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PubMed | Katharine Dormandy Haemophilia Center and Thrombosis Unit, Royal Free London NHS Foundation Trust, University College London and Haemonetics
Type: Case Reports | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2016

Here, we describe the first use of thromboelastography (TEG) in the management of 2 cases of Ebola virus disease. Early in their illness, both patients had evidence of a consumptive coagulopathy. As this resolved, TEG demonstrated that both developed a marked hypercoagulable state, which was treated with low-molecular-weight heparin.


McLaughlin P.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Chowdary P.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Woledge R.,King's College London | McCarthy A.,University of Brighton | Mayagoitia R.,King's College London
Clinical Biomechanics | Year: 2013

Background The ankle continues to be one of the most affected joints in the haemophilia patient, and as cartilage damage progresses, the joint can feel unstable, painful and stiff. Anecdotally, patients often report that sports trainers can improve their pain and daily function, however the actual mechanism for this remains unclear. Methods Nine patients with ankle haemarthropathy and three controls were examined using 'CODAmotion' analysis and a force plate. Kinematic and kinetic variables of the hip, knee and ankle were recorded. Data was imported from CODA to Excel, where a programme using 2D modelling of the ankle joint forces was employed. This calculated intra-articular force from heel strike to toe-off. Findings The haemophilia group at midstance showed an increase in intra-articular force in the ankle when wearing the trainer compared to the shoe (P = < 0.05). Overall the haemophilia cohort had an increased joint force in both the trainers and shoes, compared to controls. Interpretation The type of footwear worn by individuals with ankle arthropathy has a significant effect on the amount of force acting at the joint surface. Sports shoes, in providing better comfort and foot support, may facilitate an increased muscular activity around the ankle and therefore improved dynamic joint stability, accounting for why some patients with ankle arthropathy report less pain. Further research is needed to establish levels of acceptable force and the combined effects of orthotics and footwear. © 2013 Elsevier Ltd.


Foley J.H.,Freeline Therapeutics | Foley J.H.,Katharine Dormandy Haemophilia Center and Thrombosis Unit
Thrombosis Research | Year: 2016

The coagulation and complement systems are ancestrally related enzymatic cascades of the blood. Although their primary purposes have diverged over the past few hundred million years, they remain inextricably connected. Both complement and coagulation systems limit infection by pathogens through innate immune mechanisms. Recently, it has been shown that hyperactive complement (in particular, elevated C5a/C5b-9) is involved in the pathogenesis (including thrombosis) of diseases such as paroxysmal nocturnal hemoglobinuria, atypical haemolytic uremic syndrome, antiphospholipid syndrome and bacteremia. Although these diseases together account for many thrombosis cases, there are many more where complement activation is not considered a causative factor leading to thrombosis. To better understand what role complement may play in the pathogenesis of thrombosis a better understanding of the mechanisms that cause over-active complement in thrombotic disease is required. © 2016 Elsevier Ltd


Van De Putte D.E.F.,University Utrecht | Makris M.,Royal Hallamshire Hospital | 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.


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.


Ozelo M.,University of Campinas | Chowdary P.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Regnault A.,Mapi | Busk A.K.,Novo Nordisk AS
Haemophilia | Year: 2015

Summary: Haemophilia and its treatment interfere with patients' life and may affect adherence to treatment. This study explored the impact of severe haemophilia A on patients' health status, especially in young adults (YA), using data from guardian™ 1, a multinational, open-label, non-controlled phase 3 trial investigating safety and efficacy of turoctocog alfa (NovoEight®) in previously treated patients aged 12 years and older with severe haemophilia A (FVIII ≤ 1%). Health status was assessed using the EuroQoL-5 dimensions (EQ-5D-3L), covering 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), and a visual analogue scale (VAS) measuring self-rated overall health status. EQ-5D was administered pretreatment (screening/baseline) and posttreatment (end-of-trial). Baseline responses to the EQ-5D dimensions and VAS were described overall and by age and compared to reference values from UK general population. Guardian™ 1 included 150 patients (16 adolescents, 83 YA aged 16-29 and 51 adults aged 30+). All five dimensions of patients' health status were impacted at baseline. The percentage of haemophilia patients reporting problems was consistently significantly greater than age-matched general population reference values. Likewise, for all age groups mean baseline EQ-5D VAS score was significantly lower for haemophilia patients (YA: 78.0) than for the general population (YA aged 18-29: 87.3). The health status of patients with severe haemophilia A entering guardian™ 1 was markedly poorer than that of the general population, particularly regarding mobility and pain. YA patients reported better health status than older patients, but considerably lower than that of the general YA population. © 2015 John Wiley & Sons Ltd214 July 2015 10.1111/hae.12617 Original Article Original Articles Clinical haemophilia © 2015 The Authors. Haemophilia Published by John Wiley & Sons Ltd..


Rallapalli P.M.,University College London | Kemball-Cook G.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Tuddenham E.G.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Gomez K.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Perkins S.J.,University College London
Journal of Thrombosis and Haemostasis | Year: 2013

Background: Factor IX (FIX) is important in the coagulation cascade, being activated to FIXa on cleavage. Defects in the human F9 gene frequently lead to hemophilia B. Objective: To assess 1113 unique F9 mutations corresponding to 3721 patient entries in a new and up-to-date interactive web database alongside the FIXa protein structure. Methods: The mutations database was built using MySQL and structural analyses were based on a homology model for the human FIXa structure based on closely-related crystal structures. Results: Mutations have been found in 336 (73%) out of 461 residues in FIX. There were 812 unique point mutations, 182 deletions, 54 polymorphisms, 39 insertions and 26 others that together comprise a total of 1113 unique variants. The 64 unique mild severity mutations in the mature protein with known circulating protein phenotypes include 15 (23%) quantitative type I mutations and 41 (64%) predominantly qualitative type II mutations. Inhibitors were described in 59 reports (1.6%) corresponding to 25 unique mutations. Conclusion: The interactive database provides insights into mechanisms of hemophilia B. Type II mutations are deduced to disrupt predominantly those structural regions involved with functional interactions. The interactive features of the database will assist in making judgments about patient management. © 2013 International Society on Thrombosis and Haemostasis.


Lheriteau E.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Lheriteau E.,University College London | Davidoff A.M.,St Jude Childrens Research Hospital | Nathwani A.C.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | And 2 more authors.
Blood Reviews | Year: 2015

Current treatment for haemophilia entails life-long intravenous infusion of clotting factor concentrates. This is highly effective at controlling and preventing haemorrhage and its associated complications. Clotting factor replacement therapy is, however, demanding, exceedingly expensive and not curative. In contrast, gene therapy for haemophilia offers the potential of a cure as a result of continuous endogenous expression of biologically active factor VIII (FVIII) or factor IX (FIX) proteins following stable transfer of a normal copy of the respective gene. Our group has recently established the first clear proof-of-concept for a gene therapy approach to the treatment of severe haemophilia B. This entails a single intravenous administration of an adeno-associated virus vector encoding an optimised FIX gene, resulting in a long-term (> 4 years) dose dependent increase in plasma FIX levels at therapeutic levels without persistent or late toxicity. Gene therapy therefore has the potential to change the treatment paradigm for haemophilia but several hurdles need to be overcome before this can happen. This review provides a summary of the progress made to date and discusses the remaining changes. © 2015 Elsevier Ltd.


Vinayagam S.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Simons L.R.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Chowdary P.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | Thurlow P.,Katharine Dormandy Haemophilia Center and Thrombosis Unit | And 2 more authors.
Haemophilia | Year: 2014

Haemostatic management of surgery in patients with von Willebrand disease (VWD) includes DDAVP® or von Willebrand factor (VWF)-containing concentrates. Although the recommendations are for monitoring by VWF activity assays, it is quite common for clinicians to use factor VIII due usually to longer turnaround times required for VWF ristocetin cofactor assay (VWF:RCo) measurements. The aim of this study was to evaluate use of the rapid HaemosIL™ VWF activity (VWF:Act) latex immuno assay (LIA) on an automated coagulometer (ACL TOP™ 700; Instrumentation Laboratory, Bedford, MA, USA) compared to platelet-based VWF:RCo assays in this setting. One hundred and sixty-seven plasma samples from 42 patients [Type 1 (n = 22), Type 2A (n = 2), Type 2B (n = 3), Type 2M (n = 10), Type 3 (n = 3)] and acquired von Willebrand syndrome (n = 2) with VWD treated with DDAVP® or VWF-containing concentrates were included in the study. Method comparison and method bias were evaluated by Bland-Altman analysis (BA) and Passing and Bablok regression modelling respectively. BA of baseline samples (n = 39) showed a mean difference of -3.0 (±1.96 SD -25.2 to +19.4). Post (treatment) samples (n = 120) were separated into two groups. Group 1 contained samples with VWF:RCo levels 10 to ≤175 IU dL-1 (n = 97) and group 2, samples with VWF:RCo levels >175 IU dL-1 (n = 23). BA of group 1 postsamples showed a mean difference of +3.4 (±1.96 SD -44.6 to +51.5), and the BA of Group 2 samples was -23.9 (±1.96 SD -136.1 to +88.3). In conclusion, use of HaemosIL VWF:Act LIA test on an automated coagulometer is a reproducible and rapid assay that can be used as an alternative test for monitoring VWF replacement therapy, facilitating dose adjustments on a real-time basis. © 2014 John Wiley & Sons Ltd.


PubMed | Katharine Dormandy Haemophilia Center and Thrombosis Unit and University of Cambridge
Type: | Journal: British journal of haematology | Year: 2016

Inherited disorders of platelet granules are clinically heterogeneous and their prevalence is underestimated because most patients do not undergo a complete diagnostic work-up. The lack of a genetic diagnosis limits the ability to tailor management, screen family members, aid with family planning, predict clinical progression and detect serious consequences, such as myelofibrosis, lung fibrosis and malignancy, in a timely manner. This is set to change with the introduction of high throughput sequencing (HTS) as a routine clinical diagnostic test. HTS diagnostic tests are now available, affordable and allow parallel screening of DNA samples for variants in all of the 80 known bleeding, thrombotic and platelet genes. Increased genetic diagnosis and curation of variants is, in turn, improving our understanding of the pathobiology and clinical course of inherited platelet disorders. Our understanding of the genetic causes of platelet granule disorders and the regulation of granule biogenesis is a work in progress and has been significantly enhanced by recent genomic discoveries from high-powered genome-wide association studies and genome sequencing projects. In the era of whole genome and epigenome sequencing, new strategies are required to integrate multiple sources of big data in the search for elusive, novel genes underlying granule disorders.

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