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Thromb Haemost 2012; 107(02): 288-301
DOI: 10.1160/TH11-05-0331
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

A putative inhibitory mechanism in the tenase complex responsible for loss of coagulation function in acquired haemophilia A patients with anti-C2 autoantibodies

Tomoko Matsumoto
1   Department of Pediatrics, Nara Medical University, Kashihara, Japan
,
Keiji Nogami
1   Department of Pediatrics, Nara Medical University, Kashihara, Japan
,
Kenichi Ogiwara
1   Department of Pediatrics, Nara Medical University, Kashihara, Japan
,
Midori Shima
1   Department of Pediatrics, Nara Medical University, Kashihara, Japan
› Author Affiliations Financial support: This work was partly supported by the grants for Bayer Hemophilia Award, 2009 and MEXT KAKENHI 21591370, 2009.
Further Information

Publication History

Received: 16 May 2011

Accepted after major revision: 20 January 2011

Publication Date:
29 November 2017 (online)

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Summary

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.

Presented in abstract form at the 52nd annual meeting of the American Society of Hematology, Orlando, Florida, USA, December 6, 2010.

Keywords

Acquired haemophilia A - anti-C2 autoantibody - thrombin generation - tenase complex - FXa generation
 

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