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Inhibitor haemophilia

H-H Brackmann, G C White, E Berntorp, T Andersen, C Escuriola-Ettingshausen
Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates continues to be the most serious complication of haemophilia A management. Induction of immune tolerance by administering high doses of FVIII concentrate (antigen) and prothrombin complex concentrates to control bleeding was originated in the 1970s in Bonn, Germany, by Dr Hans-Hermann Brackmann, and became known as the Bonn protocol. ITI transformed the life of the index patient, who was 19 years of age when he began treatment, and dramatically improved the medical landscape for all patients with haemophilia and inhibitors...
April 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
A Bar-Ilan, T Livnat, M Hoffmann, L Binder, M Zakar, R Guy, Y Felikman, L Moschcovich, B Shenkman, D Monroe, O Hershkovitz, G Kenet, G Hart
INTRODUCTION: Recombinant FVIIa (rFVIIa) is an effective treatment for haemophilia through frequent administration. However, the short half-life of rFVIIa decreases its prophylactic ability to reduce bleeding. Carboxy-terminal peptide (CTP)-modified FVIIa (MOD-5014) is a long-acting rFVIIa developed for on-demand treatment of haemophilia using either an intravenous or subcutaneous injection with the aim of less frequent administrations, as well as for prophylactic use. AIM: The comprehensive evaluation of the activity MOD-5014 vs commercially available rhFVIIa, as well as their interaction with cofactors and inhibitors...
March 14, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Cecilia Augustsson, Anders Svensson, Birgitte Kjaer, Tzu-Yuan Chao, Xia Wenjuan, Berit Olsen Krogh, Jens Breinholt, Jes Thorn Clausen, Ida Hilden, Helle Heibroch Petersen, Lars Christian Petersen
BACKGROUND: Initiation of coagulation is induced by binding of activated factor VII (FVIIa) to tissue factor (TF) and activation of factor X (FX) in a process regulated by tissue factor pathway inhibitor (TFPI). TFPI contains three Kunitz-type protease inhibitor domains (K1-K3) of which K1 and K2 block the active sites of FVIIa and FXa respectively. OBJECTIVE: To produce a monoclonal antibody (mAb) directed towards K1, to characterize the binding epitope, and to study its effect on TFPI inhibition...
March 12, 2018: Journal of Thrombosis and Haemostasis: JTH
Massimo Franchini, Pier Mannuccio Mannucci
One of the most challenging issues facing us in the treatment of haemophilia is the development of alloantibodies against infused factor VIII (FVIII) or factor IX (FIX). Inhibitors render factor replacement therapy ineffective, exposing patients to an unacceptably high risk of morbidity and mortality. Besides the well-known bypassing agents (i.e. activated prothrombin complex concentrate and recombinant activated factor VII) used to treat or prevent bleeding in haemophilia patients with inhibitors, there is growing interest in a new class of therapeutic agents which act by enhancing coagulation (i...
February 14, 2018: Blood Transfusion, Trasfusione del Sangue
K Vepsäläinen, P Riikonen, R Lassila, M Arola, P Huttunen, P Lähteenmäki, M Möttönen, T Selander, J Martikainen
AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use...
March 1, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Anita Árokszállási, Katalin Rázsó, Péter Ilonczai, Zsolt Oláh, Zsuzsanna Bereczky, Zoltán Boda, Ágota Schlammadinger
: In acquired haemophilia A (AHA), risk for recurrent bleeding exists until the inhibitor is detectable. Thus, patients with persisting inhibitor may benefit from prophylaxis with activated prothrombin complex concentrate (aPCC). Potential thromboembolic complications and cost are also factors to consider. Today, no high level evidence or clear recommendations are available on aPCC prophylaxis in AHA. Recently, a small prospective study demonstrated a favourable outcome with short-term, daily administered aPCC infusion...
February 22, 2018: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
S Dunkley, J C M Lam, M J John, R S M Wong, H Tran, R Yang, S C Nair, M Shima, A Street, A Srivastava
Optimal haemophilia care is best established and implemented through a well-coordinated plan guided by clearly defined principles and priorities. A document which enunciates those details is therefore important. A successful example of this approach is the definition of principles of haemophilia care (PHC) outlined by the European Association for Haemophilia and Associated Disorders (EAHAD) and also the World Federation of Hemophilia. A similar document applicable to the Asia-Pacific region must take into account not only the highly varied healthcare systems but also the tremendous socio-economic and cultural diversities which impact provision of such care...
February 21, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
B Boylan, C H Miller
INTRODUCTION: The use of pre-analytical heat treatment (PHT) with the Nijmegen-Bethesda assay (NBA) for inhibitors to factor VIII (FVIII) can remove/destroy infused or endogenous FVIII from patient plasma samples, allowing testing of recently infused patients with haemophilia. Two PHT methods have been described as follows: heating to 56°C for 30 minutes and heating to 58°C for 90 minutes. Data examining the effects of PHT on anti-FVIII IgG4 , the antibodies known to correlate most closely with the presence of FVIII inhibitors, are limited...
February 20, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Stella Thomassen, Tom G Mastenbroek, Frauke Swieringa, Kristien Winckers, Marion A H Feijge, Roy Schrijver, Judith M E M Cosemans, Susan A Maroney, Alan E Mast, Tilman M Hackeng, Johan W M Heemskerk
Tissue factor pathway inhibitor-alpha (TFPI-α) is a Kunitz-type serine protease inhibitor, which suppresses coagulation by inhibiting the tissue factor (TF)/factor VIIa complex as well as factor Xa. In static plasma-phospholipid systems, TFPI-α thus suppresses both factor Xa and thrombin generation. In this article, we used a microfluidics approach to investigate how TFPI-α regulates fibrin clot formation in platelet thrombi at low wall shear rate. We therefore hypothesized that the anticoagulant effect of TFPI-α in plasma is a function of the local procoagulant strength-defined as the magnitude of thrombin generation under flow, due to local activities of TF/factor VIIa and factor Xa...
February 16, 2018: Thrombosis and Haemostasis
C H Miller
Inhibitors are antibodies directed against haemophilia treatment products which interfere with their function. Factor VIII (FVIII) inhibitors in haemophilia A and factor IX (FIX) inhibitors in haemophilia B are significant clinically when they require a change in a patient's treatment regimen. Their persistence may increase morbidity and mortality. Multiple laboratory tests are now available for detecting and understanding inhibitors in haemophilia. Inhibitors are traditionally measured by their interference in clotting or chromogenic factor assays...
February 15, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
C Keipert, C J Jonker, H M van den Berg, A Hilger
INTRODUCTION: The "Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products" (ClinGL) provides the requirements for the performing of clinical trials (CTs) for marketing authorization in Europe. The number of eligible previously untreated patients (PUPs) for CTs might be difficult to meet because of the concurrent development of FVIII concentrates, and additional data sources must be explored. AIM: The extent to which CTs and the PedNet registry met relevant parameters, identified in the ClinGL, as well as inhibitor incidences were investigated in patients from both sources...
February 13, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
M Carcao, A Shapiro, J M Staber, N Hwang, C Druzgal, K Lieuw, M Belletrutti, C D Thornburg, S P Ahuja, J Morales-Arias, J Dumont, G Miyasato, E Tsao, N Jain, S W Pipe
INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI...
February 13, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
E Dubé, A Bonnefoy, C Merlen, J-F Castilloux, S Cloutier, C Demers, C A Sabapathy, J St-Louis, C Vezina, M Warner, G-É Rivard
INTRODUCTION: Following a provincial tender, most subjects with haemophilia A in Quebec switched their treatment to a third-generation recombinant B-domain-deleted factor VIII (FVIII). AIM: Our objective was to evaluate the incidence of inhibitor development and FVIII recovery in patients following the switch of factor replacement therapy. METHODS: One hundred and thirty-five subjects were enrolled and tested for FVIII activity and inhibitors every 6 months during 1 year...
February 1, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Gavin Ling, Amit C Nathwani, Edward G D Tuddenham
Haemophilia therapy has undergone very rapid evolution in the last 10 years. The major limitation of current replacement therapy is the short half-life of factors VIII and IX. These half-lives have been extended by the addition of various moieties, allowing less frequent infusion regimens. Entirely novel approaches have also entered the clinic, including a bispecific antibody that mimics factor VIII and strategies that rebalance the haemostatic mechanism by reducing antithrombin through inhibition of synthesis...
January 23, 2018: British Journal of Haematology
Lesley J Scott, Esther S Kim
Emicizumab-kxwh (Hemlibra®) is a bispecific humanized monoclonal antibody that restores the function of missing activated FVIII by bridging activated FIX and FX to facilitate effective haemostasis in patients with haemophilia A. Subcutaneous emicizumab-kxwh is approved in the USA for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and paediatric patients with haemophilia A (congenital FVIII deficiency) with FVIII inhibitors. Subcutaneous emicizumab-kxwh is awaiting approval in several countries worldwide, including in the EU and Japan, and is undergoing phase 3 development in haemophilia A without FVIII inhibitors...
February 2018: Drugs
Jamie O'Hara, Shaun Walsh, Charlotte Camp, Giuseppe Mazza, Liz Carroll, Christina Hoxer, Lars Wilkinson
OBJECTIVES: Target joints are a common complication of severe haemophilia. While factor replacement therapy constitutes the majority of costs in haemophilia, the relationship between target joints and non drug-related direct costs (NDDCs) has not been studied. METHODS: Data on haemophilia patients without inhibitors was drawn from the 'Cost of Haemophilia across Europe - a Socioeconomic Survey' (CHESS) study, a cost assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the United Kingdom) in which 139 haemophilia specialists provided demographic and clinical information for 1285 adult patients...
January 16, 2018: Health Economics Review
Gary Benson, Günter Auerswald, Gerry Dolan, Anne Duffy, Cedric Hermans, Rolf Ljung, Massimo Morfini, Silva Zupančić Šalek
Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU/mL and is characterised by traumatic bleeds. Major issues associated with mild haemophilia are that it may not present for many years after birth, and that awareness, even within families, may be low. Methodological problems exist in diagnosis, such as inconsistencies in results obtained from different assays used to measure factor levels in mild haemophilia. Advances in genetic testing provide insight into diagnosis as well as the likelihood of inhibitor development, which is not uncommon in patients with mild or moderate haemophilia and can increase morbidity...
November 14, 2017: Blood Transfusion, Trasfusione del Sangue
J A Mason, S Parikh, H Tran, J Rowell, S McRae
INTRODUCTION: With the emergence of novel treatment products for haemophilia and an increasing focus on the benefits of pharmacokinetic driven individualized prophylaxis, robust national data with regard to current patterns of factor consumption and adherence are required. AIM: To characterize current Australian practice with regard to use of prophylactic clotting factor infusions in patients with moderate or severe haemophilia A (HA) and haemophilia B (HB). METHODS: This was a retrospective, non-interventional study utilizing Australian Bleeding Disorder Registry (ABDR) data collected over a 12 month period...
January 3, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
A Klukowska, V Komrska, V Vdovin, A Pavlova, M Jansen, S Lowndes, L Belyanskaya, O Walter, P Laguna
INTRODUCTION: Octanate® is a human, plasma-derived, von Willebrand factor-stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients with haemophilia A. AIM: This prospective, open-label study aimed to assess the immunogenicity of octanate® in previously untreated patients (PUPs). METHODS: The study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate® for the prevention and treatment of bleeds and in surgical procedures were also assessed...
January 3, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
H Husseinzadeh, T Chiasakul, P A Gimotty, B Pukenas, R Wolf, M Kelty, E Chiang, P F Fogarty, A Cuker
INTRODUCTION: Cerebral microbleeds (CMBs) represent clinically silent haemorrhagic events. Cerebral microbleeds (CMBs) portend negative neurovascular and cognitive outcomes in the general population and are associated with cognitive impairment in persons with haemophilia (PWH). Prevalence, patterns, and risk factors for CMBs in PWH have not been directly compared to persons without coagulopathy. AIM: To examine prevalence, patterns, and risk factors for CMBs in PWH vs normal controls...
December 28, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
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