Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A.

INTRODUCTION: Valoctocogene roxaparvovec is an investigational AAV5-based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A. AIM: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795). METHODS: Men ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti-AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 1013 vg/kg dose, n = 7) and 4 years (4 × 1013 vg/kg dose, n = 6). RESULTS: Over the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was -0.14 (95% confidence interval [CI]: -.32 to .03) IU/dl/wk in the 6 × 1013 vg/kg cohort in year 5 and -.06 (95% CI: -.14 to .01) IU/dl/wk in the 4 × 1013 vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 1013 vg/kg cohort; all six Haemo-QOL-A domain scores increased. For the 4 × 1013 vg/kg cohort, high baseline Haemo-QOL-A scores persisted. CONCLUSION: These results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A

Adenovirus-Associated Virus Vector-Mediated Gene Transfer in Hemophilia B

NIHR (RP-PG-0310-1001), the Medical Research Council, the Katharine Dormandy Trust, the U.K. Department of Health, NHS Blood and Transplant, the NIHR Biomedical Research Centers (to University College London Hospital and University College London), the ASSISI Foundation of Memphis, the American Lebanese Syrian Associated Charities, the Howard Hughes Medical Institute, the National Heart, Lung, and Blood Institute (HL094396), the Royal Free Hospital Charity Special Trustees Fund 35, the Royal Free Hospital NHS Trust, and St. Jude Children’s Research Hospita

Will gene therapy trump factor treatment in hemophilia?

Hemophilia treatment is entering a new phase, with the exciting possibility of gene therapy promising a cure. Novel gene transfer strategies are being considered for patients with inhibitors.Improvement of factor-replacement therapy is being aggressively pursued with long-acting factor concentrates, many of which are in clinical trials. Whether gene therapy will be safe and cost effective to eventually supersede factor-replacement therapy is yet to be determined. It is hoped that with the profusion of clinical trial programs in hemophilia care, it will eventually provide affordable treatment to many patients who currently cannot access adequate treatment in the developing countries.</p

Haemostasis screening

Haemostasis comprises the balanced orchestration of vascular integrity, circulating procoagulant and anticoagulant proteins, and cellular blood components (Moore and Rangarajan, 2009). Disturbances of one or more of these integrated compartments can lead to abnormal bleeding. The main reasons for requiring haemostasis screening tests are preoperative checks, investigation of bleeding or monitoring of anticoagulant therapy. </jats:p

The clinical implications of ADAMTS13 function: The perspectives of Haemostaseologists

Apart from TTP, ADAMTS13 may be an important player in those conditions where Von Willebrand Factor and the Platelet Glycoprotein GP Ib axis have a part to play in the pathogenesis. This includes stroke, myocardial infarction, sepsis and inflammatory condition. This article reviews the literature in these conditions.</p

The activated seven lupus anticoagulant assay detects clinically significant antibodies

Lupus anticoagulants are a heterogeneous group of autoantibodies detected by their effects on phospholipid-dependent coagulation assays. Persistent lupus anticoagulants are associated with thrombotic disease, but not all are clinically significant. Antibody heterogeneity and reagent and test variability dictate that at least 2 tests, of different types, should be used to screen lupus anticoagulants. The objective of this study was to investigate whether the activated seven lupus anticoagulant assay detects clinically significant antibodies. Eighty-two patients with antiphospholipid syndrome (APS) and 32 with systemic lupus erythematosus + positive for activated seven lupus anticoagulant and who were without thrombosis, who were positive by activated seven lupus anticoagulant assay, were investigated for lupus anticoagulants by dilute Russell's viper venom time, dilute activated partial thromboplastin time, and Taipan snake venom time, and for anticardiolipin antibodies. Fifty-seven of the APS patients were positive for lupus anticoagulants in multiple assays, 25 in activated seven lupus anticoagulant alone. Fourteen of the latter group were previously positive in other antiphospholipid antibodies assays, and 11 had only been positive for lupus anticoagulants by activated seven lupus anticoagulant. Twenty-eight had elevated anticardiolipin antibodies, 6 of whom were from the group that was positive in activated seven lupus anticoagulant only. Eight of the systemic lupus erythematosus + lupus anticoagulants (without thrombosis) patients were positive for lupus anticoagulant by activated seven lupus anticoagulant alone and had only been positive in activated seven lupus anticoagulant previously, and none had elevated anticardiolipin antibodies. The remaining 24 patients were lupus-anticoagulant positive in multiple assays, and 9 had elevated anticardiolipin antibodies. Dilute Russell's viper venom time and Dilute activated partial thromboplastin time are widely used to detect lupus anticoagulants and are considered to detect clinically significant antibodies. Activated seven lupus anticoagulant detected antibodies in APS patients who were positive by these assays and also lupus anticoagulants undetectable by the dilute Russell's viper venom time/dilute activated partial thromboplastin time reagents used, demonstrating its utility as a first-line or second-line assay.</p

Management of haemophilia A with inhibitors: A regional cross-talk

Introduction The development of inhibitors with factor VIII (FVIII) replacement therapy is one of the most common and challenging complications of haemophilia A (HA) treatment, jeopardising treatment efficacy and predisposing patients to high risks of morbidity and mortality. The management of patients with inhibitors is particularly challenging in countries where resources are limited. Aim To provide a comprehensive summary of the management of HA with inhibitors while focusing on differences in practice between Western and non-Western countries and how resource scarcity can impact HA management, leading to suboptimal outcomes in patients with inhibitors. Methods Summary of key evidence and regional expert opinion. Results We address, particularly, the diagnosis of and testing for inhibitors, as well as the epidemiology of inhibitors, including incidence, prevalence and disease burden. Secondly, we provide an overview of the current treatment landscape in HA with inhibitors regarding the eradication of inhibitors with immune tolerance induction and the treatment and prevention of bleeding with bypassing agents, non-factor replacement agents and other experimental therapies. This is complemented with insights from the authors around the applicability of, and challenges associated with, such therapies in their settings of practice. Conclusions We conclude by proposing some key steps towards bridging the gaps in the management of HA with inhibitors in resource-limited countries, including: (1) the collection of quality data that can inform healthcare reforms and policies; (2) improving disease knowledge among healthcare practitioners and patients with the aim of standardising disease management across centres and (3) working towards promoting equal access to HA care and therapies for everyone.Takeda Pharmaceuticals FZCOAll authors have contributed equally to this manuscript. The authors thank Sarah Keyrouz of AMICULUM for medical editorial assistance. Financial support for medical editorial assistance was provided by Takeda Pharmaceuticals FZCO

COVID‐19 and preeclampsia: the unique and the mutually nonexclusive clinical manifestations

Preeclampsia (PE) is a serious, unpredictable hypertensive disorder of pregnancy present in around 8–10% of all pregnancies resulting in high rate of maternal and fetal morbidity and mortality. With the pathophysiology partially known, delivery is the only cure for PE. The disease sets due to multiple pathologic processes involving endothelial cell activation, inflammation, multiorgan damage and syncytiotrophoblast stress. Though the primary target organ is lungs in COVID-19, other systemic manifestations which include endothelial dysfunction, dysregulated angiogenesis, thrombosis, liver injury, thrombocytopenia, hypertension and kidney damage overlap with PE. COVID-19 patients show a higher incidence of PE as compared to their noninfected counterparts and vice versa. Similar pathophysiology and clinical features make differential diagnosis challenging. For effective and specific management, it is important to differentiate actual PE from COVID-19 with PE like features. There are contradictory reports about the accuracy of diagnostic tools in distinguishing PE from severe COVID-19 with PE like features. With the available data, it can only be stated that PE is a common adverse pregnancy event, which may be exacerbated by, or may exacerbate, COVID-19. Future research should focus on cohesive understanding of the pathophysiology of the clinical manifestations, and preventive strategies during pregnancy