4.6 Article

Heme binds to factor VIII and inhibits its interaction with activated factor IX

Journal

JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 10, Issue 6, Pages 1062-1071

Publisher

WILEY-BLACKWELL
DOI: 10.1111/j.1538-7836.2012.04724.x

Keywords

coagulation; factor VIII; factor IX; heme; von Willebrand factor

Funding

  1. INSERM
  2. CNRS
  3. UPMC-Paris6
  4. Agence Nationale de la Recherche [ANR-07-JCJC-0100-01, ANR-07-MRAR-028-01]
  5. Fondation pour le Recherche Medicale (Paris, France)
  6. Agence Nationale de la Recherche (ANR) [ANR-07-JCJC-0100] Funding Source: Agence Nationale de la Recherche (ANR)

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Background: Heme is a redox active macrocyclic compound that is released upon tissue damage or hemorrhages. The extracellular release of large amounts of heme saturates scavenging heme-binding proteins. Free heme has been proposed to affect coagulation and has been co-purified with the factor VIII (FVIII)-von Willebrand factor (VWF) complex. The sites from which heme is released upon injury overlap with the sites to which FVIII is targeted for performing its hemostatic functions. Objectives: To investigate the interaction of heme with FVIII and the consequence for the procoagulant activity of FVIII in vitro. Methods and results: Heme bound to several sites on FVIII with high apparent affinity. Heme-binding inhibited FVIII procoagulant activity in a dose-dependent manner. FVIII inactivation in the presence of saturating amounts of heme implicated a reduced interaction of FVIII with activated FIX, as shown by ELISA, surface plasmon resonance and fluorescence quenching. Heme-mediated inactivation of FVIII was prevented by VWF, but not by human serum albumin, a heme-binding protein known for its protective activity in hemolytic conditions. Conclusions: Our data identify FVIII as a novel heme-binding protein. Occupation of high affinity heme-binding sites on FVIII at low concentrations of free heme did not inactivate FVIII. Conversely, large molar excesses of heme over FVIII, which correspond to conditions of extensive heme release, inhibited FVIII activity in vitro. It remains to be demonstrated whether, under such conditions, heme-mediated modulation of the activity of FVIII plays some role in the regulation of coagulation.

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