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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/2770

Title: A putative inhibitory mechanism in the tenase complex responsible for loss of coagulation function in acquired haemophilia A patients with anti-C2 autoantibodies.
Other Titles: 後天性血友病A (抗C2 自己抗体)の凝固機能低下におけるFX 複合体阻害様式の解明
Authors: Matsumoto, Tomoko
Nogami, Keiji
Ogiwara, Kenichi
Shima, Midori
Keywords: thrombin generation
tenase complex
Acquired haemophilia A
anti-C2 autoantibody
FXa generation
Issue Date: Feb-2012
Publisher: Schattauer
Citation: Thrombosis and haemostasis Vol.107 No.2 p.288-301
Abstract: Acquired haemophilia A (AHA) is caused by the development of factor (F)VIII autoantibodies, demonstrating type 1 or type 2 inhibitory behaviour, and results in more serious haemorrhagic symptoms than in congenital severe HA. The reason(s) for this remains unknown, however. The global coagulation assays, thrombin generation tests and clot waveform analysis, demonstrated that coagulation parameters in patients with AHA-type 2 inhibitor were more significantly depressed than those in patients with moderate HA with similar FVIII activities. Thrombin and intrinsic FXa generation tests were significantly depressed in AHA-type 1 and AHA-type 2 compared to severe HA, and more defective in AHA-type 1 than in AHA-type 2. To investigate these inhibitory mechanism(s), anti-FVIII autoantibodies were purified from AHA plasmas. AHA-type 1 autoantibodies, containing an anti-C2 ESH4-epitope, blocked FVIII(a)-phospholipid binding, whilst AHA-type 2, containing an anti-C2 ESH8-epitope, inhibited thrombin-catalysed FVIII activation. The coagulation function in a reconstituted AHA-model containing exogenous ESH4 or ESH8 was more abnormal than in severe HA. The addition of anti-FIX antibody to FVIII-deficient plasma resulted in lower coagulation function than its absence. These results support the concept that global coagulation might be more suppressed in AHA than in severe HA due to the inhibition of FIXa-dependent FX activation by steric hindrance in the presence of FVIII-anti-C2 autoantibodies. Additionally, AHA-type 1 inhibitors prevented FVIIIa-phospholipid binding, essential for the tenase complex, whilst AHA-type 2 antibodies decreased FXa generation by inhibiting thrombin-catalysed FVIII activation. These two distinct mechanisms might, in part, contribute to and exacerbate the serious haemorrhagic symptoms in AHA.
Description: 博士(医学)・乙第1298号・平成24年5月28日
© Schattauer Publishers, Stuttgart, 2012
URI: http://hdl.handle.net/10564/2770
ISSN: 03406245
Appears in Collections:2012年度

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