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J. Biol. Chem., Vol. 267, Issue 33, 23652-23657, Nov, 1992
P Lollar, ET Parker and PJ Fay
Human and porcine factor VIII (fVIII) are activated by thrombin to form a
heterotrimer composed of subunits designated A1 and A2 derived from the
fVIII heavy chain (HC) and a subunit designated A3-C1-C2 derived from the
fVIII light chain (LC). Human and porcine fVIII were activated at the same
rate to the same peak levels but dissociation of the A2 subunit and
concomitant loss of fVIIIa activity at pH 7.4 and 22 degrees C was 3-fold
faster with human fVIIIa compared to porcine fVIIIa (0.35 min-1 versus 0.12
min-1, respectively). To determine structural requirements for the
increased activity of porcine fVIII, plasma-derived hybrid human/porcine
fVIII molecules were isolated. Porcine HC/human LC (pHC/hLC) fVIII had
44-fold higher coagulant activity than reconstituted human fVIII (hHC/hLC),
40-fold higher activity than hHC/pLC, and slightly (1.4-fold) higher
activity than reconstituted porcine fVIII (pHC/pLC). Additionally, human
and porcine A2 subunits and inactive A1/A3-C1-C2 human and porcine dimers
were isolated and reconstitution experiments were done. Addition of the
porcine A2 subunit to the human A1/A3-C1-C2 dimer produced coagulant
activity similar to that found with porcine fVIIIa and superior to human
fVIIIa. These results suggest that human fVIII has weaker coagulant
activity than porcine fVIII due to faster dissociation of the A2 subunit
and that the A2 subunit itself is responsible for the difference.
Coagulant properties of hybrid human/porcine factor VIII molecules
Department of Medicine, Emory University, Atlanta, Georgia 30322.
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