Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is ...used off-label.
The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT.
In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings.
Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed “true“ HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux.
Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238)
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From 1998 to 2003, 133 Caucasian women aged 17-40 years (median 29 years) suffering from unexplained recurrent miscarriage (uRM) were consecutively enrolled. In patients and 133 age-matched healthy ...controls prothrombotic risk factors (factor V (FV) G1691A, factor II (FII) G20210A, MTHFR T677T, 4G/5G plasminogen activator inhibitor (PAI)-1, lipoprotein (Lp) (a), protein C (PC), protein S (PS), antithrombin (AT), antiphospholipid/anticardiolipin (APA/ACA) antibodies) as well as associated environmental conditions (smoking and obesity) were investigated. 70 (52.6%) of the patients had at least one prothrombotic risk factor compared with 26 control women (19.5%; p<0.0001). Body mass index (BMI; p=0.78) and smoking habits (p=0.44) did not differ significantly between the groups investigated. Upon univariate analysis the heterozygous FV mutation, Lp(a) > 30 mg/dL, increased APA/ACA and BMI > 25 kg/m(2) in combination with a prothrombotic risk factor were found to be significantly associated with uRM. In multivariate analysis, increased Lp(a) (odds ratio (OR): 4.7/95% confidence interval (CI): 2.0-10.7), the FV mutation (OR:3.8/CI:1.4-10.7), and increased APA/ACA (OR: 4.5/CI: 1.1-17.7) had independent associations with uRM.
Introduction
Etranacogene dezaparvovec gene therapy for haemophilia B demonstrated superior efficacy at 24 months in reducing bleeds versus a ≥6‐month lead‐in period of prophylaxis with FIX products ...in the phase 3 trial, HOPE‐B. In the absence of head‐to‐head comparisons of etranacogene dezaparvovec versus FIX products, indirect treatment comparisons (ITC) can be used.
Aim
To compare the efficacy of etranacogene dezaparvovec versus rIX‐FP, rFIXFc and N9‐GP using ITC, and support HOPE‐B results.
Methods
Data were leveraged from Phase 3 pivotal trials: HOPE‐B, PROLONG‐9FP, B‐LONG and Paradigm 2. Annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption were assessed using inverse probability of treatment weighting and matching adjusted indirect comparisons.
Results
Etranacogene dezaparvovec demonstrated statistically significantly lower bleeding rates versus all comparators. Rate ratios for ABR, AsBR and AjBR versus rIX‐FP were 0.19 (p < .0001), 0.08 (p < .0001) and 0.09 (p < .0001), respectively. Rate ratios for ABR, AsBR and AjBR versus rFIXFc were 0.14 (p < .0001), 0.13 (p = .0083) and 0.15 (p = .0111), respectively. Rate ratios for ABR and AsBR, versus N9‐GP were 0.24 (p = .0231) and 0.13 (p = .0071), respectively. Etranacogene dezaparvovec demonstrated significantly higher percentage of patients with no bleeds versus rIX‐FP and rFIXFc; odds ratios: 17.60 (p < .0001) and 5.65 (p = .0037), respectively. Etranacogene dezaparvovec resulted in significantly lower FIX consumption than all comparators.
Conclusions
ITC suggests that etranacogene dezaparvovec offers patients with haemophilia B (≤2% of normal FIX expression) a single dose treatment that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies.
Acquired hemophilia A (AHA) is an autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy (IST) is standard of care to ...eradicate autoantibody production and protect from further bleeding but carries a risk of severe infection and mortality in frail patients with AHA. Recently, emicizumab has been studied for its potential to reduce the need for early and aggressive IST.
To compare outcomes of two studies that used either IST (GTH-AH 01/2010; n=101) or prophylaxis with emicizumab (GHT-AHA-EMI; n=47) early after diagnosis of AHA.
Baseline characteristics were balanced by propensity score matching. Primary endpoint was the rate of clinically relevant new bleeds during the first 12 weeks; secondary endpoints were adverse events and overall survival.
The negative binominal model-based bleeding rate was 68% lower with emicizumab as compared with IST (incident rate ratio 0.325, 95% confidence interval (CI) 0.182-0.581). No difference was apparent in the overall frequency of infections (emicizumab 21%, IST 29%) during the first 12 weeks, but infections were less often fatal in emicizumab treated patients (0%) compared with IST treated patients (11%). Thromboembolic events occurred less often with emicizumab (2%) than IST (7%). Overall survival after 24 weeks was better with emicizumab (90% versus 76%, HR 0.44; 95% CI 0.24-0.81).
Using emicizumab instead of IST in the early phase after initial diagnosis of AHA reduced bleeding and fatal infections, and improved overall survival.
Introduction
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.
Aim
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.
Methods
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.
Results
Retention of panellists was high. Four statements required amending and consensus on all statements was achieved after three rounds of voting.
Conclusion
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.
Introduction: AHA is a serious autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII (FVIII). Standard of care involves immunosuppressive therapy (IST) to ...suppress formation of anti-FVIII autoantibodies. Recently, prophylaxis with emicizumab (EMI) has been used instead of IST to manage patients with AHA. Aim: This analysis aimed to compare outcomes of treatment with EMI or IST in patients with AHA. It was prospectively planned as an exploratory analysis of the GTH-AHA-EMI trial (NCT04188639, registered at www.clinicaltrials.gov). Methods: Individual patient data were retrieved from the GTH-AHA-EMI (n=47, treatment with EMI) and the GTH-AH 01/2010 (n=101, treatment with IST). Propensity score (PS) matching was used accounting for covariates that were previously established to influence bleeding risk and overall survival. Standardized mean differences were used to compare baseline characteristics before and after matching. Results: Baseline characteristics of the study populations were very similar and further improved by PS matching. IST treated patients had a high risk of bleeding in the first 3 weeks (0.25 to 0.30 clinically relevant new bleeds CRNB per patient-week), whereas EMI treated patients were largely protected from bleeding throughout the entire observation period (<0.1 CRNB per patient-week). For the first 12 weeks of observation, the negative-binomial model-based mean bleeding rate of EMI treated patients was 68% lower as compared to IST treated patients (incident rate ratio 0.325, 95% confidence interval CI 0.182-0.581, p<0.001). During the first 12 weeks, infections occurred with similar frequency but were less often fatal (IST: 36 events in 29 patients 29% of patients, 11 fatal events; EMI: 11 events in 10 patients 21%, no fatal events). Thromboembolic events were less frequent with EMI (1 event (2%, no fatal event) as compared with IST (7 events in 7 patients 7%, 4 fatal events). Overall survival after 24 weeks was 91% and 76% (hazard ratio 0.44, 95% CI 0.24-0.81, p=0.008, figure). Conclusions: This PS-matched individual patient data analysis showed better bleed protection and improved survival in patients treated with EMI as compared to patients treated with IST. These observations suggest a change of clinical practice. Patients with newly diagnosed AHA should be offered prophylaxis with EMI to reduce the risk bleeding, and provided sufficient time to allow for clinical stabilization and improvement of their general health status before IST is considered.
Introduction
The international certification of haemophilia centres in Europe is run by the European Association of Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) ...since 2013. The centres are designated as European Haemophilia Comprehensive Care Centres (EHCCC) or European Haemophilia Treatment Centres (EHTC), based on the specific requirements which evaluate centres’ ability to provide care for patients with haemophilia and allied disorders.
Aim
To establish the new protocol for accreditation of European Haemophilia Centres.
Methods
EAHAD, in collaboration with EHC, established Accreditation Working Group with the aim to define necessary measures to safeguard quality and improvement of bleeding disorders care throughout Europe and to build a novel model for accreditation of European Haemophilia Centres.
Results
The European guidelines for certification of haemophilia centres have been updated to guidelines for the accreditation and include all the requirements regarding facilities, laboratory and personnel needed for optimal management of novel treatment options, including the introduction of the hub‐and‐spoke model for delivery of gene therapy. A pilot project for the accreditation of haemophilia centres including on‐site audit has been designed.
Conclusion
Implementation of the novel accreditation protocol of the haemophilia treatment and haemophilia gene therapy centres has been made to further improve the quality of care for patients with haemophilia and other inherited bleeding disorders.
Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity ...against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (
= 56), 46.2% in Russia (
= 91), 40% in Italy (
= 20), 37.2% in France (
= 86), 26.8% in the United States (
= 71), 26.9% in Brazil (
= 26), 28.1% in Germany (
= 89), 29.8% in Japan (
= 84), and 5.9% in the United Kingdom (
= 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.
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