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Factor VIII antibody

Lilija Miller, Eva Ringler, Klaus Maximilian Kistner, Zoe Waibler
The most severe side effect in haemophilia A (HA) treatment is the development of anti-factor VIII antibodies, also called inhibitors. Why inhibitors develop in a proportion of treated HA patients and how this can be prevented remains largely unanswered. Among numerous theories, the presence of immunological danger signals, associated with events such as surgery or infection, has been proposed to play a role. In this study, we demonstrate that human dendritic cells (DC) synergistically activated by a combination of factor VIII (FVIII) concentrate plus the bacterial danger signal lipopolysaccharide (LPS) induce a significantly stronger activation of autologous CD4+ T cells than DC pretreated with FVIII or LPS alone...
March 19, 2018: Thrombosis and Haemostasis
Jae-Il Lee, Yun-Jung Choi, Hi-Jung Park, Kyeong Cheon Jung, Seong Hoe Park
Antibody formation against therapeutic agents, such as tumor necrosis factor inhibitors and Factor VIII, that leads to treatment failure has become a major challenge in the treatment of rheumatoid arthritis and hemophilia. It is well known that anti-CD154 antibodies have the highest potential to inhibit these types of adverse immune responses. Nevertheless, the formation of thromboemboli is the major hurdle in the clinical application of these anti-CD154 blocking antibodies. For this, we attempted to derive an idea as to how this major complication can be eliminated...
March 16, 2018: Biochemical and Biophysical Research Communications
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
Qizhen Shi
Gene therapy is an attractive approach for disease treatment. Since platelets are abundant cells circulating in blood with the distinctive abilities of storage and delivery and fundamental roles in hemostasis and immunity, they could be a unique target for gene therapy of diseases. Recent studies have demonstrated that ectopic expression of factor VIII (FVIII) in platelets under control of the platelet-specific promoter results in FVIII storage together with its carrier protein von Willebrand factor (VWF) in α-granules and the phenotypic correction of hemophilia A...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
S J Schep, R E G Schutgens, K Fischer, M L Boes
At first sight the bleeding disorder hemophilia A seems to have little in common with immune disorders, but immunology research intersects with other disciplines including hematology. Nowadays, the most important complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against exogenous administered factor VIII (FVIII), which occurs in approximately 30% of all patients with severe hemophilia A. This antibody response renders FVIII replacement therapy ineffective, thereby increasing the risk for uncontrollable bleeding and morbidity, decreasing quality of life and increasing healthcare costs...
February 15, 2018: Blood Reviews
Yesim Dargaud, Anne Lienhart, Maissaa Janbain, Sandra LeQuellec, Nathalie Enjolras, Claude Negrier
Emicizumab is a recombinant, humanized, bispecific, monoclonal antibody that bridges activated factor IX and factor X to restore the function of deficient factor VIII. Treatment of bleeding in patients with hemophilia and inhibitors involves the use of bypassing agents (BPA).These molecules are also used for the management of breakthrough bleeds in patients on prophylaxis with emicizumab, with increased concerns about the risks of combining two procoagulant drugs. Using thrombin generation assay, we tailored the dosage of activated prothrombin complex concentrate (APCC) and successfully treated an acute spontaneous arterial bleeding in a patient on prophylaxis with emicizumab 1...
February 22, 2018: Haematologica
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
Thomas Morrow
Hemlibra demonstrates how far antibody science has progressed. Genentech's drug, approved late last year, connects two clotting factors to prevent the devastating bleeds in hemophilia patients with inhibitors. The high price may be offset by avoided costs in patients with factor VIII inhibitors.
February 2018: Managed Care
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
Ruth A Ettinger, Joseph A Liberman, Devi Gunasekera, Komal Puranik, Eddie A James, Arthur R Thompson, Kathleen P Pratt
Factor VIII (FVIII)-neutralizing antibodies (inhibitors) are a serious complication in hemophilia A (HA). The peptide FVIII 2194-2213 contains an immunodominant HLA-DRA*01-DRB1*01:01 (DRB1*01:01)-restricted epitope recognized by CD4 + T-effector cells from HA subjects. The aim of this study was to identify amino acid substitutions to deimmunize this epitope while retaining procoagulant function and expression levels comparable to those of wild-type (WT) FVIII proteins. The shortest DRB1*01:01-binding peptide was FVIII 2194-2205 , and residues important for affinity were identified as F2196, M2199, A2201, and S2204...
February 27, 2018: Blood Advances
B T Samuelson Bannow, B A Konkle
INTRODUCTION: Despite high rates of venous thromboembolism (VTE) among patients with hematologic malignancies, few tools exist to assist providers in identifying those patients at highest risk for this potentially fatal complication. Laboratory biomarkers, such as d-dimer, have demonstrated utility in some clinical settings to distinguish patients at increased risk. MATERIALS AND METHODS: We performed a systematic review of the literature utilizing search terms including "biomarker", "venous thromboembolism", "hematologic malignancy", "lymphoma", "myeloma" and "leukemia" in the Medline database...
January 31, 2018: Thrombosis Research
Ivan Peyron, Jordan D Dimitrov, Sandrine Delignat, Bagirath Gangadharan, Alok Srivastava, Srinivas V Kaveri, Sébastien Lacroix-Desmazes
The development of antibodies against therapeutic factor VIII (FVIII) represents the major complication of replacement therapy in patients with severe hemophilia A. Amongst the environmental risk factors that influence the anti-FVIII immune response, the presence of active bleeding or hemarthrosis has been evoked. Endothelium damage is typically associated with the release of oxidative compounds. Here, we addressed whether oxidation contributes to FVIII immunogenicity. The control with N-acetyl cysteine of the oxidative status in FVIII-deficient mice, a model of severe hemophilia A, reduced the immune response to exogenous FVIII...
January 30, 2018: Cellular Immunology
Pauline Balkaransingh, Guy Young
The evolution of hemophilia treatment and care is a fascinating one but has been fraught with many challenges at every turn. Over the last 50 years or so patients with hemophilia and providers have witnessed great advances in the treatment of this disease. With these advances, there has been a dramatic decrease in the mortality and morbidity associated with hemophilia. Even with the remarkable advancements in treatment, however, new and old challenges continue to plague the hemophilia community. The cost of factor replacement and the frequency of infusions, especially in patients with severe hemophilia on prophylaxis, remains a significant challenge for this population...
February 2018: Therapeutic Advances in Hematology
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
Nicole Jungwirth, Johannes Junginger, Christoph Andrijczuk, Wolfgang Baumgärtner, Peter Wohlsein
Plexiform vasculopathy refers to an endothelial proliferative disorder affecting cervical or inguinal lymph nodes of cats. The cause of this disorder and the origin of the proliferating endothelial cells are still unknown. In 4 cats with a history of a slowly growing, well-demarcated, nonpainful mass adjacent to the thyroid gland, an enlarged dark brown to red lymph node was removed. Histologically, the lymph nodes showed severe loss of lymphoid tissue with accumulations of erythrocytes. In addition, networks of capillary structures with well-differentiated endothelial cells on a collagen-rich stroma were observed, consistent with benign plexiform vasculopathy...
January 1, 2018: Veterinary Pathology
Uma H Athale, T Mizrahi, C Laverdière, T Nayiager, Y-L Delva, G Foster, L Thabane, M David, J-M Leclerc, A K C Chan
BACKGROUND: Children with acute lymphoblastic leukemia (ALL) have increased risk of thromboembolism (TE). However, the predictors of ALL-associated TE are as yet uncertain. OBJECTIVE: This exploratory, prospective cohort study evaluated the effects of clinical (age, gender, ALL risk group) and laboratory variables (hematological parameters, ABO blood group, inherited and acquired prothrombotic defects [PDs]) at diagnosis on the development of symptomatic TE (sTE) in children (aged 1 to ≤18) treated on the Dana-Farber Cancer Institute ALL 05-001 study...
January 15, 2018: Pediatric Blood & Cancer
Jian Zhang Wang, Yu Jing Xiong, Gene Chi Wai Man, Xiao Yan Chen, Joseph Kwong, Chi Chiu Wang
OBJECTIVE: The study aimed to systematically review the association between angiogenesis and clinicopathological characteristics and its prognostic value in patients with endometrial cancer. METHODS: Eligible studies were searched in PubMed, Embase, China National Knowledge Infrastructure, and Wanfang database. Studies that assessed blood microvessel density (BMVD) and correlated with clinicopathological features and/or overall survival (OS) were included. Geometric mean values and hazard ratio with 95% confidence interval were pooled to examine the risk or hazard association...
March 2018: Archives of Gynecology and Obstetrics
Midori Shima, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato, Katsuyuki Fukutake, Ryu Kasai, Koichiro Yoneyama, Hiroki Yoshida, Keiji Nogami
Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33...
October 10, 2017: Blood Advances
J D Lai, D Cartier, R B Hartholt, L L Swystun, A S van Velzen, J M M den Haan, C Hough, J Voorberg, D Lillicrap
BACKGROUND: Developing factor VIII (FVIII) inhibitory antibodies is the most serious complication in hemophilia A treatment, representing a significant health and economic burden. A better understanding of the early events in an immune response leading to this outcome may provide insight into inhibitor development. OBJECTIVE: To identify early mediators of FVIII immunity and to detail immune expression profiles in the spleen and liver. METHODS: C57Bl/6 F8 E16 knockout mice were infused with 5-20 μg (2000-8000 IU/kg) of recombinant FVIII...
December 28, 2017: Journal of Thrombosis and Haemostasis: JTH
Ayse B Ergul, Yasemin Altuner Torun, Umut Altug, Fatma T Mutlu, Serkan F Celik, Ahmet S Guven
Here, we report a case of hemophilia A with myocarditis, encephalopathy, and spontaneous intramedullary hemorrhage. A 14-month-old male infant presented with loss of consciousness, generalized tonic-clonic convulsions, and cardiac failure. The neurological examination was normal. Myocarditis was diagnosed. After administration of fresh frozen plasma, the aPTT did not return to normal. The factor VIII (FVIII) level was 10.2% the normal level, and the patient was diagnosed with hemophilia A. The cerebrospinal fluid (CSF) evaluation was unremarkable, with the exception of elevated CSF protein levels...
December 12, 2017: Journal of Pediatric Hematology/oncology
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