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Measurement of Factor V Activity in Human Plasma Using a Microplate Coagulation Assay
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Published on: September 9, 2012

Activated factor X cleaves factor VIII at arginine 562, limiting its cofactor efficiency.

J L Plantier1, V Rolli, C Ducasse

  • 1Laboratoire d'hémobiologie EA4174, Faculté RTH Laennec, Université de Lyon, Université Lyon 1, Lyon, France. plantier@sante.univ-lyon1.fr

Journal of Thrombosis and Haemostasis : JTH
|October 31, 2009
PubMed
Summary

Activated Factor X (FXa) cleaves Factor VIII (FVIII) at R562, a new inactivation pathway. This FXa-mediated FVIII degradation in the A2 domain impacts cofactor function and is inhibited by Von Willebrand factor and activated FIX.

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Area of Science:

  • Biochemistry
  • Hematology
  • Molecular Biology

Background:

  • Factor VIII (FVIII) and its activated form (FVIIIa) are crucial for blood coagulation.
  • Proteolysis by proteases like activated protein C (APC) and activated Factor X (FXa) regulates FVIII activity.
  • APC cleaves FVIII at R562 in the A2 domain, fully inactivating it.

Purpose of the Study:

  • To investigate the role of FXa cleavage at R562 in the A2 domain of FVIII.
  • To understand the mechanism of FVIII inactivation by FXa.

Main Methods:

  • Utilized an antibody (GMA012/R8B12) targeting the A2 C-terminus (A2C) to detect FXa activity.
  • Generated an FVIII mutant at R562 (R562K) to assess the functional significance of this residue.

Main Results:

  • FXa cleaves FVIII and FVIIIa within the A2 domain at R562, evidenced by A2C domain appearance.
  • This cleavage requires phospholipids, occurs rapidly, and is inhibited by Von Willebrand factor and activated FIX.
  • The R562K mutation enhanced FVIII activity and catalytic efficiency, preventing A2C fragment formation.

Conclusions:

  • Identified a novel FXa-mediated FVIII degradation pathway involving A2 domain cleavage at R562.
  • This mechanism contributes to the regulation of FVIII cofactor function.
  • FXa-mediated cleavage at R562 is a significant factor in FVIII inactivation.