 0.0-2.3) in women with VTE associated with estrogens (P < 0.001 for three-group comparison). Risk of recurrence at 5 years was 21.5% (95% CI, 16.4-26.5) overall, 29.7% (95% CI, 22.1-37.3) in men, 17.0% (95% CI, 8.1-25.9) in non-estrogen women, and 2.3% (95% CI, 0.0-6.8) in estrogen women., Conclusion: The long-term risk of recurrence in patients with a first unprovoked VTE who have negative d-dimer results is not low enough to justify stopping anticoagulant therapy in men, but appears to be low enough in women for many to choose stopping therapy (ClinicalTrials.gov; NCT00720915)., (© 2019 International Society on Thrombosis and Haemostasis.)
- Published
- 2019
- Full Text
- View/download PDF
31. Efficacy and safety of simoctocog alfa (Nuwiq®) in patients with severe hemophilia A: a review of clinical trial data from the GENA program.
- Author
-
Lissitchkov T, Klukowska A, Pasi J, Kessler CM, Klamroth R, Liesner RJ, Belyanskaya L, Walter O, Knaub S, Bichler J, Jansen M, and Oldenburg J
- Abstract
Simoctocog alfa (human-cl rhFVIII, Nuwiq®) is a 4th generation recombinant FVIII (rFVIII), without chemical modification or fusion with any other protein/fragment. Nuwiq® is produced in a human embryonic kidney cell line (HEK293F), which ensures human-specific post-translational protein processing. Nuwiq® was evaluated in seven prospective clinical studies in 201 adult and pediatric previously treated patients (PTPs) with severe hemophilia A. The NuProtect study in 110 previously untreated patients (PUPs) is ongoing. The mean half-life of Nuwiq® was 15.1-17.1 h in PTP studies with adults and adolescents, and 12.5 h in children aged 2-12 years. Clinical trials in PTPs demonstrated the efficacy and safety of Nuwiq® in the prevention and treatment of bleeds and as surgical prophylaxis. In the NuPreviq study of pharmacokinetic (PK)-guided personalized prophylaxis in 66 adult PTPs, 83% of patients had no spontaneous bleeds during 6 months of personalized prophylaxis and 57% were treated ⩽2 per week. No FVIII inhibitors were detected in PTPs after treatment with 43,267 injections and >80 million IU of Nuwiq®. Interim data for 66 PUPs with ⩾20 exposure days to Nuwiq® in NuProtect demonstrated a low cumulative high-titer inhibitor rate of 12.8% [actual incidence 12.1% (8/66)] and convincing efficacy and safety., Competing Interests: Conflict of interest statement: T. Lissitchkov reports grants and/or personal fees from Bayer, Novo Nordisk, Octapharma, Shire and Swedish Orphan Biovitrum. A. Klukowska reports personal fees from Novo Nordisk, Octapharma, Pfizer, Shire and Swedish Orphan Biovitrum. J. Pasi reports grants, personal fees and/or nonfinancial support from Alnylam, Bayer, Biomarin, Bioverativ, Catalyst Bio, Novo Nordisk, Octapharma, Pfizer, Shire and Swedish Orphan Biovitrum. C. M. Kessler reports grants and personal fees from Baxalta, Bayer, Biogen, Grifols, Novo Nordisk, Octapharma, Pfizer and Roche. R. Klamroth reports grants and personal fees from Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Shire and Swedish Orphan Biovitrum. R. Liesner reports grants and personal fees from Baxalta, Bayer, Novo Nordisk, Octapharma, Roche and Swedish Orphan Biovitrum. J. Oldenburg has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Bayer, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire and Swedish Orphan Biovitrum. L. Belyanskaya, O. Walter, S. Knaub, J. Bichler and M. Jansen are employees of Octapharma.
- Published
- 2019
- Full Text
- View/download PDF
32. Bleeding and safety outcomes in persons with haemophilia A without inhibitors: Results from a prospective non-interventional study in a real-world setting.
- Author
-
Kruse-Jarres R, Oldenburg J, Santagostino E, Shima M, Kempton CL, Kessler CM, Lehle M, Chebon S, Selak Bienz N, Asikanius E, and Mahlangu J
- Subjects
- Adolescent, Adult, Aged, Child, Factor VIII adverse effects, Factor VIII pharmacokinetics, Gastrointestinal Hemorrhage etiology, Half-Life, Hemarthrosis etiology, Hemophilia A drug therapy, Humans, Male, Medication Adherence, Middle Aged, Prospective Studies, Respiratory Tract Infections etiology, Young Adult, Factor VIII therapeutic use, Hemophilia A diagnosis
- Abstract
Introduction: Prospectively collected real-world data on bleeds, haemophilia treatment and safety in persons with haemophilia A (PwHA) without factor VIII (FVIII) inhibitors are limited. A global, non-interventional study (NIS; NCT02476942) prospectively collected real-world data in PwHA who were treated per local routine clinical practice., Aim: Assess annualized bleeding rate (ABR), haemophilia treatment practices and adverse events (AEs) in adult/adolescent PwHA without inhibitors., Methods: Eligible participants aged ≥12 years with severe HA without history of inhibitors prospectively collected bleeding and treatment information., Results: Ninety-four participants were enrolled (median [range] age, 34 [12-76] years) and monitored for a median (range) of 29.8 (12.4-47.7) weeks. In the episodic (n = 45) and prophylactic (n = 49) treatment groups, respectively, 872/1066 (81.8%) and 151/189 (79.9%), bleeds were treated; ABRs (95% confidence interval) were 36.1 (30.8-42.3) and 5.0 (3.3-7.5), respectively, for treated bleeds and 43.1 (36.5-50.9) and 6.2 (4.2-9.2), respectively, for all bleeds, and median (interquartile range) ABRs were 31.1 (19.8-51.6) and 1.9 (0.0-8.2), respectively, for treated bleeds and 35.3 (21.7-62.9) and 2.7 (0.0-9.4), respectively, for all bleeds. Half of the participants on FVIII prophylaxis had relatively high adherence to treatment, using 2.9 and 2.1 median doses/wk of standard and extended half-life FVIII, respectively. Serious AEs included gastrointestinal polyp haemorrhage and haemarthrosis; the most common AE was viral upper respiratory tract infection., Conclusion: PwHA without inhibitors continue to bleed on prophylaxis, consistent with the literature, and require treatment for breakthrough bleeds. This prospective NIS demonstrates the need for more efficacious haemostatic approaches., (© 2019 John Wiley & Sons Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
33. Reliability and validity of patient-reported outcome instruments in US adults with hemophilia B and caregivers in the B-HERO-S study.
- Author
-
Buckner TW, Sidonio R Jr, Guelcher C, Kessler CM, Witkop M, Clark D, Owens W, Fridman M, Iyer NN, and Cooper DL
- Subjects
- Adult, Comorbidity, Female, Hemophilia B complications, Hemophilia B diagnosis, Humans, Male, Patient Reported Outcome Measures, Population Surveillance, United States epidemiology, Young Adult, Caregivers, Hemophilia B epidemiology, Quality of Life
- Abstract
Objective: To assess the reliability and validity of six patient-reported outcomes (PRO) instruments for evaluating health-related quality of life in adults with mild-severe hemophilia B and caregivers of children with hemophilia B, including affected women/girls., Methods: Adults with hemophilia B and caregivers completed separate online surveys containing several PRO instruments, which were administered to adult participants only (EQ-5D-5L, Brief Pain Inventory v2 Short Form, Hemophilia Activities List, and International Physical Activities Questionnaire), both adults and caregivers (Patient Health Questionnaire [PHQ-9]), or caregivers only (Generalized Anxiety Disorder 7-Item [GAD-7] scale). Construct validity and item-total correlation were assessed using Pearson product-moment correlation, internal consistency was assessed using Cronbach's alpha coefficient, and known-group validity was assessed by comparisons to self-reported characteristics based on the Kruskal-Wallis test., Results: Patient-reported outcomes instruments generally showed satisfactory reliability for adults (n = 299) and caregivers (n = 150). In adults, PRO instruments generally showed high construct validity. Most PRO instruments showed expected significant differences among known groups for adults and caregivers. PHQ-9 and GAD-7 did not show significant differences among caregiver age groups., Conclusions: Patient-reported outcomes instruments administered in B-HERO-S demonstrated reliability and validity in the broader population of adults with hemophilia B and caregivers when including all severities and genders., (© 2018 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
34. Treatment of Venous Thromboembolism in Elite Athletes: A Suggested Approach to Individualized Anticoagulation.
- Author
-
Nazha B, Pandya B, Spyropoulos AC, and Kessler CM
- Subjects
- Hemorrhage prevention & control, Heparin, Low-Molecular-Weight therapeutic use, Humans, Precision Medicine methods, Recurrence, Venous Thromboembolism physiopathology, Anticoagulants therapeutic use, Athletes, Blood Coagulation drug effects, Venous Thromboembolism drug therapy
- Abstract
Venous thromboembolism (VTE) is a leading cause of morbidity with potentially detrimental career consequences in elite athletes. Their unique predisposing factors entail a higher-than-expected VTE incidence. Anticoagulation treatment is challenging, especially among those athletes wishing to resume their competitive activities. The authors review the current VTE treatment guidelines from the perspective of treating elite athletes. They then provide an expert opinion individualized treatment approach based on the pharmacokinetic properties of direct oral anticoagulants that permits tailoring the drug's timing to the athlete's competitive endeavors. They also present low-molecular-weight heparin as an alternative. The proposed risk management approach allows mitigation against VTE recurrence, reducing the chance of major bleeding, and honoring the athlete's self-determination to resume their career while accepting the risks involved. A shared decision making with the athlete and his/her team along with the presence of adequate resources are key components. Ultimately, the authors hope this work will serve as a stepping stone to validated VTE treatment regimens that consider the particularities of elite athletes., Competing Interests: Dr. Alex Spyropoulos has served as a consultant for Daichi Sankyo, Boehringer Ingelheim, Janssen, Bayer, BMS, Pfizer, and Portola.Dr. Bassel Nazha, Dr. Bhavi Pandya, and Dr. Craig Kessler have no conflict of interests to declare., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)
- Published
- 2018
- Full Text
- View/download PDF
35. Methodologies for data collection in congenital haemophilia with inhibitors (CHwI): critical assessment of the literature and lessons learned from recombinant factor VIIa.
- Author
-
Kessler CM, Benchikh El Fegoun S, and Worster A
- Subjects
- Hemophilia A genetics, Hemophilia A physiopathology, Hemophilia B genetics, Hemophilia B physiopathology, Hemostasis drug effects, Humans, Recombinant Proteins immunology, Recombinant Proteins therapeutic use, Data Collection methods, Factor VIIa immunology, Factor VIIa therapeutic use, Hemophilia A drug therapy, Hemophilia A immunology, Hemophilia B drug therapy, Hemophilia B immunology
- Abstract
Aims: To systematically review the effectiveness of on-demand treatment with recombinant coagulation factor VIIa (rFVIIa) in congenital haemophilia with inhibitors and, if feasible, perform a meta-analysis of the data., Materials and Methods: Publications from Embase
® , MEDLINE® , MEDLINE® In-Process and the Cochrane Central Register of Controlled Trials were searched. Selected publications were reviewed for inclusion by two independent expert reviewers. Discrepancies were reconciled by a third independent reviewer. Data from selected studies were extracted using a predefined grid to ensure uniform and comparable results were captured., Results: A systematic search (cut-off date of 2 May 2016) identified 20 studies (13 observational; seven randomized controlled trials). All studies were of sufficient quality to include in this analysis and comprised 1221 participants, with 5981 bleeds in 746 individuals treated with rFVIIa. Haemostatic overall effectiveness of the individual studies identified ranged from 68% to 100% at ≤12 hours, 86% to 96% at 13-24 hours and 76% to 99% at 24-48 hours with rFVIIa <100 μg/kg, with similar rates reported for the ≥250 μg/kg dose. However, heterogeneity between the studies precluded pooling of results., Conclusions: Data from the individual studies confirmed that rFVIIa is an effective therapy for the on-demand treatment of bleeds in congenital haemophilia with inhibitors. However, the high levels of heterogeneity between studies precluded pooling of results for a valid, reliable or precise summary measure. There remains a need to implement standardized clinical definitions and measurements for the effectiveness and safety of haemophilia therapies in future clinical trials., (© 2018 John Wiley & Sons Ltd.)- Published
- 2018
- Full Text
- View/download PDF
36. A cross-sectional analysis of cardiovascular disease in the hemophilia population.
- Author
-
Sood SL, Cheng D, Ragni M, Kessler CM, Quon D, Shapiro AD, Key NS, Manco-Johnson MJ, Cuker A, Kempton C, Wang TF, Eyster ME, Kuriakose P, von Drygalski A, Gill JC, Wheeler A, Kouides P, Escobar MA, Leissinger C, Galdzicka S, Corson M, Watson C, and Konkle BA
- Subjects
- Aged, Cross-Sectional Studies, Female, Hemophilia A complications, Hemophilia B complications, Humans, Male, Middle Aged, Electrocardiography, Hemophilia A epidemiology, Hemophilia B epidemiology, Myocardial Infarction epidemiology, Myocardial Infarction etiology, Myocardial Infarction physiopathology, Stroke epidemiology, Stroke etiology, Stroke physiopathology
- Abstract
Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population., (© 2018 by The American Society of Hematology.)
- Published
- 2018
- Full Text
- View/download PDF
37. Impact of hemophilia B on quality of life in affected men, women, and caregivers-Assessment of patient-reported outcomes in the B-HERO-S study.
- Author
-
Buckner TW, Witkop M, Guelcher C, Sidonio R, Kessler CM, Clark DB, Owens W, Frick N, Iyer NN, and Cooper DL
- Subjects
- Adolescent, Adult, Aged, Anxiety, Caregivers, Depression, Female, Hemophilia B diagnosis, Hemophilia B psychology, Hemophilia B therapy, Humans, Male, Middle Aged, Patient Reported Outcome Measures, Severity of Illness Index, Young Adult, Hemophilia B epidemiology, Quality of Life
- Abstract
Introduction: Health-related quality of life (HRQoL) is impaired in patients with hemophilia; however, the impact in mild/moderate hemophilia B and affected women is not well characterized., Objective: To evaluate factors that affect HRQoL in adults with hemophilia B and caregivers of affected children., Methods: US adult patients and caregivers of affected children completed distinct ~1-hour online surveys including patient-reported outcome instruments., Results: In total, 299 adult patients and 150 caregivers participated. Adults with moderate hemophilia reported poorer health status (median EQ-5D-5L index score, 0.63) than those with mild (0.73) or severe (0.74) hemophilia. Women reported greater pain severity than men on the Brief Pain Inventory v2 Short Form (median, 7.00 vs 5.00). Based on the Patient Health Questionnaire, mild or worse depression was observed in >50% of adult respondents, and depression was reported more often in those with moderate and severe hemophilia vs those with mild hemophilia. Most caregivers reported at least mild depression., Conclusion: Pain, functional impairment, and depression/anxiety are present at higher-than-expected levels in individuals with hemophilia B. The large proportion of individuals with mild/moderate hemophilia and women with reduced health status suggests significant unmet needs in this population., (© 2018 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
38. Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism.
- Author
-
Kearon C, Parpia S, Spencer FA, Baglin T, Stevens SM, Bauer KA, Lentz SR, Kessler CM, Douketis JD, Moll S, Kaatz S, Schulman S, Connors JM, Ginsberg JS, Spadafora L, Bhagirath V, Liaw PC, Weitz JI, and Julian JA
- Subjects
- Adolescent, Adult, Aged, Autoantibodies immunology, Blood Coagulation, Blood Coagulation Tests, Female, Fibrin Fibrinogen Degradation Products, Humans, Immunoglobulin G immunology, Immunoglobulin M immunology, Male, Middle Aged, Risk Factors, Venous Thromboembolism blood, Venous Thromboembolism diagnosis, Young Adult, Antibodies, Antiphospholipid immunology, Venous Thromboembolism etiology
- Abstract
It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-β2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915., (© 2018 by The American Society of Hematology.)
- Published
- 2018
- Full Text
- View/download PDF
39. Lenalidomide as a novel therapy for gastrointestinal angiodysplasia in von Willebrand disease.
- Author
-
Khatri NV, Patel B, Kohli DR, Solomon SS, Bull-Henry K, and Kessler CM
- Subjects
- Aged, Angiodysplasia pathology, Angiogenesis Inhibitors pharmacology, Female, Humans, Lenalidomide, Male, Retrospective Studies, Thalidomide pharmacology, Thalidomide therapeutic use, Angiodysplasia drug therapy, Angiogenesis Inhibitors therapeutic use, Thalidomide analogs & derivatives, von Willebrand Diseases complications
- Abstract
Introduction: Lenalidomide is a thalidomide analog with anti-angiogenic properties. Previous case reports suggest its efficacy in preventing gastrointestinal bleeding (GIB) secondary to angiodysplasia (AD) in hereditary haemorrhagic telangiectasia and potentially in reversing AD. We present the first case series to explore lenalidomide as a treatment for AD-related GIB in patients with von Willebrand disease (VWD)., Methods: A retrospective chart review was conducted to include patients with VWD, who were evaluated from 2010 to 2013 and who had received lenalidomide to treat recurrent GIB secondary to AD. All patients had failed single-agent use of antifibrinolytic agents. Patients were observed for at least 2 years on therapy., Results: Five patients (3 males; 68.2 ± 4.9 years) with VWD (3 with type 3 and 1 each with types 1 and 2a) and AD were found. Sites of AD included the stomach, duodenum, jejunum and colon. Lenalidomide was started at 5 mg oral daily. Uptitration to 10 and 15 mg in 1 patient each was necessary due to recurrence of GIB. The mean number of endoscopies performed for control of GIB post lenalidomide was significantly lower compared to pretherapy (0.25 vs 5.50; P = .001). Mean bleed-free duration on lenalidomide was 12.6 ± 4.7 months. Three patients have reported no GIB on lenalidomide., Conclusion: This case series demonstrates significantly reduced number of endoscopies and increased bleed-free duration with lenalidomide treatment in selected patients with VWD and recurrent GIB from AD. Prospective multicenter trials are needed to further define the role of lenalidomide in the management of GIB from angiodysplasia and VWD., (© 2018 John Wiley & Sons Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
40. Efficacy and safety of Nuwiq ® (human-cl rhFVIII) in patients with severe haemophilia A undergoing surgical procedures.
- Author
-
Zozulya N, Kessler CM, Klukowska A, von Depka M, Hampton K, Hay CRM, Jansen M, Bichler J, Knaub S, and Rangarajan S
- Subjects
- Adult, Child, Child, Preschool, Factor VIII adverse effects, Hemophilia A pathology, Hemophilia A surgery, Humans, Male, Middle Aged, Perioperative Care, Postoperative Care, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Severity of Illness Index, Treatment Outcome, Factor VIII therapeutic use, Hemophilia A drug therapy
- Abstract
Introduction: Haemophilia A patients are at a high risk of excess bleeding during surgeries. The aim of haemostatic therapy during the perioperative period is to normalize FVIII level perioperatively and postoperatively to maintain normal haemostasis until wound healing is complete., Aims/methods: To examine the efficacy of Nuwiq
® (simoctocog alfa, human-cl rhFVIII), a 4th generation recombinant FVIII produced in a human cell line, for surgical prophylaxis in patients with severe haemophilia A. This analysis assessed the efficacy of Nuwiq® during surgical procedures and in the postoperative period in seven clinical studies of previously treated patients (PTPs) with severe haemophilia A., Results: Thirty-six patients, aged 3-55 years, received surgical prophylaxis with Nuwiq® for 60 surgeries (28 major and 32 minor). Efficacy was evaluated for 52 surgeries (25 major and 27 minor). The success rate of Nuwiq® treatment was 98.1% (51 of 52 evaluated surgeries); haemostatic efficacy was assessed as "excellent" or "good" in all but one major surgery (assessed as "moderate"). The number of infusions ranged from 1 to 19 for minor surgeries and from 3 to 76 for major surgeries. The median (range) daily doses were 42.0 (28.2-100.9) IU kg-1 for minor surgeries and 69.3 (43.3-135.6) IU kg-1 for major surgeries. There were no serious treatment-related adverse events, and none of the patients developed FVIII inhibitors., Conclusions: The results of this pooled analysis show that Nuwiq® was efficacious in maintaining haemostasis during and after major and minor surgical procedures in PTPs with severe haemophilia A., (© 2017 John Wiley & Sons Ltd.)- Published
- 2018
- Full Text
- View/download PDF
41. Acquired haemophilia in cancer: A systematic and critical literature review.
- Author
-
Napolitano M, Siragusa S, Mancuso S, and Kessler CM
- Subjects
- Adrenal Cortex Hormones therapeutic use, Antineoplastic Agents therapeutic use, Blood Coagulation Factor Inhibitors blood, Blood Coagulation Factors therapeutic use, Factor VIIa therapeutic use, Hematologic Neoplasms complications, Hematologic Neoplasms drug therapy, Hemophilia A drug therapy, Humans, Neoplasms complications, Neoplasms drug therapy, Recombinant Proteins therapeutic use, Treatment Outcome, Hematologic Neoplasms diagnosis, Hemophilia A etiology, Neoplasms diagnosis
- Abstract
Aim: There is a paucity of data on the clinical presentation and management of cancer patients with acquired haemophilia (AH), we here report a systematic literature review on acquired haemophilia in the context of cancer., Methods: Treatment outcomes of AH were defined as complete response (CR), partial response (PR) or no response (NR), based on inhibitor eradication, coagulation factor VIII levels and bleeding control. Reported deaths were either related to cancer or bleeding., Results: Overall, 105 cases were collected and analyzed according to classification of cancer and efficacy of treatments for inhibitor and malignancy. The mean age was 68 years for both males (range 37-86 years) and females (range 43-89 years), 39 patients were female subjects and 66 were males. A solid cancer was diagnosed in 60 subjects, while 45 patients suffered a haematological malignancy. Solid cancers affected mainly males; however, the incidence of solid tumours vs haematological malignancies was not statistically significant (P = .09). Not all patients were treated for their underlying cancer, bleeding and/or inhibitor, in two cases outcome is unavailable. CR was reported in 62.1% (64/103) cases, PR in 9.7% (10/103) cases, NR with or without death was reported in 28.1% (29/103) cases., Conclusion: CR was best achieved when successful and complete elimination of autoantibodies occurred contemporaneously with the successful treatment of the underlying malignancy. In some cases, recurrent autoantibodies were harbingers of relapsed cancer. Type of cancer, inhibitor titer, treatments administered for bleeding control and inhibitor eradication did not significantly affect clinical outcome of analyzed cases., (© 2017 John Wiley & Sons Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
42. Feasibility of the Von Willebrand disease PREVENT trial.
- Author
-
Ragni MV, Machin N, James AH, Seaman CD, Malec LM, Kessler CM, Konkle BA, Kouides PA, Neff AT, Philipp CS, and Brooks MM
- Subjects
- Adult, Feasibility Studies, Female, Humans, Pregnancy, Retrospective Studies, von Willebrand Diseases complications, Postpartum Hemorrhage etiology, von Willebrand Diseases blood
- Abstract
Background: Despite treatment, women with von Willebrand disease (VWD) have lower von Willebrand factor (VWF) levels and greater blood loss at delivery than controls. Current weight-based dosing does not account for the ~1.5-fold increase in blood volume in pregnancy., Methods: To evaluate the feasibility of a trial to prevent postpartum hemorrhage (PPH), we reviewed pre-pregnancy and 8th month VWF levels in women with VWD with and without PPH following vaginal delivery, assessed VWF concentrate use at delivery by U.S. hemophilia treatment center physician survey, and reviewed thrombosis risk with VWF concentrate by literature review. We determined trial interest and acceptability by structured interviews of physicians and patients. Analysis was by Student's t-test for continuous data, and chi-square or Fisher's exact test for discrete data., Results: PPH was associated with lower pre-pregnancy VWF:RCo, p<0.005; higher pre-pregnancy, 8th and 9th-month weight, each p<0.001; a family bleeding history, p=0.036; and VWF concentrate treatment, p=0.005. Surveyed physicians reported first-line therapy at delivery was VWF concentrate, at a mean dose 50IU/kg. A trial of a 1.5-fold volume-based dose increase was acceptable to physicians and patients, if it is safe and if costs and visits are minimized. A literature review determined thrombosis risk with VWF concentrate is low, 0.4%., Conclusions: This study suggests pre-pregnancy VWF:RCo may predict PPH, but 50-80IU/kg VWF concentrate dosing may not prevent PPH. If pharmacokinetic modeling confirms volume-based dosing achieves VWF levels comparable to pregnant controls, it may be possible to determine if volume-modified VWF concentrate dosing will reduce PPH in VWD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
43. Pinpointing clinical phenotypes - Is there evidence to support the use of a simple scoring system to define a milder bleeding phenotype in severe haemophilia A?
- Author
-
Humphries TJ, Mathew P, and Kessler CM
- Subjects
- Adult, Hemorrhage diagnosis, Humans, Hemophilia A complications, Hemorrhage complications, Phenotype, Severity of Illness Index
- Published
- 2017
- Full Text
- View/download PDF
44. Self-reported prevalence, description and management of pain in adults with haemophilia: methods, demographics and results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.
- Author
-
Witkop M, Neff A, Buckner TW, Wang M, Batt K, Kessler CM, Quon D, Boggio L, Recht M, Baumann K, Gut RZ, Cooper DL, and Kempton CL
- Subjects
- Adult, Female, Hemophilia A complications, Humans, Male, Middle Aged, Prevalence, Hemophilia A epidemiology, Hemophilia A physiopathology, Pain complications, Pain Management statistics & numerical data, Quality of Life, Self Report
- Abstract
Introduction: Haemophilia is characterized by frequent haemarthrosis, leading to acute/chronic joint pain., Aim: To assess self-reported prevalence, description and management of pain in adult males with mild-to-severe haemophilia and history of joint pain/bleeding., Methods: Participants completed a pain survey and five patient-reported outcome instruments assessing pain, functional impairment and health-related quality of life (HRQoL)., Results: Of 381 participants enrolled, median age was 34 years; 77% had haemophilia A, 71% had severe disease and 65% were overweight/obese. Many (56%) were not receiving routine infusions; 30% never received routine infusions. During the prior 6 months, 20% experienced acute pain, 34% chronic pain and 32% both acute/chronic pain. Subjects with both acute/chronic pain (vs. none, acute or chronic) were more likely to be depressed (30% vs. 0-15%), obese (35% vs. 20-29%) and have lower HRQoL (mean EQ-5D visual analog scale, 69 vs. 83-86) and function (median overall Hemophilia Activities List, 60 vs. 88-99). Most common analgesics used for acute/chronic pain during the prior 6 months were acetaminophen (62%/55%) and non-steroidal anti-inflammatory drugs (34%/49%); most common non-pharmacologic strategies were ice (65%/33%) and rest (51%/33%). Hydrocodone-acetaminophen was the most common opioid for both acute/chronic pain (30%); other long-acting opioids were infrequently used specifically for chronic but not acute pain (morphine, 7%; methadone, 6%; fentanyl patch, 2%)., Conclusion: Patients with chronic pain, particularly those with both acute/chronic pain, frequently experience psychological issues, functional disability and reduced HRQoL. Treatment strategies for acute pain (e.g. routine infusions to prevent bleeding) and for chronic pain (e.g. long-acting opioids) may be underused., (© 2017 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
45. Acquired hemophilia A: Updated review of evidence and treatment guidance.
- Author
-
Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, and Kessler CM
- Subjects
- Combined Modality Therapy, Diagnosis, Differential, Disease Management, Female, Hemophilia A epidemiology, Hemophilia A etiology, Hemorrhage etiology, Hemorrhage prevention & control, Hemorrhage therapy, Humans, Isoantibodies immunology, Male, Mortality, Phenotype, Pregnancy, Hemophilia A diagnosis, Hemophilia A therapy
- Abstract
Acquired hemophilia A (AHA) is a rare disease resulting from autoantibodies (inhibitors) against endogenous factor VIII (FVIII) that leads to bleeding, which is often spontaneous and severe. AHA tends to occur in elderly patients with comorbidities and is associated with high mortality risk from underlying comorbidities, bleeding, or treatment complications. Treatment, which consists of hemostatic management and eradication of the inhibitors, can be challenging to manage. Few data are available to guide the management of AHA-related bleeding and eradication of the disease-causing antibodies. Endorsed by the Hemostasis and Thrombosis Research Society of North America, an international panel of experts in AHA analyzed key questions, reviewed the literature, weighed the evidence and formed a consensus to update existing guidelines. AHA is likely underdiagnosed and misdiagnosed in real-world clinical practice. Recommendations for the management of AHA are summarized here based on the available data, integrated with the clinical experience of panel participants., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
46. SIPPET trial: the answers.
- Author
-
Makris M and Kessler CM
- Subjects
- Hemophilia A blood, Humans, Clinical Trials as Topic, Hemophilia A drug therapy
- Published
- 2017
- Full Text
- View/download PDF
47. Management of US men, women, and children with hemophilia and methods and demographics of the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.
- Author
-
Buckner TW, Witkop M, Guelcher C, Frey MJ, Hunter S, Peltier S, Recht M, Walsh C, Kessler CM, Owens W, Clark DB, Frick N, Rice M, Iyer NN, Holot N, Cooper DL, and Sidonio R Jr
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cross-Sectional Studies, Female, Humans, Male, Sex Factors, United States epidemiology, Delivery of Health Care, Hemophilia B epidemiology, Hemophilia B physiopathology, Hemophilia B psychology, Hemophilia B therapy, Hemorrhage epidemiology, Hemorrhage physiopathology, Hemorrhage psychology, Hemorrhage therapy, Patient Education as Topic, Severity of Illness Index, Surveys and Questionnaires
- Abstract
The Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) initiative was launched in an effort to address specific gaps in the understanding of the psychosocial impact of mild-moderate-severe hemophilia B. The original Hemophilia Experiences, Results and Opportunities (HERO) qualitative study evaluated the needs of people with hemophilia A or B in multiple countries; however, a majority of participants had the more common moderate-severe hemophilia A. The B-HERO-S study was designed in collaboration with the hemophilia community to evaluate the needs of adults with hemophilia B and caregivers of children with hemophilia B, including affected women and caregivers of girls with hemophilia. The report presented here describes participant demographics and comorbidities, as well as treatment regimens and access to treatment. Bleeding symptoms were reported by 27% of mothers of children with hemophilia B who participated. Women were more likely than men to self-report arthritis and depression/anxiety as comorbidities associated with hemophilia B. More adults and children with hemophilia B were on routine treatment than on on-demand treatment, and a high percentage of adults with moderate hemophilia B received routine treatment (86%). Many adults with hemophilia B (78%) and caregivers (69%) expressed concern about access to factor in the next 5 years, and of adults with hemophilia B, women more commonly experienced issues with access to factor in the past than did men (72% vs 44%). The findings of the B-HERO-S study reveal potential unmet needs of some patients with mild-moderate hemophilia B, and the results may be leveraged to inform patient outreach by hemophilia treatment centers and education initiatives., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
48. Efficacy and safety of a VWF/FVIII concentrate (wilate ® ) in inherited von Willebrand disease patients undergoing surgical procedures.
- Author
-
Srivastava A, Serban M, Werner S, Schwartz BA, and Kessler CM
- Subjects
- Adolescent, Adult, Aged, Child, Factor VIII administration & dosage, Factor VIII pharmacokinetics, Female, Humans, Male, Middle Aged, Prospective Studies, Treatment Outcome, Young Adult, von Willebrand Diseases drug therapy, Factor VIII therapeutic use, von Willebrand Diseases surgery
- Abstract
Introduction: Surgical procedures in von Willebrand disease (VWD) patients may require prophylactic treatment with exogenous von Willebrand factor (VWF) and coagulation factor VIII (FVIII) to prevent excessive bleeding. Wilate
® is a plasma-derived, double virus-inactivated, highly purified, freeze-dried VWF/FVIII concentrate, containing both factors in a physiological activity ratio of 1:1., Aim: To investigate the efficacy and safety of wilate® in maintaining haemostasis in VWD patients undergoing surgical procedures., Methods: This prospective, open-label multinational clinical study documents 28 individuals who underwent 30 surgical procedures managed with wilate® . Twenty-one patients had VWD Type 3, and 21 surgeries were major. Efficacy was assessed intra- and postoperatively by the surgeon and investigator, respectively, and adjudicated by an Independent Data Monitoring Committee, using an objective scale based on blood loss, transfusion requirements and postoperative bleeding and oozing. Treatment success (primary endpoint) was determined using a composite assessment algorithm and was formally assessed., Results: Surgical prophylaxis with wilate® was successful in 29 of 30 procedures. The overall rate of success was 96.7% (98.75% CI: 0.784, 1.000). All 21 surgeries in patients with VWD Type 3 were managed successfully. There was no accumulation of VWF or FVIII after multiple dosing, and no thromboembolic events or inhibitors to VWF or FVIII were observed., Conclusions: Wilate® demonstrated effective prevention and treatment of bleeding in inherited VWD patients undergoing surgery, with no clinically significant safety concerns., (© 2016 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)- Published
- 2017
- Full Text
- View/download PDF
49. Pilot randomized, non-inferiority, cross-over trial of once-weekly vs. three times-weekly recombinant factor VIII prophylaxis in adults with severe haemophilia A.
- Author
-
Ragni MV, Yabes JG, Fogarty PF, Josephson NC, Kessler CM, Neff AT, Raffini L, Brummel-Ziedins K, and Moore CG
- Subjects
- Cross-Over Studies, Humans, Male, Pilot Projects, Factor VIII therapeutic use, Hemophilia A drug therapy
- Abstract
Competing Interests: of Conflict of Interest: MVR has received research funding from Alnylam, Baxalta, Biogen, CSL Behring, Dimensions, Genentech/Roche, Pfizer, Shire, SPARK; and honoraria for consulting for Alnylam, Baxalta, Biogen, Biomarin, and Tacere Benitec. PFF has received research funding from Baxter, Bayer, Biogen, CSL Behring, Pfizer; and SPARK Therapeutics; and advisory board fees from Bayer, Baxter/Baxalta, Biogen, Chugai, CSL Behring, Novo Nordisk, and Pfizer; and is an employee of Pfizer. CMK has received research funding from Bayer, NovoNordisk, Octapharma, Roche, and Shire; and acted as a paid consultant for Bayer, Biogen, Grifols, Octapharma, Pfizer, Roche Shire. ATN has received fees as a member of an advisory board for Shire. NCJ, LR, JGY, KBZ, and CGM declare no competing interests.
- Published
- 2017
- Full Text
- View/download PDF
50. Use of recombinant activated factor VII for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society Registry acquired hemophilia study.
- Author
-
Ma AD, Kessler CM, Al-Mondhiry HA, Gut RZ, and Cooper DL
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Hemophilia A, Humans, Male, Middle Aged, Registries, Young Adult, Factor VIIa therapeutic use, Hemostasis genetics, Thrombosis genetics
- Abstract
The Hemostasis and Thrombosis Research Society Registry was used to monitor the postapproval use and safety of recombinant activated factor VII (rFVIIa). The objective of this article is to evaluate the data from the Hemostasis and Thrombosis Research Society Registry related to rFVIIa-treated bleeding episodes in patients with acquired hemophilia. For each rFVIIa-treated bleeding episode, the initial dose, total dose, average infused dose, number of doses, and treatment duration were calculated. Efficacy was assessed on a three-point scale. Out of the 166 registered patients with acquired hemophilia, 110 patients were treated for 237 bleeding episodes (139 rFVIIa treated); the majority (70%) were in patients older than 60 years. The most frequently reported bleeding locations were subcutaneous (40%) and mucosal (32%). Subcutaneous bleeding episodes were more commonly reported in women (55% vs. 40% men) and white patients (44 vs. 27% black). Of the 139 rFVIIa-treated bleeding episodes, rFVIIa was used as first-line treatment in 127 bleeding episodes. The median initial dose was 90 μg/kg; the median total dose per episode was 333.5 μg/kg. Physician-rated efficacy of rFVIIa for each bleeding episode was reported as 'bleeding stopped' in 85% of bleeding episodes, 'bleeding slowed' in 11% of bleeding episodes, 'no improvement' in 4% of bleeding episodes, and was not documented in 1 bleeding episode. One thromboembolic event was reported; transient neurologic symptoms were reported in a 31-year-old postpartum patient after 110 doses of rFVIIa. Adequate hemostasis was provided for most rFVIIa-treated bleeding episodes at doses largely conforming to the package insert. No major safety concerns were reported.
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.