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Hedner U.,Lund University | Lee C.A.,University of London | Lee C.A.,Oxford Haemophilia and Thrombosis Center
Haemophilia | Year: 2011

This review describes the background for the development of recombinant FVIIa (rFVIIa; NovoSeven) for use in haemophilic patients with inhibitors. The first proof of principle for using pharmacological doses of FVIIa as a haemostatic agent was obtained by producing small amounts of pure plasma-derived FVIIa, which showed encouraging effect in two patients with haemophilia A and inhibitors. To make pure FVIIa available for use in a larger number of patients, rFVIIa was produced that was approved for use in patients with inhibitors against coagulation factors (congenital haemophilia and acquired haemophilia) in 1996 (EU), 1999 (USA) and 2000 (Japan). The efficacy rate in severe bleedings and in major surgery including major orthopaedic surgery has been found to be around 90% in controlled studies, and no serious safety concerns have been demonstrated. The availability of rFVIIa has facilitated the performance of elective major surgery in haemophilia patients with inhibitors. Further steps along the vision of providing a treatment for inhibitor patients similar to non-inhibitor patients have been the efficacy of rFVIIa in home-treatment and recently the encouraging experience in prophylaxis. The concept of using pharmacological doses of rFVIIa as a haemostatic agent is a new one, which has caused difficulties in finding the correct dose. A step forward has been the demonstration that similar efficacy can be achieved after one single dose of 270μgkg-1 instead of three injections of a dose of 90μgkg-1. The higher clearance rate in children suggests that higher doses may be beneficial in children. The availability of rFVIIa has made advances in the understanding of coagulation processes possible. In a cell-based in vitro model, it has been shown that rFVIIa binds to preactivated platelets if present in concentrations of 30nm or higher. By doing so, it activates FX into FXa and enhances the thrombin generation on the activated platelet surface in the absence of FVIII/FIX. Through the increased thrombin generation, a firm, well-structured fibrin haemostatic plug, which is resistant to premature lysis, is formed. By exploiting this mechanism of action, rFVIIa may also be effective in situations other than haemophilia, characterized by an impaired thrombin generation. © 2010 Blackwell Publishing Ltd. Source


Alsousou J.,University of Oxford | Ali A.,University of Oxford | Willett K.,University of Oxford | Harrison P.,Oxford Haemophilia and Thrombosis Center
Platelets | Year: 2013

Platelet-rich plasma (PRP), an autologous derivative of whole blood that contains a supraphysiological concentration of platelets, has gained increasing attention in both the scientific literature and the wider media for its potential application in the treatment of traumatic musculoskeletal injury. The theoretical benefit of PRP in providing a local environment for tissue regeneration which is rich in growth factors and other cytokines has been supported by in vitro and animal studies which suggest a positive influence on the migration and proliferation of a number of cell types. However, the reported clinical use of PRP is largely confined to the last two decades and initially centred around its application in dental and maxillofacial surgery. More recently, developments in research of the regenerative effects of PRP in a range of tissue types including bone, cartilage, tendon and muscle, particularly in the context of traumatic injury, have attracted interest in fields such as orthopaedic and plastic surgery where effective union of sometimes poorly vascularised and damaged tissue is a critical determinant of successful clinical outcome. Despite the lack of high-quality trial data, results from clinical studies have been encouraging, and PRP administration remains an attractive strategy given its cost-effective and minimally invasive nature. In this review, we summarise the current literature on the use of PRP and highlight areas of controversy and emerging clinical applications. © 2013 Informa UK Ltd. Source


van der Pol E.,University of Amsterdam | Boing A.N.,University of Amsterdam | Harrison P.,Oxford Haemophilia and Thrombosis Center | Sturk A.,University of Amsterdam | Nieuwland R.,University of Amsterdam
Pharmacological Reviews | Year: 2012

Both eukaryotic and prokaryotic cells release small, phospholipid-enclosed vesicles into their environment. Why do cells release vesicles? Initial studies showed that eukaryotic vesicles are used to remove obsolete cellular molecules. Although this release of vesicles is beneficial to the cell, the vesicles can also be a danger to their environment, for instance in blood, where vesicles can provide a surface supporting coagulation. Evidence is accumulating that vesicles are cargo containers used by eukaryotic cells to exchange biomolecules as transmembrane receptors and genetic information. Because also bacteria communicate to each other via extracellular vesicles, the intercellular communication via extracellular cargo carriers seems to be conserved throughout evolution, and therefore vesicles are likely to be a highly efficient, robust, and economic manner of exchanging information between cells. Furthermore, vesicles protect cells from accumulation of waste or drugs, they contribute to physiology and pathology, and they have a myriad of potential clinical applications, ranging from biomarkers to anticancer therapy. Because vesicles may pass the blood-brain barrier, they can perhaps even be considered naturally occurring liposomes. Unfortunately, pathways of vesicle release and vesicles themselves are also being used by tumors and infectious diseases to facilitate spreading, and to escape from immune surveillance. In this review, the different types, nomenclature, functions, and clinical relevance of vesicles will be discussed. © 2012 by The American Society for Pharmacology and Experimental Therapeutics. Source


Negrier C.,University of Lyon | Knobe K.,Lund University | Tiede A.,Hannover Medical School | Giangrande P.,Oxford Haemophilia and Thrombosis Center | Moss J.,Novo Nordisk AS
Blood | Year: 2011

Replacement therapy with factor IX (FIX) concentrates is the recommended treatment for patients with hemophilia B, an X-linked bleeding disorder occurring in 1:25 000 male births. N9-GP is a recombinant FIX molecule with a prolonged half-life which is obtained by site-directed glycoPEGylation where a 40-kDa polyethylene glycol molecule is attached to the activation peptide of FIX. This first human dose trial in patients with hemophilia B investigated the safety and pharmacokinetic properties of a single IV dose of N9-GP. Sixteen previously treated patients received one dose of their previous FIX product followed by one dose of N9-GP at the same dose level (25, 50, or 100 U/kg). None of the patients developed inhibitors. One patient developed transient hypersensitivity symptoms during administration of N9-GP and was excluded from pharmacokinetic analyses. In the remaining 15 patients, N9-GP was well-tolerated. The half-life was 93 hours, which was 5 times higher than the patient's previous product. The incremental recovery of N9-GP was 94% and 20% higher compared with recombinant and plasma-derived products, respectively. These results indicate that N9-GP has the potential to reduce dosing frequency while providing effective treatment of bleeding episodes with a single dose. The trial was registered at www.clinicaltrials.gov as NCT00956345. © 2011 by The American Society of Hematology. Source


Lordkipanidze M.,University of Birmingham | Harrison P.,Oxford Haemophilia and Thrombosis Center
Journal of Thrombosis and Haemostasis | Year: 2012

See also Rocca B, Santilli F, Pitocco D, Mucci L, Petrucci G, Vitacolonna E, Lattanzio S, Mattoscio D, Zaccardi F, Liani R, Vazzana N, Del Ponte A, Ferrante E, Martini F, Cardillo C, Morosetti R, Mirabella M, Ghirlanda G, Davi G, Patrono C. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. This issue, pp 1220-30. © 2012 International Society on Thrombosis and Haemostasis. Source

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