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Acquired Circulating Anticoagulants Other than Lupus Anticoagulants
Published in E. Nigel Harris, Thomas Exner, Graham R. V. Hughes, Ronald A. Asherson, Phospholipid-Binding Antibodies, 2020
Several attempts have been made to standardize the titer of factor VIII inhibitors. The Oxford and New Oxford units are based on diluting test plasmas in lu/ml factor VIII for 4 h at 37°C.43 More recently a standard method based on pooled normal plasma as a source of factor VIII was agreed on by a number of laboratories in the U.S. and is called the Bethesda unit.44 Such quantitation is useful for the measurement of inhibitors arising in hemophiliacs, but the complexity of reaction kinetics and variations in antibody affinities for factor VIII, particularly in nonhemophilic inhibitors with high residual factor VIII, limits its usefulness to judging individual patient’s responses to treatment.2,14 In principal the test plasma is diluted in saline and the dilutions are mixed with pooled normal plasma for a period of 2 h at 37°C. Then a factor VIII assay is performed on each of these mixtures and the dilution of test plasma which inhibits 50% of the factor VIII level is assigned one Bethesda unit. From this dilution the inverse is calculated to yield the concentration of the original sample in Bethesda units/ml. The two methods are not exactly comparable.45
Hereditary Causes for Plasma Clotting Bleeding
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
The amount of inhibitor present in a milliliter of plasma can be quantified. In the United States this is usually done by a calculation decided at a consensus conference held in Bethesda and called the Bethesda unit (12). Although the kinetics of the interaction between the inhibitor and factor VIII:C is complex, quantifying by a widely accepted method such as the Bethesda unit is useful for following the progression of the inhibitor concentration.
Safety of recombinant coagulation factors in treating hemophilia
Published in Expert Opinion on Drug Safety, 2019
Massimo Morfini, Carlo Antonio Paolo Rapisarda
The alloantibodies against FVIII belong to subclass IgG4. They are directed against the clotting epitopes and can block the clotting activity of FVIII. This is the reason why they are also called ‘inhibitors’. The efficiency of the replacement therapy may be entirely or partially reduced, according to the inhibitor’s titer. The inhibitors anti-C1 and C2 domains of FVIII inhibit the binding of phospholipids and VWF and the cleavage of FVIII by thrombin and FXa. Those against anti-A3 domain inhibit the binding with FIX/FIXa, while those with anti-A2 domain specificity block another FIX binding site (Figure 1). Even though anti-FVIII antibodies, specific for every domain of the molecule have been reported, anti C1 and C2 domains as well as against A2 domain antibodies represent the more significant components of the immune response in acquired and congenital hemophilia [5]. Complement does not bind to FVIII-Inhibitors immune-complexes, which are stable in plasma. On the contrary, inhibitors against FIX and VWF are fixing the Complement, and the immune-complexes are not stable in solution: precipitating antibodies. In these cases, the patients may undergo severe anaphylactic reactions after the replacement therapy [6]. The titer of anti-FVIII/IX inhibitors is assayed by the decrease of FVIII concentration in a mixture of equal amount, v/v, of pooled normal plasma and patient’s plasma according to the Bethesda test. One Bethesda Unit is by definition the amount of FVIII/IX inhibitor that reduces by 50%, the content of FVIII/IX present in the mixture after incubation at 37°C for 1 h. The Nijmegen modification of the Bethesda test represents a standardization of the assay’s procedure, aimed to reduce its variability [7].
Results of multicenter registry for patients with inherited factor VII deficiency in Turkey
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2022
Aydan Akdeniz, Ayşegül Ünüvar, Muhlis Cem Ar, Esra Pekpak, Arzu Akyay, Özgür Mehtap, Fatma Keklik Karadağ, Can Acıpayam, Ali Doğan, Ömer Ekinci, Sultan Aydın Köker, Canan Albayrak, Ufuk Demirci, Tekin Güney, Meltem Kurt, Serap Karaman, Özge Şahin Kimyon, Sinan Albayrak, Yurday Öncül, Serkan Ünal, Fahri Şahin, Rumeysa Tuna, Bulent Zulfikar, Burcu Belen Apak, Elif Gülsüm Ümit, Ahmet Muzaffer Demir
FVII inhibitor was detected in one patient. He had intracranial bleeding of the newborn, high titer inhibitor, (8 Bethesda unit (BU)), and a history of consanguinity. He is still on prophylaxis treatment with rFVIIa with the dosage of 70 µg/kg 3 times per week.