Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH).

Gene therapy has recently become a realistic treatment perspective for patients with haemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of haemophilia A and B gene therapy with vectors derived from adeno-associated virus (AAV), 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 centres 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 primary source of data for pharmacovigilance, post-marketing 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

Perioperative management for patients with von Willebrand disease: Defining the optimal approach

von Willebrand disease (VWD) is the most common inherited bleeding disorder characterised by a quantitative or qualitative deficiency in von Willebrand factor (VWF). During invasive surgical procedures, patients with VWD require additional treatment to maintain haemostasis; however, due to the complexity of VWD, there is a lack of consensus on the optimal management. In the perioperative period, patients are usually treated with VWF and factor FVIII (FVIII)‐containing concentrates to provide an immediate haemostatic response to prevent excessive bleeding during both elective and emergency surgery. With the introduction of recombinant VWF (rVWF), there is a need for guidance on the use of the various VWF products in the perioperative period for all types of patients and surgeries. This review provides an overview of the current evidence for the surgical management of patients with VWD and, summarises the optimal treatment approach during the perioperative period, and highlights key unanswered questions and the research needed to address the evidence gaps

When von Willebrand disease comes into age - A matter of change?

The population of elderly patients with von Willebrand Disease (VWD) is growing due to the improvement of medical care. The increase of co-morbidities and their treatment as well as standard preventive measures like anti-platelet or anticoagulation therapy constitute a challenge in the overall treatment of patients with coagulation disorders. Due to the lack of literature on older VWD patients, we discuss different aspects related to ageing in those patients. Plasma levels of von Willebrand factor (VWF) and factor VIII (FVIII), bleeding symptoms, treatment requirements and co-morbidities are possibly changing with age. Development of an evidence-based approach to the management of ageing VWD patients is therefore necessary

Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues

In the last decade, enormous progress has been made in the development of gene therapy for hemophilia A and B. After the first encouraging results of intravenously administered adeno-associated virus (AAV)-based liver-directed gene therapy in patients with severe hemophilia B were reported in 2011, many gene therapy studies have been initiated. Most of these studies, using AAV vectors with various gene constructs, showed sufficient factor VIII and IX expression in patients to significantly reduce the number of bleeds and the need for prophylaxis in most patients with severe hemophilia. This resulted in great clinical benefit for nearly all patients. In this review, we will summarize the most recent findings of reported and ongoing gene therapy trials. We will highlight the successful outcome of trials with focus on the results of recently reported phase 1 trials and preliminary results of phase 2b/3 trials for hemophilia A and B. These new reports also reveal the impact of side effects and drawbacks associated with gene therapy. We will therefore also discuss the limitations and remaining issues of the current gene therapy approaches. These issues must be resolved before gene therapy will be widely available for the hemophilia patient population

Long-Term Remission of Acquired Von-Willebrand's Disease and Platelet Dysfunction after High-Dose Melphalan in a Patient with Multiple Myeloma

Background: Autologous stem cell transplantation is considered a standard of care treatment in eligible patients with multiple myeloma, but puts the patient at high risk for infections and bleeding complications. Acquired von-Willebrand's disease (AVWD) and acquired platelet dysfunction are rare bleeding disorders that are associated with lymphoproliferative disorders such as multiple myeloma. Patients with acquired bleeding disorders who are planned for ASCT to treat the underlying condition are considered at highest risk for bleeding complications, and optimal treatment strategies are not known. Materials and Methods: We summarized the diagnostic and therapeutic approach to a patient affected by AVWD and acquired platelet disorder related to multiple myeloma. The patient who was planned for ASCT presented with moderate to severe bleeding symptoms. Results: Acute bleeding episodes were successfully controlled and prevented during induction and consolidation therapy with immunoglobulins, whereas replacement of plasma-derived VW factor showed no clinical improvement. High-dose melphalan-based consolidation therapy supported with autologous stem-cell transplantation led to an immediate and sustainable rise of von-Willebrand antigen and activity and a subsequent normalization of platelet aggregation activity. After a follow-up of 40 weeks, the patient maintained normalized VW levels and platelet aggregation capacity. There were no further signs or symptoms of bleeding. Conclusion: This case report highlights the necessity for combined supportive and causal treatment in patients with AVWD and paraproteinemic PD. High-dose melphalan with autologous stem cell support may function as a treatment option in patients with myeloma-related AVWD

Biomarkers and immunological parameters in haemophilia and rheumatoid arthritis patients: a comparative multiplexing laboratory study

Introduction: Haemophilia (HA) and rheumatoid arthritis (RA) patients may develop joint damage caused by recurrent joint bleedings in HA or by chronic inflammation in RA. Only few data exist for biomarker studies in these patients. Aim: The objective of the present study is to assess a large array of biomarkers in peripheral blood samples obtained from HA patients without or with arthropathy and to compare pattern to RA patients and healthy controls. Methods: A panel of biomarkers was assessed in 129 men (40 HA patients without arthropathy, 23 HA patients with arthropathy, 23 RA patients and 43 control subjects). 37 different biomarkers (cytokines, angiogenesis‐related proteins) were analysed using a multiple analyte profiling technology and supplemented by acute phase proteins, coagulation and immunological parameters. Results: Evidence for systemic inflammation was obtained by increased acute phase reactants in all patient groups. 13 or 14 from 42 soluble parameters demonstrated significant differences (p < .05) between HA patients without arthropathy and healthy controls, or between HA patients with arthropathy and healthy controls, respectively. Largely overlapping patterns were obtained except for interleukin‐7 being increased in HA patients without arthropathy and being decreased in HA in the presence of arthropathy. Conclusions: In addition to data supporting systemic inflammation, we provide evidence for a common biomarker profile in HA patients and RA patients compared to healthy controls. A distinctive biomarker profile for HA patients with arthropathy did not appear except for interleukin‐7 demonstrating specific changes depending on the absence or presence of arthropathy in HA patients

Evaluation of a rapid turn-over, fully-automated ADAMTS13 activity assay: a method comparison study

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severely reduced activity of the von-Willebrand factor-cleaving protease ADAMTS13, mainly caused by anti-ADAMTS-13 antibodies. Although several test systems for ADAMTS13 measurement exist, long turn-around times hamper the usability in daily practice. We performed a method comparison study for two commercially available ADAMTS13 assays and evaluated the agreement between the fully-automated rapid turn-over HemosIL AcuStar ADAMTS13 Activity assay and the manually performed TECHNOZYM ADAMTS-13 Activity assay. Twenty-four paired test samples derived from 10 consecutively recruited patients (n = 8, acquired TTP; n = 1, atypical hemolytic uremic syndrome; n = 1, control), of which nine test samples were collected in case of clinically apparent TTP and 13 samples were collected from TTP patients in clinical remission were included. Overall correlation between the TECHNOZYM and AcuStar assay was good with a Pearson R of 0.93 (p &amp;lt; 0.001). Agreement between the assays assessed with the Passing-Bablok analysis showed high agreement with an Intercept of  - 2.56 (95% confidence interval [CI], - 5.07 to  - 0.86) and Slope of 1.04 (95% CI 0.84-1.17). The absolute mean bias was 2.54% (standard difference [SD], 6.38%; 95% CI to 10.0-15.05%). Intra-method reliability was high with an absolute mean bias of - 0.13% (SD 3.21%; 95% CI to 6.42-6.16%). The observer agreement for categorial thresholds (&amp;gt; or &amp;lt; 10% ADAMTS3 activity) was kappa = 0.82 (95% CI 0.59-1.0). Conclusively, overall agreement between the testing methods was sufficient and we support previously published data suggesting the AcuStar assay being a valuable and accurate tool for ADAMTS13 activity testing and TTP diagnostics

Is gingival bleeding a symptom of type 2 and 3 von Willebrand disease?

Background: Von Willebrand disease (VWD) is the most common inherent bleeding disorder. Gingival bleeding is a frequently reported symptom of VWD. However, gingival bleeding is also a leading symptom of plaque-induced gingivitis and untreated periodontal disease. In type 1 VWD gingival bleeding was not increased compared to controls. Thus, this study evaluated whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm. Methods: Twenty-four cases and 24 controls matched for age, sex, periodontal diagnosis, number of teeth and smoking were examined hematologically (VWF antigen, VWF activity, factor VIII activity) and periodontally (Gingival Bleeding Index [GBI]), bleeding on probing [BOP], Plaque Control Record [PCR], periodontal inflamed surface area [PISA], vertical probing attachment level). Results: BOP (VWD: 14.5±10.1%; controls: 12.3±5.3%; p = 0.542) and GBI (VWD: 10.5±9.9%; controls: 8.8±4.8%; p = 0.852) were similar for VWD and controls. Multiple regressions identified female sex, HbA1c, PCR and PISA to be associated with BOP. HbA1c and PCR were associated with GBI. Number of remaining teeth was negatively correlated with BOP and GBI. Conclusion: Type 2 and 3 VWD are not associated with a more pronounced inflammatory response to the oral biofilm in terms of BOP and GBI

Platelet aggregation testing on a routine coagulation analyzer: a method comparison study

Platelet function (PF) plays a pivotal role in both hemostasis and thrombosis, and manual light transmission aggregometry (LTA) is considered the standard of care for platelet function testing but is an error-prone and time-consuming procedure. We aimed to test the agreement regarding maximum aggregation (MA), velocity (VEL), and lag-phase (LagP) of platelet aggregation of the automated Sysmex CS-2100i analyzer (Siemens, Germany) against the APACT 4004 (Elitech, France) in samples derived from healthy participants and patients with hemostaseologic disorders. In total, 123 patient-derived samples were investigated, including 42 patients with acetylsalicylic acid and/or clopidogrel intake and 20 patients with other hemostaseologic disorders. Both MA and VEL showed good or excellent intermethod correlation. Agreement between the testing methods was only partially achieved, and values were indicative for a systematic bias to lower measurements below a threshold of 50% MA with the CS-2100i compared to the APACT 4004. All patients with impaired PF in the APACT 4004 were successfully identified with the CS-2100i, and reference values for automated LTA are provided. Conclusively, automated LTA with the CS-2100i is a highly standardized and reliable PF testing method and represents a decisive step in the simplification of platelet function testing in clinical routine

Implications of haemophilia gene therapy for the changing role of the multidisciplinary team

Wolfgan