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The root cause of autoantibody formation against factor VIII (FVIII) in acquired hemophilia A (AHA) remains unclear. We aimed to assess whether AHA is exclusively associated with autoantibodies toward FVIII or whether patients also produce increased levels of autoantibodies against other targets. A case-control study was performed enrolling patients with AHA and age-matched controls. Human epithelial cell (HEp-2) immunofluorescence was applied to screen for antinuclear (ANA) and anticytoplasmic autoantibodies. Screening for autoantibodies against extractable nuclear antigens was performed by enzyme immunoassay detecting SS-A/Ro, SS-B/La, U1RNP, Scl-70, Jo-1, centromere B, Sm, double-stranded DNA, and α-fodrin (AF). Patients with AHA were more often positive for ANA than control patients (64% vs 30%; odds ratio [OR] 4.02, 1.98-8.18) and had higher ANA titers detected than controls. Cytoplasmic autoantibodies and anti-AF immunoglobulin A autoantibodies were also more frequent in patients with AHA compared with controls. Autoantibodies against any target other than FVIII were found in 78% of patients with AHA compared with 46% of controls (OR 4.16, 1.98-8.39). Results were similar preforming sensitivity analyses (excluding either subjects with autoimmune disorders, cancer, pregnancy, or immunosuppressive medication at baseline) and in multivariable binary logistic regression. To exclude that autoantibody staining was merely a result of cross-reactivity of anti-FVIII autoantibodies, we tested a mix of 7 well-characterized monoclonal anti-FVIII antibodies. These antibodies did not stain HEp-2 cells used for ANA detection. In conclusion, a diverse pattern of autoantibodies is associated with AHA, suggesting that a more general breakdown of immune tolerance might be involved in its pathology.

Introduction The sixth angstrom land Islands Conference on von Willebrand disease (VWD) on the angstrom land 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.

Gene therapy (GT) is becoming a realistic treatment option for patients with haemophilia. Outside clinical trials, the complexity and potential complications of GT will pose unprecedented challenges to haemophilia care centres.To explore the potential use of electronic tools to improve the delivery of GT under real-world conditions.Considering the hub-and-spoke model, the GTH working group on GT considered the entire patient pathway and reached consensus on requirements for an integrative software tool to secure documenting and sharing information between treaters, pharmacies and patients.Six steps of the gene therapy process were identified, each requiring completion of the previous step as a prerequisite for entry. The responsibilities of GT dosing and follow-up treatment centres, read/write access rules, and the minimum data set were outlined. Data contributed by patients through mobile devices was also considered.Important information needs to be shared between patients and treatment centres in a real-world GT hub-and-spoke model. Collecting and sharing this information in well-organised electronic applications will not only improve patient care but also enable national and international data collection in clinical registries.

Although cancer-associated thrombosis (CAT) is a frequent complication in patients with malignancies, its treatment remains a challenge in daily practice. Here, we report the clinical course of a 51-year-old woman presenting with a highly thrombogenic paraneoplastic coagulopathy. Despite therapeutic anticoagulation with various agents, including rivaroxaban, fondaparinux, and low-molecular-weight heparin, the patient suffered from recurrent venous and arterial thromboembolism. Locally advanced endometrial cancer was identified. Tumor cells showed strong expression of tissue factor (TF), and significant concentrations of TF-bearing microvesicles were detected in patient plasma. Coagulopathy was controlled only by continuous intravenous anticoagulation with the direct thrombin inhibitor, argatroban. Multimodal antineoplastic treatment, including neoadjuvant chemotherapy followed by surgery and postoperative radiotherapy, resulted in clinical cancer remission, which was paralleled by normalization of tumor markers, CA125 and CA19–9, D-dimer levels, and TF-bearing microvesicles. In summary, continuous anticoagulation with argatroban and multimodal anticancer treatment may be necessary to control TF-driven coagulation activation with recurrent CAT in endometrial cancer.

Synovitis, a common feature in haemophilia, is triggered by the presence of blood in joints, and represents the first step towards the development of chronic arthropathy. Synovitis may be detected early by means of ultrasound or magnetic resonance imaging scan; clinical joint scores are less sensitive in this setting. Regular long-term prophylaxis with clotting factor concentrates, as primary prophylaxis and tailored to individual needs, has high efficacy in preventing synovitis. In general, higher factor levels lower bleeding risk, but no direct correlation between factor levels and synovitis incidence has been demonstrated.This study aimed to develop an expert consensus relating to the definition, pathophysiology, diagnosis, prevention, follow-up and treatment of synovitis, recognising its relevance for joint health and taking into account existing knowledge gaps.A Delphi consensus study was designed and performed. An expert group prepared 22 statements based on existing literature; a wider expert panel subsequently voted on these.Retention of panellists was high. Four statements required amending and consensus on all statements was achieved after three rounds of voting.This e-Delphi consensus study addressed the importance of synovitis in joint health of people with haemophilia and highlighted knowledge gaps in this field. Studies on the natural course of synovitis are lacking and the biological mechanisms underlying this process are not yet fully elucidated. While basic and clinical research proceeds in this field, expert consensus can help guide clinicians in their routine clinical practice, and Delphi methodology is often used to produce best-practice guidelines.

Low bone mineral density (BMD) is common in patients with hemophilia (PWHs). The aim of the present study was to describe BMD and microarchitecture in PWHs in Northern Germany and to determine factors contributing to possible skeletal alterations. Demographic characteristics, BMD and microarchitecture, bone metabolism markers, and orthopaedic joint score (OJS) were assessed during routine check-ups. Areal BMD was assessed by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine. Volumetric BMD and microarchitecture were quantified by high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Eighty male PWHs (median age, 33 years; range, 18–77) were retrospectively analyzed, of whom 67 (84.0%) and 13 (16.0%) had hemophilia A and B, respectively. Fifty-four (68.0%), six (7.0%), and 20 (25.0%) patients had severe, moderate, or mild hemophilia, and 35 (44.0%) were hepatitis C virus (HCV) positive. DXA analysis revealed low BMD (Z-score ≤ − 2.0) in 27.5% of PWHs, and higher bone turnover values were associated with lower BMD. Bone microarchitecture was dominated by cortical deficits at the radius and trabecular deficits at the tibia. Cortical deficits at the radius were influenced by lower body mass index, low-grade inflammation, and treatment regimen (higher cortical thickness on primary prophylaxis). Trabecular alterations at the tibia were mainly associated with OJS and HCV status. A positive effect of self-reported sportive activity on BMD could be shown. In conclusion, our findings demonstrate that the site-specific microarchitectural deficit observed in PWHs is primarily negatively influenced by poor joint status, inflammation, HCV infection, and high bone turnover.

Chronic diseases, such as inherited bleeding disorders (IBD) are often associated with high costs of medical care. COVID-19 containment measures, including isolation and triage, led to restrictions in the health care of chronically ill patients. The aim of the present study was to investigate the effects of the COVID-19 pandemic on the health care of IBD patients.In this multicentre cross-sectional study to evaluate the effects of COVID-19 on the mental health and quality of care of patients with inherited bleeding disorder, an ad hoc questionnaire was sent to 586 patients/parents of children with haemophilia A, B or von Willebrand syndrome type 3. In addition to demographic and clinical data, patients/parents of patients with inherited bleeding disorders were asked about their thoughts, concerns and experiences regarding their medical care during the COVID-19 pandemic. Differences between clinical subgroups were calculated.Significant differences were found between subgroups (severity, type of therapy, product class, comorbidities) with regard to the transmission of COVID-19 through plasma products, the effects of COVID-19 positive test results, fear of getting COVID-19, delayed drug supply and physiotherapy treatment.The medical care of patients with inherited bleeding disorders, who need a continuous supply of essential drugs, is a particular challenge in times of pandemics. Therefore, worries and fears of IBD patients should be taken seriously and innovative communication channels established to maintain therapy standards and quality of care.Chronische Erkrankungen, wie z. B. angeborene Blutungsneigungen (IBD: Inherited Bleeding Disorders), gehen häufig mit einem erhöhten Versorgungsaufwand einher. Maßnahmen zur Eindämmung der COVID-19 Pandemie, inklusive Isolation und Triageierung, haben zu Einschränkungen in der Krankenversorgung von chronisch kranken Patienten geführt. Ziel der vorliegenden Arbeit ist es, die Auswirkungen der COVID-19 Pandemie auf die Krankenversorgung von IBD-Patienten zu untersuchen.In dieser multizentrischen Querschnittsstudie zur Bewertung der Auswirkungen von COVID-19 auf die psychische Gesundheit und Versorgungsqualität von Patienten mit angeborener Blutungsneigung wurde ein ad-hoc Fragebogen an 586 Patienten/Eltern von Kindern mit Hämophilie A, B oder von Willebrand Syndrom Typ 3 verschickt. Neben demografischen und klinischen Daten wurden IBD Patienten zu ihren Gedanken, Sorgen und Erfahrungen in Bezug auf ihre medizinische Versorgung während der COVID-19 Pandemie befragt. Unterschiede zwischen klinischen Subgruppen wurden berechnet.Signifikante Unterschiede zeigten sich zwischen Subgruppen (Schweregrad, Art der Therapie, Produktklasse, Komorbiditäten) bezüglich Übertragung von COVID-19 durch Plasmaprodukte, Auswirkungen COVID-19 positiver Testergebnisse, Angst COVID-19 zu bekommen, verzögerter Medikamentenversorgung und Physiotherapiebehandlung.Die medizinische Versorgung von IBD-Patienten, die eine kontinuierliche Versorgung mit lebensnotwendigen Medikamenten benötigen, stellt in Pandemiezeiten eine besondere Herausforderung dar. Daher sollten Sorgen und Ängste von IBD-Patienten ernst genommen und innovative Kommunikationswege zur Aufrechterhaltung von Therapiestandards und Versorgungsqualität etabliert werden.

Introduction Patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), particularly those carrying the JAK2V617F mutation, are at increased risk of thrombosis. While an association of MPNs with autoimmune disorders has been established, the prevalence of inherited or acquired thrombophilias in JAK2V617F-positive patients remains obscure. We therefore investigated the coincidence of the JAK2V617F mutation with additional thrombogenic risk factors. Methods In a retrospective study, we analyzed all patients referred for thrombophilia work-up between 01/2011 and 08/2019, in whom additional JAK2V617F mutation analysis was performed because of thromboembolic events that were recurrent, atypically located and/or associated with abnormal blood counts. Results Of 472 tested patients, 49 (10.4%) were JAK2V617F-positive. While the frequency of inherited thrombophilias (factor V Leiden and prothrombin G20210A mutation, deficiency of antithrombin, protein C, protein S) was not different between the two groups, the prevalence of definite antiphospholipid syndrome (APS), mostly associated with a moderate- or high-risk antibody profile, was significantly higher in patients with (22.4%) than in those without (8.4%) JAK2V617F mutation (p Conclusion We found a significant association between JAK2V617F-positive MPN and definite APS. The presence of concomitant APS in patients carrying the JAK2V617F mutation may lead to earlier manifestation of thromboembolic events and may warrant more aggressive antithrombotic treatment strategies to prevent recurrence.

Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research.B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations.Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing.Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (5-40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis.B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

In haemophilia, thrombin generation and fibrin deposition upon vascular injury critically depend on the tissue factor (TF)-driven coagulation pathway. TF expression by monocytes/macrophages and circulating microvesicles contributes to haemostasis, thrombosis and inflammation. Inflammation is a hallmark of blood-induced joint disease. The aim of this study is to correlate TF production by whole-blood monocytes with inflammatory markers and clinical parameters in patients with moderate-to-severe haemophilia A or B (n = 43) in comparison to healthy males (n = 23). Monocyte TF antigen and microvesicle-associated TF procoagulant activity (MV TF PCA) were measured immediately after blood draw (baseline) and following incubation of whole blood with buffer or lipopolysaccharide (LPS) using two-colour flow cytometry and chromogenic FXa generation assay, respectively. Patients with HIV or uncontrolled HBV/HCV infections were excluded. TF was hardly detectable and not different in baseline and buffer-treaded samples from both groups. Stimulation with LPS, however, induced monocyte TF production, with increased TF-specific mean fluorescence intensity (P = 0.08) and MV TF PCA (P P n = 16), who were older and also had a significantly worse orthopaedic joint score than patients with no history of viral hepatitis (P

Patients with myeloproliferative neoplasms (MPNs) are at increased risk of both thromboembolic and hemorrhagic complications. Among the risk factors for bleeding is the development of an acquired qualitative von Willebrand factor defect with loss of larger VWF plasma multimers, resulting in acquired von Willebrand syndrome (aVWS). The diagnosis of aVWS is challenging, because no single automated test is sufficient to prove or exclude aVWS. We aimed to compare different diagnostic tools used for the detection of MPN-associated aVWS in daily practice.Patients with polycythemia vera (PV) or essential thrombocythemia (ET), who had been routinely assessed for quantitative and qualitative abnormalities of plasma VWF, were retrospectively studied.Sixty-four patients (37 with PV and 27 with ET) were analyzed. Using multimer analysis of plasma VWF, aVWS with a loss of VWF high-molecular-weight multimers was detected in 51.4 % and 55.6 % of PV and ET patients, respectively.GPIbM/Ag threshold oflt;0.8 was defined as useful screening tool for aVWS, with acceptable sensitivity (88.2 %) and specificity (76.7 %) and good agreement with VWF multimer analysis (κ = 0.653). VWF:GPIbM/Ag showed better performance than VWF:CB/Ag. Regarding hematological parameters, there was no difference in hematocrit between patients with and without aVWS. However, leukocyte and platelet counts were significantly increased in the aVWS cohort.For the first time, we identified a VWF:GPIbM/Ag ratio oflt;0.8 as simple screening tool for aVWS in patients with PV or ET. This observation, however, should be confirmed in a larger patient cohort.

Guidelines recommend that patients with haemophilia should preferably receive vaccination subcutaneously. COVID-19 and other vaccines, however, are only licenced for intramuscular application.To assess the safety of intramuscular COVID-19 vaccination in patients living with haemophilia.Part A of this prospective observational study enrolled consecutive patients with haemophilia A (HA) and B (HB) of all ages and severities and assessed injection site bleeding and other complications within 30 days of vaccination. Part B enrolled patients providing informed consent for detailed data collection including medication and prophylaxis around the time of vaccination. Logistic regression was performed to assess potential risk factors for bleeding.Four hundred and sixty-one patients were enrolled into part A. The primary endpoint injection site bleeding occurred in seven patients (1.5%, 95% confidence interval .7-3.1%). Comprehensive analysis of 214 patients (404 vaccinations, part B) revealed that 97% of patients with severe haemophilia had prophylaxis before vaccination, either as part of their routine prophylaxis or using additional doses. 56% and 30% of patients with moderate and mild haemophilia, respectively, received prophylaxis before vaccination. Among the seven bleeds recorded, three occurred when intramuscular vaccination was done without prophylaxis (odds ratio 12).This is the first prospective study reporting on the safety of intramuscular vaccination in haemophilia. The rate of injection site bleeding was low in mild haemophilia, and in moderate and severe haemophilia if patients received factor prophylaxis.

Introduction The development of inhibitory antibodies is a severe complication of clotting factor replacement therapy in patients with severe haemophilia A (HA). Current World Federation of Hemophilia (WFH) guidelines for haemophilia care indicate that eradication of inhibitors is best achieved through immune tolerance induction (ITI) therapy. Aim The European Collaborative Haemophilia Network conducted a survey to determine whether ITI is still used in the routine management of patients with HA, and whether the availability of emicizumab prophylaxis has influenced treatment decisions. Methods The survey was conducted in late 2020/early 2021 in 18 centres representing 17 countries in the Europe/Middle East region treating a total of 4955 patients, and included sections specific to patient and centre demographics, treatment protocols (both ITI and prophylactic), inhibitor development and initiation of ITI, treatment success, and the incidence of adverse events. Results While our results indicate that ITI can still be considered a mainstay of treatment for patients with HA with inhibitors, less than daily dosing of ITI in combination with emicizumab prophylaxis is becoming commonplace across the spectrum of disease severity, with initiation being guided by bleeding patterns. The most frequently cited reasons for not initiating emicizumab prophylaxis were availability or reimbursement issues. Conclusion ITI remains a mainstay for haemophilia treatment of patients with HA with inhibitors, but emicizumab has become a preferred first-line approach to protect against bleeds and represents an alternative to burdensome ITI in certain patient groups.

BACKGROUND Ankle arthropathy is a frequent complication of haemophilia, reducing the patients' quality of life. Despite intensive conservative therapy, end-stage arthropathy requires surgical treatment, either by ankle fusion (AF) or total ankle replacement (TAR). METHODS Eleven consecutive AFs were performed in nine patients and 11 TARs were implemented in 10 patients. Outcomes were assessed clinically by AOFAS score and radiologically by the Pettersson and Gilbert scores. RESULTS The mean age of the patients in these groups were 35.7 years and 49.4 years, respectively. Of the 11 ankles that underwent fusion, 10 showed bony consolidation not later than 12 weeks after surgery, whereas one still showed non-union after 6 months. VAS pain scores decreased significantly in both groups. Mean AOFAS scores also improved significantly, from 28.1 before to 80.3 after AF and from 21.5 before to 68.0 after ankle replacement. No perioperative complications were observed in either group. Late deep infection was observed in two patients that underwent TAR, which required removal of the implant. CONCLUSION Our data indicate that both AF and TAR result in significantly reduced pain in patients with haemophilia with end-stage haemophilic arthropathy. While TAR is associated with a higher risk of deep infection and minimal persistent pain, it preserves the pre-operative range of motion. AF on the other hand is associated with the risk of non-union and a longer post-operative recovery period but results in greater pain reduction.

Recombinant porcine factor VIII (rpFVIII, OBI-1, susoctocog alfa) is used for the treatment of acute bleeds in patients with acquired hemophilia A (AHA). Inhibitors in AHA can sometimes cross-react with rpFVIII.To assess the frequency, strength, and determinants of cross-reactivity.Baseline samples from 70 patients of the prospective, observational cohort study GTH-AH 01/2010 were assessed for anti-human FVIII and anti-rpFVIII inhibitors using modified Nijmegen-Bethesda assays, as well as anti-human FVIII domain reactivity using enzyme-linked immunoassay (ELISA).Anti-human FVIII inhibitors were present in all samples ranging between 0.7 and 3891 Bethesda Units (BU)/mL. Inhibitors from 31 of 70 patients (44%) partially inhibited rpFVIII with anti-rpFVIII titers ranging between 0.5 and 471 BU/mL. Anti-rpFVIII titers were ≤5 BU in most patients. Patients with cross-reacting inhibitors, as compared to patients without, had significantly higher anti-human FVIII titers (27.8 versus 5.4 BU/mL) and lower baseline FVIII activity (1 versus 2.6 IU/dL). The ratio between anti-rpFVIII to anti-human titers was highest for inhibitors involving the C1 domain. Cross-reactivity was very rare, if inhibitors reacted only with the C2 domain of FVIII (6%). An anti-human FVIII titer of100 BU/mL predicted cross-reactivity with 97% likelihood, whereas an anti-human FVIII titer of3.8 BU/mL predicted absent cross-reactivity with 90% likelihood.Cross-reacting inhibitors should be considered when choosing a treatment for bleeding patients with AHA. Cross-reactivity is frequent in patients with anti-human FVIII titers of100 BU/mL.

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: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher. Aim: To evaluate the use and outcome of ITI in patients with HB and inhibitors. Methods: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural—an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded. Results: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment. Conclusion: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.

Background The worldwide pandemic spread of SARS-CoV-2 can lead to either respiratory infection or containment-associated isolation with possible higher impact on chronic diseases such as inherited bleeding disorders (IBD). The aim of the study was to evaluate the impact of COVID-19 on patients and caregivers of IBD patients regarding their concerns and worries related to own health, access to treatment and availability of factor concentrates and their experiences related to medical care. Methods Multicentre, cross-sectional study evaluating the impact of COVID-19 on mental health of IBD patients. An ad hoc questionnaire was developed and sent to 586 patients/caregivers with haemophilia A, haemophilia B and VWD type III. The survey included information on demographic and clinical data, needs, concerns and experiences regarding medical care during COVID-19 pandemic. Results In total, 355 of the IBD-Group (200 patients, 155 caregivers) completed the survey (61.7% response rate). Most patients suffered from haemophilia A (73.8%) and were severely affected (64.7%). Eleven patients were in quarantine due to suspected COVID-19; none had symptoms. One quarter worried (very) strongly about getting the coronavirus, 71.3% asked themselves what will happen to them when they will get COVID-19, 40.1% felt unchanged, and 18.9% worried about delivery difficulties of their IBD treatment product. In 52.8%, medical appointments were postponed. Significant differences between caregivers and patients were found in most aspects. Discussion The IBD patients affected by a chronic disorder have particular thoughts and worries regarding COVID-19. Haemophilia specialists should be committed to address these concerns and guarantee treatment despite containment strategies.

Patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), particularly those carrying the JAK2In a retrospective study, we analyzed all patients referred for thrombophilia work-up between 01/2011 and 08/2019, in whom additional JAK2Of 472 tested patients, 49 (10.4%) were JAK2We found a significant association between JAK2

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 of100 U/kg for24 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. Emicizumab, ein bispezischer Antikörper, der wie aktivierter Faktor VIII (FVIII) wirkt, ist zugelassen zur Blutungsprophylaxe bei Patienten mit Hämophilie A ohne und mit FVIII-Inhibitor. Aufgrund substanzieller Unterschiede zwischen Emicizumab und FVIII hat die „Ständige Kommission Hämophilie“ der deutschen, österreichischen und schweizerischen Gesellschaft für Thrombose- und Hämostaseforschung (GTH) beschlossen, einen praxisorientierten Leitfaden für den Einsatz von Emicizumab bei Patienten mit Hämophilie A (PWHA) zu entwickeln. Daten aus der Literatur (systematische Literaturrecherche in PubMed) und persönliche Erfahrungen wurden zusammengetragen und daraus Empfehlungen entwickelt. Diese wurden in der „Ständigen Kommission Hämophilie“ diskutiert und entsprechend revidiert. Die finalen Empfehlungen wurden von allen Autoren mittels Delphi-Abstimmung freigegeben. Die Empfehlungen beziehen sich auf Patienten ohne und mit FVIII-Inhibitor und beinhalten generelle Aspekte, Patientenaufklärung, Blutungsbehandlung, Operationen, Anwendung von Emicizumab bei zuvor unbehandelten Patienten (PUPs), Patienten mit neudiagnostizierten Inhibitoren und älteren Patienten. Patienten sollten in spezialisierten Behandlungszentren behandelt werden und adäquate Labortests zum Monitoring von Emicizumab, einer Faktor VIII-Substitution oder von FVIII-Inhibitoren sollten zur Verfügung stehen. Erste Erfahrungen mit Protokollen zu Immuntoleranz -Induktion in Kombination mit Emicizumab und die begrenzte Erfahrung mit sehr jungen Kindern wird berichtet. Bis jetzt wurden keine thrombotischen Komplikationen bei der zusätzlichen Blutungsbehandlung mit rFVIIa oder FVIII berichtet. aPCC-Dosierungen von 100 U/kg über 24 Stunden müssen vermieden werden, wegen des Risikos von Thrombosen und/oder thrombotischer Mikroangiopathien. Die Empfehlungen wurden anhand der aktuell verfügbaren Erfahrung entwickelt als Leitfaden für Hämophiliebehandler, die Emicizumab bei PWHA einsetzen. Mit weiterer Erfahrung und neuen Studien ist ein regelmäßiges Überarbeiten der Empfehlungen erforderlich.

Objectives 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. Methods 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. Results 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. Conclusions 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.

ZusammenfassungIm Folgenden wird das elektronische Substitutionstagebuch smart medication ™ vorgestellt, sowie eine Analyse der damit erhobenen Echtzeitdaten. Seit 2012 wurde smart medication ™ von 663 Patienten in 30 Deutschen Hämophilie Zentren (HZ) genutzt. Daten aus 9 HZ wurden für die nachfolgende Analyse zusammengeführt. Entsprechend der Mittelwerte des jährlichen Faktorenverbrauchs und der Anzahl von Gelenkblutungen wurden vier Gruppen gebildet. Die größte Gruppe (A, 42%) war die mit unterdurchschnittlichem Faktorenverbrauch und weniger als 2,25 Gelenkblutungen pro Jahr. Die zweitgrößte Gruppe (B, 32%) zeigte ähnlich niedrige Blutungsraten bei überdurchschnittlichem Faktorenverbrauch. Eine Reduktion des Faktorenverbrauchs bei einigen dieser Patienten wäre ggf. möglich. Hingegen könnten andere Patienten mit häufigen Gelenkblutungen bei gleichzeitig niedrigem Faktorenverbrauch (D, 13%), von einer Erhöhung der Dosis profitieren. Patienten mit häufigen Gelenkblutungen trotz überdurchschnittlichem Faktorenverbrauch (C, 13%) benötigen eine intensivierte Behandlung jenseits einer Dosisanpassung, wie pharmakokinetisch adaptierte Dosisanpassungen oder orthopädische Maßnahmen. Mit Hilfe von smart medication ™ können Patienten, die eine Änderung ihrer laufenden Behandlung benötigen, lange vor der nächsten Vorstellung im HZ identifiziert werden. Der ständig wachsende Datenpool erlaubt zudem eine kontinuierliche Analyse von Echtzeitdaten und damit eine Optimierung der zur Verfügung stehenden Ressourcen.

Acquired hemophilia A (AHA) is due to autoantibodies against coagulation factor VIII (FVIII) and most often presents with unexpected bleeding. In contrast to congenital hemophilia, the patient’s residual FVIII activity does not seem to correlate with the risk of bleeding as suggested from previous studies. Risk factors for bleeding have not been described. We used data from the prospective GTH-AH 01/2010 study to assess the risk of bleeding and the efficacy of hemostatic therapy. FVIII activity was measured at baseline and weekly thereafter. Bleeding events were assessed by treating physicians. A total of 289 bleeds were recorded in 102 patients. There were 141 new bleeds observed starting after day 1 in 59% of the patients, with a mean rate of 0.13 bleed per patient-week in weeks 1 to 12, or 0.27 bleed per patient-week before achieving partial remission. Weekly measured FVIII activity was significantly associated with the bleeding rate, but only achieving FVIII activity ≥50% abolished the risk of bleeding. A good World Health Organization performance status assessed at baseline (score 0 vs higher) was associated with a lower bleeding rate. Hemostatic treatment was reportedly effective in 96% of bleeds. Thus, the risk of new bleeds after a first diagnosis of AHA remains high until partial remission is achieved, and weekly measured FVIII activity may aid in assessing the individual risk of bleeding. These results will help to define future strategies for prophylaxis of bleeding in AHA.

SummaryThe impact of inherited bleeding disorders on the socioeconomic status (SES) of affected individuals is not clear. The SES of adult patients with congenital bleeding disorders (PWBD) from a centre in Germany (age 42.3 ± 15.0 years) was compared to that of a gender- and age-matched control group of patients with thrombophilia or a thrombotic event (PWT). Patients completed a questionnaire including aspects of SES, impact of the disease on their lives, and health-related quality of life (HRQoL). Forty-five patients were enrolled in each group; 71 % of PBWD had a severe form of the bleeding disorder (FVIII/IX activity

Introduction Despite similar residual factor VIII activity, patients with haemophilia A (HA) show significant interindividual variability with regard to bleeding frequency and severity, suggesting that additional factors modulate thrombin generation and fibrin deposition. Protein disulphide isomerase (PDI) is an abundant oxidoreductase that exerts pleiotropic effects in primary and secondary haemostasis and contributes to thrombosis and vascular inflammation. Aim We conducted a pilot study to explore a potential role of platelet PDI in patients with HA. Methods Expression and release of platelet PDI were studied by flow cytometry and enzyme-linked immunosorbent assay, respectively. Results Compared to healthy male controls (n = 12), patients with HA (n = 24) showed significantly increased expression of PDI antigen on ADP- or TRAP-6-, but not on buffer-treated platelets, a finding that could not be explained by enhanced platelet activation, as indicated by expression of the α-granule protein, CD62P (P-selectin). While platelet agonists did not affect PDI secretion in healthy male controls, increased levels of PDI antigen were found in supernatants of TRAP-6-treated platelets from patients with HA. Importantly, in two patients with exceedingly high TRAP-6-induced PDI release over baseline, findings were consistent when platelets were isolated and stimulated on a separate occasion. No obvious association was found between platelet PDI and bleeding phenotype in this patient cohort. Conclusion Agonist-induced expression and release of platelet PDI were increased in patients with HA. Larger studies are needed to clarify if variations in this platelet response contribute to the diversity in bleeding frequency and severity among patients with congenital factor VIII deficiency.

Neutralizing autoantibodies against factor VIII (FVIII), also called FVIII inhibitors, are the cause of acquired hemophilia A (AHA). They are quantified in the Bethesda assay or Nijmegen-modified Bethesda assay by their ability to neutralize FVIII in normal human plasma. However, FVIII inhibitors do not represent the whole spectrum of anti-FVIII autoantibodies. Here, we studied isotypes, immunoglobulin G subclasses, and apparent affinities of anti-FVIII autoantibodies to assess their prognostic value for the outcome in AHA. We analyzed baseline samples from patients enrolled in the prospective GTH-AH 01/2010 study. Our data suggest that anti-FVIII immunoglobulin A (IgA) autoantibodies are predictors of poor outcome in AHA. Anti-FVIII IgA-positive patients achieved partial remission similar to anti-FVIII IgA-negative patients but had a higher risk of subsequent recurrence. Consequently, IgA-positive patients achieved complete remission less frequently (adjusted hazard ratio [aHR], 0.35; 95% confidence interval [CI], 0.18-0.68; P < .01) and had a higher risk of death (aHR, 2.62; 95% CI, 1.11-6.22; P < .05). Anti-FVIII IgA was the strongest negative predictor of recurrence-free survival after achieving partial remission and remained significant after adjustment for baseline demographic and clinical characteristics. In conclusion, anti-FVIII IgA represents a potential novel biomarker that could be useful to predict prognosis and tailor immunosuppressive treatment of AHA.

Characteristic features of disseminated intravascular coagulation (DIC) are the opposing risks of bleeding (due to consumptive coagulopathy and hyperfibrinolysis) and organ failure (due to widespread microvascular thromboses). The purpose of anticoagulation in DIC is to attenuate excessive thrombin generation and fibrin deposition. While heparins have been shown to be beneficial in this context, the safety and efficacy of direct oral anticoagulants have not yet been sufficiently addressed. Here, we report two patients in whom chronic DIC was stabilized upon administration of apixaban: an elderly male with aortic dissection presenting with significant mucocutaneous bleeding and a younger female with Klippel-Trénaunay-Weber syndrome presenting with multiple superficial vein thromboses (SVTs). In addition to an improvement in DIC parameters, both patients benefited clinically with resolution of bleeding symptoms and prevention of further SVTs, respectively. Oral apixaban thus showed promising safety and efficacy in the management of DIC caused by vascular abnormalities; still further investigations are needed to support these findings.Zu den charakteristischen Komplikationen der disseminierten intravasalen Gerinnung (

The impact of inherited bleeding disorders on the socioeconomic status (SES) of affected individuals is not clear. The SES of adult patients with congenital bleeding disorders (PWBD) from a centre in Germany (age 42.3 ± 15.0 years) was compared to that of a gender- and age-matched control group of patients with thrombophilia or a thrombotic event (PWT). Patients completed a questionnaire including aspects of SES, impact of the disease on their lives, and health-related quality of life (HRQoL). Forty-five patients were enrolled in each group; 71 % of PBWD had a severe form of the bleeding disorder (FVIII/IX activity 1 % or VWD type 3), and 60 % of all PWBD were treated on-demand. PWBD had a lower monthly income (Der Einfluss angeborener Blutungsneigungen auf den sozioökonomischen Status (SES) der Betroffenen ist unklar. Der SES von Patienten mit angeborener Blutungsneigung (PWBD) aus einem Zentrum in Deutschland (Alter 42,3 ± 15,0 Jahre) wurde mit dem einer alters- und geschlechts-gematchten Kontrollgruppe von Patienten mit Thrombophilie oder einem thrombotischen Ereignis (PWT) verglichen. Die Patienten beantworteten einen Fragebogen zu Aspekten des SES, Einfluss der Erkrankung auf ihr Leben und gesundheitsbezogener Lebensqualität (HRQoL). 45 Patienten wurden in jeder Gruppe eingeschlossen; 71 % der PWBD hatten eine schwere Form der Blutungsneigung (FVIII/IX-Aktivität 1 % oder VWD Typ 3), 60 % aller PWBD erhielten Bedarfsbehandlung. PWBD hatten ein geringeres monatliches Einkommen (

Introduction Nuwiq® [human cell line-derived recombinant factor VIII (human-cl rhFVIII)] is a new generation rFVIII protein, without chemical modification or fusion to any other protein, produced in a human cell line. Aim/methods This prospective, open-label, multinational phase III study assessed the efficacy and safety of human-cl rhFVIII in 32 adult previously treated patients (PTPs) with severe haemophilia A during standard prophylaxis for ≥6 months and ≥50 exposure days. Efficacy in treating bleeds and during surgical prophylaxis was also assessed. Results Prophylactic efficacy, based on mean monthly bleeding rate, was rated as ‘excellent’ or ‘good’ in 97% of patients for all bleeds and in 100% of patients for spontaneous bleeds. Mean (SD) annualized bleeding rate was 2.28 (3.73) [median = 0.9] for all bleeds, 1.16 (2.57) [median = 0] for spontaneous bleeds and 1.00 (1.79) [median = 0] for traumatic bleeds. There were no bleeds in 50% of patients and there were no major, life-threatening bleeds. Efficacy was ‘excellent’ or ‘good’ in treating 28 (100%) of 28 bleeds. Overall efficacy was rated as ‘excellent’ during four surgical procedures (three major, one minor) and ‘moderate’ during one major surgery. Incremental in vivo recovery (IVR) data were comparable with the one-stage and chromogenic assays. IVR was >2.0% per IU kg−1 for all measurements and stable over 6 months. No patients developed FVIII inhibitors and there were no treatment-related serious or severe adverse events. Conclusion These results in adult PTPs indicate that human-cl rhFVIII is effective for the prevention and treatment of bleeds in adults with severe haemophilia A.

Introduction In haemophilia, clinical outcomes are mainly determined by the severity of clotting factor deficiency, treatment regimen, availability of clotting factor concentrate and age. Information about the relevance of patient-related factors such as education, social status or impact of the disease on the patient's life is scarce. Aim To assess the impact of social status and disease-related impairment of certain aspects of the patient's life on clinical and psychosocial outcomes in patients with inherited bleeding disorders (PWBD). Methods Consecutive patients of a single centre were assessed by questionnaires on social status and quality of life (SF-36). Social status was defined by school and professional education, employment and financial income of patients as well as school education of their parents. Results Fifty-seven PWBD (mean age, 38 ± 16 years) were enrolled, 60% were treated on-demand; PWBD had a median number of 2.5 (0–34) annual bleeds and a median orthopaedic joint score of 6 (0–38). No significant differences were found for clinical and psychosocial outcomes across social status groups. More than half of the patients reported that haemophilia had an impact on their school education, childhood and leisure activities. Patients with a high impact of haemophilia on their lives were less satisfied with their lives (P

SummaryWe describe two patients who developed an extensive catheter-related upper extremity deep vein thrombosis and a cerebral venous sinus thrombosis, respectively. Both thrombotic complications occurred in the presence of an elevated platelet count. Subsequent detection of the JAK2 V617F and MPL mutations led to the diagnosis of a myeloproliferative neoplasia.

Seed longevity is influenced by many factors, a widely discussed one of which is the seed lipid content and fatty acid composition. Here, linear and non-linear regressions based on machine learning were applied to analyse germinability and seed composition of a set of 42 oilseed rape (Brassica napusL.) accessions grown under the same single environment and at the same time following a period of up to 31 years storage at 7°C. Mean viability was halved after 27.0 years of storage, but this figure concealed a major influence of genotype. There was also wide variation with respect to fatty acid composition, particularly with respect to oleic, α-linolenic, eicosenoic and erucic acid. Linear regression (rL) revealed significant correlation coefficients between normal seedling appearance and the content of α-linolenic acid (+0.52) and total oil (+0.59). Multivariate regression using artificial neural networks including a radial basis function (RBF), a multilayer perceptron (MLP) and a partial least square (PLS) recognized underlying structures and revealed high significant correlation coefficients (rM) for oil content (+0.87), eicosenoic acid (+0.75), stearic acid (+0.73) and lignoceric acid (+0.97). Oil content or a combination of oleic, α-linolenic, arachidic, eicosenoic and eicosadienoic acids and glucosinolates resulted in highest model fitting parametersR2of 0.90 and 0.88, respectively. In addition, the glucosinolate content, predominantly in the Brassicaceae family and ranging from 4.6 to 79.5 µM, was negatively correlated with viability (rL= ‒0.43). Summarizing, oil content, some fatty acids and glucosinolates contribute to variations in average half-life (15.2 to 50.7 years) of oilseed rape seeds. In contrast to linear regression, multivariate regression using artificial neural networks revealed high associations for combinations of parameters including underestimated minor fatty acids such as arachidic, stearic and eicosadienoic acids. This indicates that genetic and seed composition factors contribute to seed longevity. In addition, multivariate regressions might be a successful approach to predict seed viability based on fatty acids and seed oil content.