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The roles of von Willebrand factor and factor VIII in arterial thrombosis:
studies in canine von Willebrand disease and hemophilia A
TC Nichols, DA Bellinger, RL Reddick, SV Smith, GG Koch, K Davis, J Sigman, KM Brinkhous, TR Griggs and MS Read
Department of Medicine, University of North Carolina School of Medicine,
Chapel Hill 27514.
We have studied the roles of von Willebrand factor (vWF) and factor VIII in
arterial thrombosis in four canine phenotypes: normal (n = 6), hemophilia A
(n = 11), von Willebrand disease (vWD) (n = 9), and hemophilia A/vWD (n =
1). vWF activity was determined by botrocetin- induced agglutination of
fixed human platelets and vWF antigen (vWF:Ag) by Laurell
electroimmunoassay and crossed immunoelectrophoresis. Plasma from normal
dogs and those with hemophilia A had vWF activity, vWF:Ag, and a full range
of vWF:Ag multimers on gel electrophoresis equivalent to normal canine
plasma pool. Platelet cytosol contents were isolated by freezing and
thawing, triton X-100 solubilization, or sonication of washed platelets
with and without protease inhibitors and inhibitors of platelet activation.
Washed platelets were also stimulated with calcium ionophore and MgCl2.
There was no measurable vWF activity or vWF:Ag in platelet lysates or
releasates in any dog regardless of phenotype. All dogs were studied using
a standard arterial stenosis and injury procedure to induce arterial
thrombosis. Thromboses were detected by cyclic reductions in Doppler blood
flow velocity. Vessels were examined by light and scanning electron
microscopy. Thrombosis developed in the arteries of normal (9 of 10) and
hemophilia A dogs (16 of 16) but in none of the vWD dogs (0 of 10).
Infusion of canine vWF cryoprecipitate into vWD dogs markedly shortened
bleeding time but did not support thrombosis as seen in dogs with vWF in
the plasma and subendothelium. Thrombosis, then, fails to occur when vWF is
absent from the plasma and subendothelial compartments or present only in
the plasma compartment. These data are consistent with the hypothesis that
vWF in the plasma and subendothelium supports thrombosis. Neither plasma
FVIII nor platelet vWF is essential for thrombosis in this model.
Volume 81,
Issue 10,
pp. 2644-2651,
05/15/1993
Copyright © 1993 by The American Society of Hematology
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