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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1637-1647
Evidence for Extracellular Processing of Pro-von Willebrand Factor
After Infusion in Animals With and Without Severe von Willebrand
Disease
P.L. Turecek,
L. Pichler,
W. Auer,
G. Eder,
K. Varadi,
A. Mitterer,
W. Mundt,
U. Schlokat,
F. Dorner,
L.O. Drouet,
J. Roussi,
J.A. van Mourik, and
H.P. Schwarz
From Baxter Hyland Immuno, Vienna, Austria; CLB, Sanquin Blood Supply
Foundation, Amsterdam, The Netherlands; Hôpital
Lariboisière, Paris, France; and Hôpital Raymond
Poincaré, Garches, France.
Although proteolytic processing of pro-von Willebrand factor
(pro-vWF) resulting in free propeptide and mature vWF is known to be
initiated intracellularly, vWF released from endothelial cells may
contain a high proportion of incompletely processed pro-vWF. Because
pro-vWF is only rarely detectable in normal human plasma, we
investigated whether extracellular processing of pro-vWF is possible. A
recombinant preparation (rpvWF) containing both pro-vWF and mature vWF
subunits was infused into 2 pigs and 1 dog with severe von Willebrand
disease, 2 mice with a targeted disruption of the vWF gene, and 2 healthy baboons. Total vWF antigen (vWF:Ag), free propeptide, and
pro-vWF were measured using enzyme-linked immunosorbent assay
techniques in blood samples drawn before and after infusion. vWF:Ag
increased promptly. No pro-vWF could be detected when the first
postinfusion sample was drawn after 30 minutes (pigs) or 60 minutes
(mice), but pro-vWF was detectable for short periods when postinfusion
samples were drawn after 15 minutes (dog) or 5 minutes (baboons). In
contrast, free propeptide was increased at the first timepoint
measured, suggesting that it was generated from the pro-vWF in the
rpvWF preparation. vWF multimers were analyzed in the rpvWF preparation
and in plasma samples drawn before and after infusion of rpvWF using
ultra-high resolution 3% agarose gels to allow separation of homo- and
hetero-forms of the vWF polymers. Within 30 minutes after
infusion in the pigs, 1 hour in the dog and the mice, and within 2 hours in the baboons, the multimer pattern had changed to that
typically seen in mature vWF. These data indicate that propeptide
cleavage from unprocessed vWF can occur extracellularly in the
circulation. The enzyme or enzymes responsible for this cleavage in
plasma remain to be identified.
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