Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.

BACKGROUND: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. METHODS: In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26. RESULTS: Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×1011 vg, 6.40×1011 vg, 8.32×1011 vg, or 1.28×1012 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels. CONCLUSIONS: Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017-000852-24 and 2017-005080-40.).

Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis.

BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a new syndrome associated with the ChAdOx1 nCoV-19 adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2. Data are lacking on the clinical features of and the prognostic criteria for this disorder. METHODS: We conducted a prospective cohort study involving patients with suspected VITT who presented to hospitals in the United Kingdom between March 22 and June 6, 2021. Data were collected with the use of an anonymized electronic form, and cases were identified as definite or probable VITT according to prespecified criteria. Baseline characteristics and clinicopathological features of the patients, risk factors, treatment, and markers of poor prognosis were determined. RESULTS: Among 294 patients who were evaluated, we identified 170 definite and 50 probable cases of VITT. All the patients had received the first dose of ChAdOx1 nCoV-19 vaccine and presented 5 to 48 days (median, 14) after vaccination. The age range was 18 to 79 years (median, 48), with no sex preponderance and no identifiable medical risk factors. Overall mortality was 22%. The odds of death increased by a factor of 2.7 (95% confidence interval [CI], 1.4 to 5.2) among patients with cerebral venous sinus thrombosis, by a factor of 1.7 (95% CI, 1.3 to 2.3) for every 50% decrease in the baseline platelet count, by a factor of 1.2 (95% CI, 1.0 to 1.3) for every increase of 10,000 fibrinogen-equivalent units in the baseline d-dimer level, and by a factor of 1.7 (95% CI, 1.1 to 2.5) for every 50% decrease in the baseline fibrinogen level. Multivariate analysis identified the baseline platelet count and the presence of intracranial hemorrhage as being independently associated with death; the observed mortality was 73% among patients with platelet counts below 30,000 per cubic millimeter and intracranial hemorrhage. CONCLUSIONS: The high mortality associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage. Treatment remains uncertain, but identification of prognostic markers may help guide effective management. (Funded by the Oxford University Hospitals NHS Foundation Trust.).

Impact of thromboprophylaxis on hospital acquired thrombosis following discharge in patients admitted with COVID-19: Multicentre observational study in the UK.

Post-discharge thromboprophylaxis in patients admitted with COVID-19 remains controversial. We aimed to determine the impact of thromboprophylaxis on hospital acquired thrombosis (HAT) in patients (≥18 years) discharged following admission for COVID-19 in an observational study across 26 NHS Trusts in the UK (01.04.2020-31.12.2021). Overall, 8895 patients were included to the study: 971 patients were discharged with thromboprophylaxis and propensity score matched (PSM) with a desired ratio of 1:1, from patients discharged without thromboprophylaxis. Patients with heparin induced thrombocytopenia, major bleeding during admission and pregnant women were excluded. As expected from 1:1 PSM, no difference was observed in parameters between the two groups, including duration of hospital stay, except the thromboprophylaxis group had a significantly higher proportion who had received therapeutic dose anticoagulation during admission. There were no differences in the laboratory parameters especially D-dimers between the two groups at admission or discharge. Median duration of thromboprophylaxis following discharge from hospital was 4 weeks (1-8 weeks). No difference was found in HAT in patients discharged with TP versus no TP (1.3% vs. 0.92%, p = 0.52). Increasing age and smoking significantly increased the risk of HAT. Many patients in both cohorts had raised D-dimer at discharge but D-dimer was not associated with increased risk of HAT.

Cardiovascular disease in hereditary haemophilia: The challenges of longevity.

The development of effective and safe treatments has significantly increased the life expectancy of persons with haemophilia (PWH). This has been accompanied by an increase in the comorbidities of ageing including cardiovascular disease, which poses particular challenges due to the opposing risks of bleeding from haemophilia and antithrombotic treatments versus thrombosis. Although mortality secondary to coronary artery disease in PWH is less than in the general population, the rate of atherosclerosis appears similar. The prevalence of atrial fibrillation in PWH and risk of secondary thromboembolic stroke are not well established. PWH can be safely supported through acute coronary interventions but data on the safety and efficacy of long-term antithrombotics are scarce. Increased awareness and research on cardiovascular disease in PWH will be crucial to improve primary prevention, acute management, secondary prevention and to best support ageing PWH.

Autoimmune disease and COVID-19: a multicentre observational study in the United Kingdom.

OBJECTIVE: To establish the demographic characteristics, laboratory findings and clinical outcomes in patients with autoimmune disease (AD) compared with a propensity-matched cohort of patients without AD admitted with COVID-19 to hospitals in the UK. METHODS: This is a multicentre observational study across 26 NHS Trusts. Data were collected both retrospectively and prospectively using a predesigned standardized case record form. Adult patients (≥18 years) admitted between 1 April 2020 and 31 July 2020 were included. RESULTS: Overall, 6288 patients were included to the study. Of these, 394 patients had AD prior to admission with COVID-19. Of 394 patients, 80 patients with SLE, RA or aPL syndrome were classified as severe rheumatologic AD. A higher proportion of those with AD had anaemia [240 (60.91%) vs 206 (52.28%), P = 0.015], elevated LDH [150 (38.08%) vs 43 (10.92%), P < 0.001] and raised creatinine [122 (30.96%) vs 86 (21.83%), P = 0.01], respectively. A significantly higher proportion of patients with severe rheumatologic AD had elevated CRP [77 (96.25%) vs 70 (87.5%), P = 0.044] and LDH [20 (25%) vs 6 (7.5%), P = 0.021]. Patients with severe rheumatologic AD had significantly higher mortality [32/80 (40%)] compared with propensity matched cohort of patients without AD [20/80 (25%), P = 0.043]. However, there was no difference in 180-day mortality between propensity-matched cohorts of patients with or without AD in general (P = 0.47). CONCLUSIONS: Patients with severe rheumatologic AD had significantly higher mortality. Anaemia, renal impairment and elevated LDH were more frequent in patients with any AD while elevated CRP and LDH were more frequent in patients with severe rheumatologic AD both of which have been shown to associate with increased mortality in patients with COVID-19.

Management of COVID-19-associated coagulopathy in persons with haemophilia.

INTRODUCTION: The SARS-CoV-2 coronavirus-induced infection (COVID-19) can be associated with a coagulopathy mainly responsible for pulmonary microvasculature thrombosis and systemic thromboembolic manifestations. The pathophysiology and management of the COVID-19 coagulopathy are likely more complex in patients with inherited bleeding diseases such as haemophilia. These individuals might indeed present with both bleeding and thrombotic complications and require simultaneous antithrombotic and haemostatic treatments. OBJECTIVE: We propose practical guidance for the diagnosis and management of COVID-19 coagulopathy in persons with haemophilia. RESULTS: Continuation of regular haemostatic treatment is recommended for ambulatory patients. For patients requiring hospital admission and on replacement therapy with factors VIII or IX concentrates, prophylaxis with concentrates should be intensified according to the risk of bleeding complications and associated with prophylactic doses of LMWH. For patients on nonreplacement therapy, emicizumab should be continued and possibly combined with factor VIII and prophylactic doses of LMWH depending on the risk of bleeding and thrombosis. Dose escalation of LMWH tailored to the risk of thrombosis can be employed but not supported by evidence. CONCLUSIONS: These practical recommendations are based on the current literature on COVID-19 with its impact on haemostasis, indications and modalities for thromboprophylaxis mainly in nonhaemophilic patients and how that is likely to affect persons with haemophilia in different circumstances. They will need to be tailored to each patient's clinical status and validated in future studies.

Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic.

This document aims to provide practical guidance for the assessment and management of patients with thrombocytopenia, with a particular focus on immune thrombocytopenia (ITP), during the COVID-19 pandemic. The intention is to support clinicians and, although recommendations have been provided, it is not a formal guideline. Nor is there sufficient evidence base to conclude that alternative approaches to treatment are incorrect. Instead, it is a consensus written by clinicians with an interest in ITP or coagulation disorders and reviewed by members of the UK ITP forum.

Kreuth V initiative: European consensus proposals for treatment of hemophilia using standard products, extended half-life coagulation factor concentrates and non-replacement therapies.

This report contains the updated consensus recommendations for optimal hemophilia care produced in 2019 by three Working Groups (WG) on behalf of the European Directorate for Quality of Medicines and Healthcare in the frame of the Kreuth V Initiative. WG1 recommended access to prophylaxis for all patients, the achievement of plasma factor trough levels of at least 3-5% when extended half-life factor VIII (FVIII) and FIX products are used, a personalized treatment regimen, and a choice of chromogenic assays for treatment monitoring. It was also emphasized that innovative therapies should be supervised by hemophilia comprehensive care centers. WG2 recommended mandatory collection of postmarketing data to assure the long-term safety and efficacy of new hemophilia therapies, the establishment of national patient registries including the core data recommended by the European Medicines Agency and the International Society on Thrombosis and Haemostasis, with adequate support under public control, and greater collaboration to facilitate a comprehensive data evaluation throughout Europe. WG3 discussed methodological aspects of hemophilia care in the context of access decisions, particularly for innovative therapies, and recommended that clinical studies should be designed to provide the quality of evidence needed by regulatory authorities, HTA bodies and healthcare providers. The dialogue between all stakeholders in hemophilia care and patient organizations should be fostered to implement these recommendations.

Haemophilia and ageing.

Advances in the development of effective and safe treatments for haemophilia over the last 50 years have resulted in a significant increase in the life expectancy of persons with haemophilia (PWH). The management of this new cohort of middle-aged and elderly PWH is challenging because of the opposing risks of haemophilia and age-related cardiovascular disease and malignancy. Furthermore, this cohort of ageing PWH has the additional comorbidities of human immunodeficiency virus/hepatitis C and chronic haemophilic arthropathy. This article reviews the prevalence, underlying mechanisms and treatment strategies for managing these comorbidities. International collaboration is essential for registry data and further prospective trials to inform optimal evidence-based management for this rare disorder in the future.

Inherited Thrombophilia and Pregnancy Complications: Should We Test?

Recurrent miscarriages and pregnancy-related complications cause significant stress to couples looking for successful pregnancy outcome as well as to health care professionals. There is conflicting evidence with respect to the presence and the strength of associations between inherited thrombophilia and these complications. A complete thrombophilia screen is expensive, and no proven effective treatment for women with recurrent miscarriage and inherited thrombophilia is currently available. Based on the concept of microvascular thrombosis of the placenta, women with recurrent miscarriage and placenta-related complications frequently get treated with antithrombotic therapy. In this narrative review, the authors explore the evolving understanding and evidence of inherited thrombophilia in recurrent miscarriages and other pregnancy complications, and whether antithrombotic treatment would modify pregnancy outcome in women with inherited thrombophilia. Finally, they provide some personal recommendations based on available evidence for clinical practice. In summary, inherited thrombophilia testing is not required outside a clinical trial for women with recurrent pregnancy losses or late pregnancy complications. The presence of thrombophilia markers does not generally indicate additional therapy during pregnancy, even if a heritable thrombophilic defect is found in women with recurrent miscarriages or late pregnancy complications.

How to discuss gene therapy for haemophilia? A patient and physician perspective.

Gene therapy has the potential to revolutionise treatment for patients with haemophilia and is close to entering clinical practice. While factor concentrates have improved outcomes, individuals still face a lifetime of injections, pain, progressive joint damage, the potential for inhibitor development and impaired quality of life. Recently published studies in adeno-associated viral (AAV) vector-mediated gene therapy have demonstrated improvement in endogenous factor levels over sustained periods, significant reduction in annualised bleed rates, lower exogenous factor usage and thus far a positive safety profile. In making the shared decision to proceed with gene therapy for haemophilia, physicians should make it clear that research is ongoing and that there are remaining evidence gaps, such as long-term safety profiles and duration of treatment effect. The eligibility criteria for gene therapy trials mean that key patient groups may be excluded, eg children/adolescents, those with liver or kidney dysfunction and those with a prior history of factor inhibitors or pre-existing neutralising AAV antibodies. Gene therapy offers a life-changing opportunity for patients to reduce their bleeding risk while also reducing or abrogating the need for exogenous factor administration. Given the expanding evidence base, both physicians and patients will need sources of clear and reliable information to be able to discuss and judge the risks and benefits of treatment.

Prophylaxis in von Willebrand Disease: Coming of Age?

Although in most cases von Willebrand disease (VWD) is a mild disorder, a subgroup of patients experience frequent bleeding. In contrast to severe hemophilia in which prophylaxis is the accepted standard of care, this is less frequently used in VWD. Most type 1 VWD patients can be adequately managed with episodic desmopressin and tranexamic acid. In patients with more severe disease, especially those with type 3 VWD, joint bleeds, epistaxis, menorrhagia, and gastrointestinal bleeding are problematic and usually require treatment with von Willebrand factor/factor VIII (VWF/FVIII) concentrate. While in the past these patients were managed with on-demand VWF/FVIII concentrate, several recent reports have demonstrated the value of prophylactic treatment. Despite some uncertainties about the economic impact of treatment of severe VWD, prophylaxis with VWF concentrate should now be considered as the standard of care for the more severe end of the spectrum of affected individuals. The recent introduction of recombinant VWF concentrate is likely to improve the acceptability of prophylaxis in VWD.

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects.

Inherited thrombocytopenias are a heterogeneous group of disorders characterized by abnormally low platelet counts which can be associated with abnormal bleeding. Next-generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease-causing genes. However its full potential has not yet been exploited. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown etiology with platelet counts varying from 11×109/L to 186×109/L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified "pathogenic" or "likely pathogenic" variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases, including novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia.