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Foley J.H.,University College London | Foley J.H.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Conway E.M.,University of British Columbia
Circulation Research | Year: 2016

Anatomic pathology studies performed over 150 years ago revealed that excessive activation of coagulation occurs in the setting of inflammation. However, it has taken over a century since these seminal observations were made to delineate the molecular mechanisms by which these systems interact and the extent to which they participate in the pathogenesis of multiple diseases. There is, in fact, extensive cross talk between coagulation and inflammation, whereby activation of one system may amplify activation of the other, a situation that, if unopposed, may result in tissue damage or even multiorgan failure. Characterizing the common triggers and pathways are key for the strategic design of effective therapeutic interventions. In this review, we highlight some of the key molecular interactions, some of which are already showing promise as therapeutic targets for inflammatory and thrombotic disorders. © 2016 American Heart Association, Inc.

Van De Putte D.E.F.,University Utrecht | Makris M.,Sheffield Haemophilia and Thrombosis Center | Fischer K.,University Utrecht | Yee T.T.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | And 5 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Patients with inherited bleeding disorders are an interesting group to study the long-term course of chronic hepatitis C virus (HCV) infection, because of their uniform mode of infection and reliable follow-up. Our aim was to assess the long-term occurrence of adverse liver-related events in these patients. Methods The occurrence and determinants of end-stage liver disease (ESLD) were assessed using retrospective data of 863 HCV infected patients with inherited bleeding disorders from the Netherlands and the UK. Results Median follow-up since HCV infection was 31 years, while 30% of patients had >35 follow-up years. Nineteen percent of patients spontaneously cleared the virus and 81% developed chronic HCV infection. Of the 700 patients with chronic HCV, 90 (13%) developed ESLD. Hepatocellular carcinoma (HCC) was diagnosed in 3% of patients with chronic HCV, 41% of which occurred in the last six years. Determinants of ESLD development were age at infection (hazard ratio (HR) 1.09 per year increase), HIV co-infection (HR 10.85), history of alcohol abuse (HR 4.34) and successful antiviral treatment (HR 0.14). Of the 487 patients who were still alive at the end of follow-up, 49% did not undergo optimal conventional antiviral treatment. Conclusions After over 30 years of HCV infection, ESLD occurred in a significant proportion of patients with inherited bleeding disorders. HCC appears to be an increasing problem. There is a significant potential for both conventional and new antiviral treatment regimens to try and limit ESLD occurrence in the future. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

High K.H.,Childrens Hospital of Philadelphia | Nathwani A.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Spencer T.,Emory University | Lillicrap D.,Kingston University
Haemophilia | Year: 2014

After many reports of successful gene therapy studies in small and large animal models of haemophilia, we have, at last, seen the first signs of success in human patients. These very encouraging results have been achieved with the use of adeno-associated viral (AAV) vectors in patients with severe haemophilia B. Following on from these initial promising studies, there are now three ongoing trials of AAV-mediated gene transfer in haemophilia B all aiming to express the factor IX gene from the liver. Nevertheless, as discussed in the first section of this article, there are still a number of significant hurdles to overcome if haemophilia B gene therapy is to become more widely available. The second section of this article deals with the challenges relating to factor VIII gene transfer. While the recent results in haemophilia B are extremely encouraging, there is, as yet, no similar data for factor VIII gene therapy. It is widely accepted that this therapeutic target will be significantly more problematic for a variety of reasons including accommodating the larger factor VIII cDNA, achieving adequate levels of transgene expression and preventing the far more frequent complication of antifactor VIII immunity. In the final section of the article, the alternative approach of lentiviral vector-mediated gene transfer is discussed. While AAV-mediated approaches to transgene delivery have led the way in clinical haemophilia gene therapy, there are still a number of potential advantages of using an alternative delivery vehicle including the fact that ex vivo host cell transduction will avoid the likelihood of immune responses to the vector. Overall, these are exciting times for haemophilia gene therapy with the likelihood of further clinical successes in the near future. © 2014 John Wiley & Sons Ltd.

Shepherd A.J.,Birkbeck, University of London | Skelton S.,Birkbeck, University of London | Sansom C.E.,Birkbeck, University of London | Gomez K.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | And 2 more authors.
British Journal of Haematology | Year: 2015

Over 500 missense F8 mutations have been reported to cause non-severe haemophilia A. Some F8 genotypes appear to confer a higher risk of inhibitor formation than others and individuals with the same F8 genotype may have differing risks of inhibitor formation. We present an in silico strategy demonstrating the heterogeneity of factor VIII (FVIII)-derived antigen presentation whilst identifying patterns of human leucocyte antigen (HLA) peptide binding that might predict future inhibitor risk. A well-validated computational tool, NetMHCII, enabled large-scale comparison of predicted antigen presentation between endogenous, mutated FVIII-derived peptides and wild-type, therapeutic FVIII-derived peptides spanning all F8 missense mutation positions reported to The Haemophilia A Mutation, Structure and Resource Site (HADB). We identify 40 F8 genotypes to be 'low risk' at a 50% inhibitory concentration (IC50)-binding threshold of 300 nmol/l (P = 0·00005), defined as absence of novel peptide-major histocompatibility complex (MHC) surfaces for all 14 common HLA-DR alleles assessed. Analysing each of the possible 7280 F8 genotype/HLA-DR permutations individually at an IC50 threshold of 300 nmol/l, 65% are predicted to not generate a novel peptide-MHC surface that would be necessary to engage T cell help for subsequent anti-FVIII antibody generation. This study demonstrates the future importance of interpreting F8 genotype in the context of an individual's HLA profile to personalize inhibitor risk prediction. © 2014 John Wiley & Sons Ltd.

Chi C.,Royal Free Hospital | Pollard D.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Tuddenham E.G.D.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Kadir R.A.,Royal Free Hospital
Journal of Pediatric and Adolescent Gynecology | Year: 2010

Study Objectives: We reviewed the management and treatment outcomes of menorrhagia in adolescents with inherited bleeding disorders and assessed the impact of menorrhagia on their quality of life. Design: Retrospective review of case notes and a questionnaire study. Setting: Comprehensive-care hemophilia treatment center. Participants: Adolescents with inherited bleeding disorders who had registered at the center and were attending the multidisciplinary hemophilia and gynecology clinic for management of menorrhagia. Interventions: Review of medical records and assessment of menstrual blood loss using the pictorial blood assessment chart and quality of life measurements during menstruation using a questionnaire. Main Outcome Measures: Scores on pictorial blood assessment charts and quality of life measurements before and after treatment. Results: Of 153 girls aged 12 to 19 years who had registered at the center and had an inherited bleeding disorder, 42 (27%) attended the multidisciplinary clinic for management of menorrhagia. The majority (38/42; 90%) had experienced menorrhagia since menarche. Of the group, 5 (12%) required hospital admission for acute menorrhagia and severe anemia. Treatment options for menorrhagia included tranexamic acid, desmopressin, combined oral contraceptive pills, clotting factor concentrate, and the levonorgestrel intrauterine system. These treatment modalities, alone or in combination, were associated with a reduction in menstrual blood loss (median pre- and posttreatment pictorial blood assessment chart scores were 215 and 88, respectively) and improvement in quality of life scores (median pre- and posttreatment were 26 and 44, respectively). Conclusions: Menorrhagia is a common symptom in adolescents with inherited bleeding disorders. It can present acutely, and it adversely affects quality of life. Treatment options include hemostatic and/or hormonal therapies and can improve the quality of life of affected girls. © 2010 North American Society for Pediatric and Adolescent Gynecology.

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