Dual platelet inhibition is commonly used for prevention of cardiovascular events in patients undergoing neuroendovascular procedures. Non-responsiveness to platelet inhibitors may be associated with ...adverse outcomes. The aim of this study was to evaluate the reliability of the platelet function analyzer PFA-100® in comparison to light transmittance aggregometry (LTA) for monitoring clopidogrel and acetylsalicylic acid (ASA) non-responsiveness in a cohort of patients treated for intracranial aneurysm or cranial artery stenosis.
Non-responsiveness to clopidogrel and ASA was assessed by LTA using adenosine diphosphate (ADP) and arachidonic acid and by PFA-100® with the ADP/prostaglandin E1 (PGE1) and collagen/epinephrine cartridges, respectively.
A total of 203 patients (145 females; median age, 57 years) were analyzed. Agreement between the two tests was poor for clopidogrel non-responsiveness (ƙ=0.19) and not better than chance for ASA non-responsiveness (ƙ=0.01). Clopidogrel non-responsiveness by LTA and PFA-100® was associated with higher von Willebrand factor antigen and activity levels. ADP-induced platelet disaggregation was lower in patients with clopidogrel non-responsiveness as assessed by PFA-100®. Clopidogrel non-responsiveness by LTA was associated with a higher prevalence of diabetes and a higher body mass index (BMI). Adverse outcomes (death, thromboembolism, or in-stent thrombosis) occurred in 13% (n=26) of all patients independently of ASA and clopidogrel non-responsiveness as assessed by both devices.
Our results show that LTA and PFA-100® are not interchangeable in the assessment of ASA and clopidogrel non-responsiveness in patients undergoing neuroendovascular interventions.
Abstract
Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and ...Emicizumab, the ‘Ständige Kommission Hämophilie’ of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the ‘Ständige Kommission Hämophilie’ and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary.
Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of ...hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centers according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as a primary source of data for pharmacovigilance, postmarketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization.
Hemophilia A is an X-linked, recessive bleeding disorder caused by congenital factor VIII (FVIII) deficiency. Although the bleeding tendency largely depends on residual FVIII activity (FVIII:C), ...there is tremendous heterogeneity in bleeding frequency and severity among individuals with similar FVIII:C plasma levels. It is therefore likely that additional factors modulate thrombin generation and fibrin deposition in patients with hemophilia A. PDI is an abundant oxidoreductase with chaperone activity that is also present in human platelets and released upon activation. Preclinical studies indicate that extracellular PDI is critical to hemostasis, thrombosis and vascular inflammation. In particular, PDI has been implicated in monocyte/macrophage tissue factor activation, integrin regulation and platelet-associated thrombin generation. Furthermore, impaired PDI release has most recently been shown to contribute to the bleeding tendency of Hermansky-Pudlak syndrome, an inherited platelet function defect. To explore the role of platelet PDI in hemophilia A, we studied 24 patients (15 severely, 5 moderately and 4 mildly affected) in comparison to 12 age- and sex-matched controls. Expression of PDI antigen on resting platelets and platelets stimulated with either 20 µM ADP or 50 µM thrombin receptor activator peptide 6 (TRAP-6) was assessed by flow cytometry using a fluorescently labeled monoclonal antibody. Analysis of CD41 and CD62P (P-selectin) served as positive controls for constitutive platelet antigen expression and α-granule secretion, respectively. In addition, release of soluble PDI antigen into platelet supernatants was measured by ELISA. There was no significant difference in baseline CD41, CD62P and PDI antigen expression between patients and controls. Furthermore, ADP- and TRAP-6-induced CD62P expression was similar between the two groups (percent positive platelets in patients vs. controls: 28±14 vs. 32±15% and 80±12 vs. 83±9% for ADP- and TRAP-6-treated platelets, respectively). However, expression of PDI antigen on platelets stimulated with either ADP (3.3±2.1 vs. 1.5±1.2%, P<0.01) or TRAP-6 (3.4±1.7 vs. 2.1±1.3%, P<0.05) was significantly increased in patients compared to controls. While ADP-induced release of PDI antigen into platelet supernatants was similar between the two groups and not significantly different from baseline, stimulation with TRAP-6 resulted in significantly increased PDI antigen levels in platelet releasates from patients vs. controls (median, range): 1.5, 0.2-23.2 ng/mL vs. 0.4, 0.2-1.9 ng/mL (P<0.01). Importantly, in two patients with exceedingly high TRAP-6-induced PDI release over baseline (4.8 vs. 0.3 ng/mL and 23.2 vs. 2.8 ng/mL), findings were consistent when platelets were isolated and stimulated on a separate occasion (5.5 vs. 1.3 ng/mL and 10.2 vs. 0.2 ng/mL). Taken together, agonist-induced platelet PDI expression was significantly increased in patients with congenital hemophilia A. Furthermore, release of PDI antigen into supernatants of TRAP-6-activated platelets was significantly increased in patients compared to healthy controls. Up-regulation of platelet PDI may thus represent a compensatory mechanism under conditions of defective thrombin generation and fibrin deposition, and variations in platelet PDI expression and release could at least partially explain the heterogeneity in bleeding severity among patients with congenital hemophilia A and similar FVIII:C plasma levels.
Langer:Baxalta: Consultancy, Other: Travel support; Pfizer: Research Funding; CSL Behring: Consultancy, Other: Travel support, Research Funding. Voigtländer:CSL Behring: Other: Travel support. Holstein:CSL Behring: Consultancy, Other: Travel support, Research Funding.
Background: Acquired hemophilia A (AHA) is a serious bleeding disorder characterized by the formation of autoantibodies against coagulation factor VIII (FVIII). The condition differs from congenital ...hemophilia A by its strikingly different bleeding phenotype. Also in contrast to congenital hemophilia, the patient's baseline FVIII activity does not seem to correlate with the risk of bleeding as demonstrated in previous registries. The objective of the current study was to reassess the effect of FVIII activity on the risk of bleeding in AHA.
Methods: GTH-AH 01/2010 was a prospective non-interventional study of 102 patients with AHA performed in 29 centers in Germany and Austria. FVIII activity was measured at study baseline and weekly thereafter by local laboratories. FVIII activity was categorized into 5 clinically meaningful intervals: <1%, 1-<5%, 5-<20%, 20-<50%, and ≥50%. Bleeding events were assessed by treating physicians.
Results: A total of 289 bleeds were recorded. 141 bleeds occurred after first diagnosis of AHA; 130 (92%) of those occurred in the first 12 weeks after diagnosis, during an observation period of 1069 patient-weeks. The estimated mean bleeding rate was 0.12 bleeds per patient-week, from weeks 1 to 12 after diagnosis of AHA. Bleeding rate strongly declined with increasing time after diagnosis. A multivariate regression model demonstrated significant effects of the current (weekly) FVIII activity on the weekly bleeding rate (figure), with a clear reduction in bleeding seen when FVIII activity recovered to 20% or higher. Achieving partial remission of AHA (FVIII ≥50%) virtually eliminated the risk of bleeding. A good WHO performance status was also associated with a significantly lower risk of bleeding. Other baseline characteristics, including underlying disorder, concomitant coronary artery disease, heart or renal failure or diabetes mellitus did not influence bleeding rate in the multivariate model. Patients with an average FVIII activity of <1% during weeks 1 to 4 received significantly higher cumulative dose of recombinant factor VIIa (rFVIIa) during this time, potentially explaining that the bleeding rate in those patients was not higher than in patients with a FVIII activity of 1-<5% or 5-<20%.
Conclusion: This study is the first to systematically assess the risk of bleeding during the course of AHA. About 50% of the bleeds in AHA occur after first diagnosis, with a rate of about 0.12 bleeds per patient-week in the first 12 weeks. The bleeding rate is influenced by the current FVIII activity as assessed weekly during this study. Patients with FVIII <1% received more rFVIIa, potentially reducing their bleeding rate as compared to other patients. These results will help to define future strategies for prophylaxis of bleeding in AHA.
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Holstein:Novo Nordisk: Consultancy, Research Funding; Shire: Research Funding. Knöbl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Dobbelstein:Novo Nordisk: Research Funding; Shire: Research Funding. Spannagl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Heinz:Novo Nordisk: Research Funding; Shire: Research Funding. Scholz:Novo Nordisk: Research Funding; Shire: Research Funding. Eichler:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding. Huth-Kühne:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Klamroth:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Tiede:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding.
Abstract
Background
Currently available coronavirus disease 2019 (COVID-19) vaccines are approved for intramuscular injection and efficacy may not be ensured when given subcutaneously. For years, ...subcutaneous vaccination was recommended in patients with hemophilia to avoid intramuscular bleeds. Therefore, recommendations for the application of COVID-19 vaccines are needed.
Methods
The Delphi methodology was used to develop consensus recommendations. An initial list of recommendations was prepared by a steering committee and evaluated by 39 hemophilia experts. Consensus was defined as ≥75% agreement and strong consensus as ≥95% agreement, and agreement as a score ≥7 on a scale of 1 to 9. After four rounds, a final list of statements was compiled.
Recommendations
Consensus was achieved that COVID-19 vaccines licensed only for intramuscular injection should be administered intramuscularly in hemophilia patients. Prophylactic factor replacement, given on the day of vaccination with a maximum interval between prophylaxis and vaccination of 24 hours (factor VIII and conventional factor IX concentrates) or 48 hours (half-life extended factor IX), should be provided in patients with moderate or severe hemophilia. Strong consensus was achieved that patients with mild hemophilia and residual factor activity greater than 10% with mild bleeding phenotype or patients on emicizumab usually do not need factor replacement before vaccination. Swelling, erythema, and hyperthermia after vaccination are not always signs of bleeding but should prompt consultation of a hemophilia care center. In case of injection-site hematoma, patients should receive replacement therapy until symptoms disappear.
Conclusions
Consensus was achieved on recommendations for intramuscular COVID-19 vaccination after replacement therapy for hemophilia patients depending on disease severity.
Introduction
The sixth Åland Islands Conference on von Willebrand disease (VWD) on the Åland Islands, Finland, was held from 20 to 22 September 2018.
Aim
The meeting brought together experts in the ...field of VWD from around the world to share the latest advances and knowledge in VWD.
Results and discussion
The topics covered both clinical aspects of disease management, and biochemical and laboratory insights into the disease. The clinical topics discussed included epidemiology, diagnosis and treatment of VWD in different countries, management of children with VWD, bleeding control during surgery, specific considerations for the management of type 3 VWD and bleeding control in women with VWD. Current approaches to the management of acquired von Willebrand syndrome were also discussed. Despite significant advances in the understanding and therapeutic options for VWD, there remain many challenges to be overcome in order to optimise patient care. In comparison with haemophilia A, there are very few registries of VWD patients, which would be a valuable source of data on the condition and its management. VWD is still underdiagnosed, and many patients suffer recurrent or severe bleeding that could be prevented. Awareness of VWD among healthcare practitioners, including non‐haematologists, should be improved to allow timely diagnosis and intervention. Diagnosis remains challenging, and the development of fast, simple assays may help to facilitate accurate and rapid diagnosis of VWD.
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