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Genetic analysis
An extensive study showed that the disease was trans-
mitted as an autosomal recessive trait [46]. The bleeder
swine are homozygous for the defect, whereas the carri-
ers are heterozygous. The latter are usually asymp-
tomatic, which renders difï¬cult the evaluation of their
980 C. V. Denis and D. D. Wagner
status. Indeed, they don’t have a bleeding tendency and
their FVIII levels are usually normal. However, their
vWf:Ag and vWf:RCoF are reduced to 30–40% of
normal [43]. It is of interest to note that in pigs, as
opposed to humans, the level of FVIII does not follow
the vWf:Ag very closely. The homozygous pigs are not
totally deï¬cient in vWf. Low, but signiï¬cant amounts of
vWf:Ag can be detected both in platelets and in
endothelial cells from the pulmonary artery and from
the inferior vena cava [47]. No gross gene deletion or
rearrangement was identiï¬ed in the vWf gene of vWd
pigs, but the defect was shown to be tightly linked to
the vWf locus, most likely representing a point muta-
tion or small insertion/deletion within the vWf gene
[48], which is located on the porcine chromosome 5 [49].
Analysis of the mRNA revealed a decrease in vWf
message levels in vWd pigs down to one-third of wild-
type levels [50]. However, the level of vWf mRNA
detected in the vWd pigs is still signiï¬cant and does not
correlate with the very low amount of vWf:Ag. This
fact indicates that posttranscriptional defects may also
be involved, such as defects in translation or instability
of the transcripts [50].
Platelet adhesion in vWd pigs
Platelets from normal pigs and vWd pigs were com-
pared, and no differences were found relative to platelet
size or number of -granules [51]. The only difference
observed was the absence of tubular structures within
the -granules in the vWd platelets, suggesting that
these granule-associated tubules of normal platelets
may represent the vWf molecule itself [52]. In order to
assess platelet function, the formation of the hemostatic
plug after ear incision was monitored in normal and
vWd pigs [53]. In the affected pigs, although there was
formation of large platelet aggregates, these aggregates
were not efï¬cient in stopping the bleeding due to their
localization far away from the arterial laceration. Fur-
thermore, these aggregates were penetrated by channels
through which bleeding could continue [53]. This in
vivo study emphasized the importance of vWf not only
in the interaction of platelets with the blood vessel and
in the localization of the hemostatic plug to the dam-
aged vessel but also in platelet-platelet interactions as
demonstrated in humans [22, 23]. The pig model was
also used to measure platelet adhesion to damaged
coronary arteries [54]. A similar platelet adhesion was
observed in both normal and vWd pigs, but the
platelets appeared less activated in the affected pigs,
keeping a round morphology and fewer pseudopodia.
The shear rate in coronary arteries is low, which could
explain the absence of defect in platelet adhesion in the
vWf-deï¬cient pigs. That study uncovered a new role for
vWf in platelet activation at low shear rate. The role of
von Willebrand disease models
vWf in mediating platelet-vessel wall interactions at
various shear rates was investigated using in vitro and
ex vivo techniques [55]. Platelet deposition on pig tho-
racic aortae is reduced in the absence of plasma vWf at
high shear rate (850 s−1), independent of the perfu-
sion method used. At low shear rate (424 s−1), a defect
was observed in the absence of plasma vWf only when
heparinized blood was perfused ex vivo over the deen-
dothelialized aorta.
Bone marrow tranplantation
The respective roles of plasma vWf and platelet vWf
were addressed for the ï¬rst time using crossed bone
marrow transplantation in the pig model [56]. A normal
bone marrow was transplanted in a vWd animal, result-
ing in a chimera with vWf-positive platelets and vWf-
negative endothelium. The plasmatic compartment was
only minimally replenished by the vWf in platelets,
suggesting that most plasma vWf is endothelial-derived.
Ear bleeding time was not consistently shortened, but
after suffering hemostatic challenges, the transplanted
pig was able to control its bleeding. Platelet vWf seems
to improve only partially the hemostatic mechanism in
severe vWd. Also, platelet vWf does not contribute to
normal FVIII activity and cannot support occlusive
thrombosis in response to stenosis and vessel injury [57].
In another study, the vWd pigs transplanted with nor-
mal bone marrow were transfused with vWf concen-
trate, restoring both the plasma and platelet vWf
compartments [58]. Both the hemostatic response and
thrombus formation were evaluated. One pig (out of
two) presented a partial reduction in bleeding time
(from 30 min to 13.5 min), and using an ex vivo
thombosis model, it was shown that at a shear rate of
1600 s−1, platelet adhesion and thrombus size were
normalized in these pigs [58]. Using the opposite ap-
proach, a normal pig transplanted with bone marrow
from a vWd pig, it was suggested that plasma and
subendothelial vWf are the major determinants of
bleeding time since the bleeding time remains normal
when vWf is absent from the platelet compartment [57].
From this latter transplantation experiment it was de-
termined that platelets do not take up much vWf from
plasma either by active or by passive absorption [59].
Role of vWf in atherosclerosis
Thrombogenesis and atherogenesis may be intimately
linked [60], and it was suggested that platelets, by ad-
hering to a damaged endothelial surface and releasing
growth factors, may play a role in atherosclerosis [61–
63]. Consequently, experimental animals known to have
an impairment of platelet function were investigated to
see if they would be less prone to develop atherosclero-
CMLS, Cell. Mol. Life Sci. Vol. 56, 1999
sis. Numerous studies have been done using vWd pigs
[64]. Early studies showed a striking difference in the
atherosclerotic lesions in the aorta between normal pigs
and vWd pigs, both in spontaneous atherosclerosis and
in diet-induced atherosclerosis [65]. Spontaneously, 7
control pigs out of 11 presented multiple or single raised
fatty atherosclerotic plaques and intimal thickening,
whereas only 1 vWd pig out of 11 had a signiï¬cant
plaque. However, the aortas of the vWd pigs presented
flat fatty lesions characterized by subendothelial deposi-
tion of fat without intimal thickening [66]. After 6
months of atherogenic diet, all control pigs developed
raised fatty atherosclerotic plaques, and most developed
raised ï¬brous atherosclerotic plaques with important
intimal thickening. In contrast, only 3 vWd pigs out of
7 developed signiï¬cant raised fatty atherosclerotic
plaques, which were smaller than those in the control
pigs. Additional studies conï¬rmed this protection
against atherosclerosis in vWd pigs [67]. However it was
noted in all these studies that normal pigs have a
tendency to have higher levels of diet-induced hyper-
cholesterolemia than do vWd pigs, a ï¬nding that was
not systematically explored and that might have been of
great importance. Indeed in one study, the amount of
coronary atherosclerosis was shown to be related to the
degree of hypercholesterolemia that the pigs develop
and not to the presence of vWf [68]. The controversy
about the involvement of vWf in atherosclerosis was
further reinforced by a report by Nichols et al. [69]
showing that the presence of a particular polymorphism
at the apolipoprotein B100 locus can signiï¬cantly influ-
ence the development of diet-induced hypercholes-
terolemia and coronary and aortic atherosclerosis in the
pig, independent of the vWd status. From this study,
the authors conclude that this polymorphism could
have affected the results of the previous atherogenesis
experiments in vWd animals. These results are in agree-
ment with autopsy ï¬ndings in three patients with vWd
[70]. Atherosclerosis lesions, but no occlusive thrombo-
sis, were present in patients with type 3 vWd. The
patients’ repeated transfusions of blood products con-
taining vWf could account for these observations.
However, considering the vWf role in platelet adhesion
and activation, a mechanism linking vWf to atherogene-
sis may still exist. It was shown that both pseudopod
formation and spreading of platelets adhering to injured
arterial walls was impaired in vWd pigs [71]. In order to
investigate the role of vWf in occlusive arterial throm-
bosis, normal and vWd pigs were fed a high cholesterol
diet, and at the end of the diet period coronary and
carotid arteries were subjected to a stenosis/injury pro-
tocol to produce occlusive thrombosis [72]. Coronary
atherosclerosis was present in both groups of pigs, but
occlusive thrombosis failed to develop in vWd pigs
despite the presence of atherosclerosis, severe hyper-
Review Article 981
cholesterolemia and the additional stenosis and injury.
vWf may be required to support progression of platelet-
ï¬brin microthrombi to occlusive arterial thrombosis.
Additionally, prevention of occlusive thrombosis was
also obtained in normal pigs after treatment of the
animals with a monoclonal antibody to vWf [73].
In arteries with altered shear stress, such as one caused
by a clamp applied on the vessel, the neointimal prolif-
eration that occurs contains large amounts of vWf. But
vWf presence is not required for the neointimal forma-
tion since it can develop similarly in arteries of vWd
pigs [74]. This high local concentration of vWf could
contribute to plaque thrombogenicity.
Treatment of the hemostatic defect
The hemostatic effect of a transfusion of vWf in vWd
pigs was monitored. When porcine cryoprecipitate was
infused, the vWf:Ag and vWf:RCoF increased rapidly
but fell back to baseline in 12 h [75]. There is a delayed
and sustained rise in FVIII level exceeding the amount
that was infused [76]. A temporary shortening of the
bleeding time was observed only when huge quantities
of cryoprecipitate were infused. This study was in agree-
ment with several observations made in patients with
vWd where it was noted that the shortening of the
bleeding time was much more transient than the persis-
tence of FVIII after the infusion of plasma or cryopre-
cipitate [77, 78]. The porcine model was also used to test
the efï¬cacy of a human recombinant preparation of
vWf [79]. A partial correction of bleeding time was
obtained in only one pig, out of three, infused with the
recombinant vWf. Bleeding time correction seems to be
very hard to obtain, whatever the source of infused
vWf. Indeed, in a vWd pig transplanted with normal
marrow, no change in bleeding time was observed after
infusion of porcine plasma derivative concentrate even
though the level of vWf:Ag was brought to normal in
platelets and in plasma. Perhaps subendothelial vWf is
necessary to achieve correction of the bleeding time [59].
Summary
The porcine model has been studied extensively since its
identiï¬cation as a type 3 vWd model and has proved
very useful. The pig is a good model because it is close
to humans in many aspects. The vWf localization in
endothelial cells and platelets mimics that of humans.
t/data/demos/11212329.utf8 view on Meta::CPAN
Mancuso D. J., Tuley E. A., Westï¬eld L. A., Worral N. K.,
Shelton-Inloes B. B., Sorace J. M. et al. (1989) Structure of
the gene for human von Willebrand factor. J. Biol. Chem.
264: 19514–19527
Ewenstein B. M. (1997) von Willebrand’s disease. Annu.
Rev. Med. 48: 525–542
Ruggeri Z. M. and Zimmerman T. S. (1981) The complex
multimeric composition of factor VIII/von Willebrand fac-
tor. Blood 57: 1140–1143
Jaffe E. A., Hoyer L. W. and Nachman R. L. (1973)
Synthesis of antihemophilic factor antigen by cultured hu-
man endothelial cells. J. Clin. Invest. 52: 2757–2764
Nachman R., Levine R. and Jaffe E. A. (1977) Synthesis of
factor VIII antigen by cultured guinea pig megakaryocytes.
J. Clin. Invest. 60: 914–921
Wagner D. D. (1990) Cell biology of von Willebrand factor.
Annu. Rev. Cell Biol. 6: 217–246
Sporn L. A., Marder V. J. and Wagner D. D. (1986)
Inducible secretion of large, biologically potent von Wille-
brand factor multimers. Cell 46: 185–190
Sakariassen K. S., Bolhuis P. A. and Sixma J. J. (1979)
Human blood platelets adhesion to artery subendothelium is
mediated by factor VIII/von Willebrand factor bound to the
subendothelium. Nature 279: 636–638
Bolhuis P. A., Sakariassen K. S., Sander H. J., Bouma B. N.
and Sixma J. J. (1981) Binding of FVIII-von Willebrand
factor to human arterial subendothelium precedes increased
platelet adherence and enhances platelet spreading. J. Lab.
Clin. Med. 97: 568–576
Meyer D. and Baumgartner H. R. (1983) Role of von
Willebrand factor in platelet adhesion to the subendothe-
lium. Br. J. Haematol. 54: 1–9
Weiss H. J., Turitto V. T. and Baumgartner H. R. (1978)
Effect of shear rate on platelet interaction with subendothe-
lium in citrate and native blood. I. Shear rate-dependent
decrease of adhesion in von Willebrand’s disease and the
Bernard-Soulier syndrome. J. Lab. Clin. Med. 92: 750–764
Baumgartner H. R., Tschopp T. B. and Meyer D. (1980)
Shear rate dependent inhibition of platelet adhesion and
aggregation on collageneous surfaces by antibodies to hu-
man FVIII/von Willebrand factor. Br. J. Haematol. 44:
127–139
Turitto V. T., Weiss H. J. and Baumgartner H. R. (1984)
Platelet interaction with rabbit subendothelium in von Wille-
brand’s disease: altered thrombus formation distinct from
defective platelet adhesion. J. Clin. Invest. 74: 1730–1741
988 C. V. Denis and D. D. Wagner
23 Ikeda Y., Handa M., Kawano K., Kamata T., Murata M., 45
Araki Y. et al. (1991) The role of von Willebrand factor and
ï¬brinogen in platelet aggregation under varying shear stress.
J. Clin. Invest. 87: 1234–1240
24 Weiss H. J., Sussman I. I. and Hoyer L. W. (1977) Stabiliza- 46
tion of factor VIII in plasma by the von Willebrand factor.
J. Clin. Invest. 60: 390–404
25 Brinkhous K. M., Robert L., Read M. S., Nichols T. C., 47
Bellinger D. A. and Griggs T. R. (1991) von Willebrand factor
and animal models: contributions to gene therapy, thrombotic
thrombocytopenic purpura and coronary thrombosis. Mayo
Clin. Proc. 66: 733–742
26 Weiss H. J. (1974) Relation of von Willebrand factor to 48
bleeding time. N. Engl. J. Med. 291: 420
27 Lind S. E. (1984) Prolonged bleeding time. Am. J. Med. 77:
305–312
28 Burns E. R. and Lawrence C. (1989) Bleeding time. A guide 49
to its diagnostic and clinical utility. Arch. Pathol. Lab. Med.
113: 1219–1224
29 Lamme S., Wallmark A., Holmberg L., Nilsson I. M. and
Sjogren H. O. (1985) The use of monoclonal antibodies in
measuring FVIII/von Willebrand factor. Scand. J. Clin. Lab. 50
Invest. 15: 17–26
30 MacFarlane D. E., Stibbe K., Kirby E. P., Zucker M. B.,
Grant R. A. and McPherson J. (1975) A method for assaying
von Willebrand factor (ristocetin cofactor). Thromb. Diath.
Haemorrh. 34: 306–308 51
31 Weiss H. J., Rogers J. and Brand H. (1973) Defective
ristocetin-induced platelet aggregation in von Willebrand’s 52
disease and its correction by factor VIII. J. Clin. Invest. 52:
2697–2707
32 Forbes C. D. and Prentice C. R. M. (1973) Aggregation of
human platelets by puriï¬ed porcine and bovine anti- 53
haemophilic factor. Nature: New Biology 241: 149
33 Altieri D., Capitanio A. M. and Mannucci P. M. (1986) von
Willebrand factor contaminating porcine FVIII concentrate
(Hyate: C) causes platelet aggregation. Br. J. Haematol. 63:
703–711 54
34 Bahnak B. R., Lavergne J.-M., Ferreira V., Kerbiriou-Nabias
D. and Meyer D. (1992) Comparison of the primary structure
of the functional domains of human and porcine von Wille-
brand factor that mediates platelet adhesion. Biochem. Bio- 55
phys. Res. Commun. 182: 561–568
35 Bakhshi M. R., Myers J. C., Howard P. S., Soprano D. R.
and Kirby E. P. (1992) Sequencing of the primary adhesion
domain of bovine von Willebrand factor. Biochem. Biophys. 56
Acta 1132: 325–328
36 Sadler J. E. (1994) A revised classiï¬cation of von Willebrand
disease. Thromb. Haemost. 71: 520–525
37 Thomas J. S. (1996) von Willebrand’s disease in the dog and 57
cat. Vet. Clin. North Am. Small Anim. Pract. 26: 1089–1110
38 Kaufman R. J. (1992) Biological regulation of Factor VIII
activity. Annu. Rev. Med. 43: 325–339
39 Hogan A. G., Muhrer M. E. and Bogart R. (1941) A
hemophilia-like disease in swine. Proc. Soc. Exptl. Biol. Med.
48: 217–219 58
40 Mertz E. T. (1942) The anomaly of a normal Duke’s and a
very prolonged saline bleeding time in swine suffering from an
inherited bleeding disease. Am. J. Physiol. 136: 360–362
41 Muhrer M. E., Lechler E., Cornell C. N. and Kirkland J. L. 59
(1965) Anti-hemophilic factor levels in bleeder swine following
infusions of plasma and serum. Am. J. Phys. 208: 508–510
42 Chan J. Y. S., Owen C. A. Jr, Bowie E. J. W., Didisheim P.,
Thompson J. H. Jr, Muhrer M. E. et al. (1968) von Willebrand
disease ‘stimulating factor’ in porcine plasma. Am. J. Phys. 60
214: 1219–1224
43 Fass D. N., Brockway W. J., Owen C.A. Jr and Bowie E. J. 61
W. (1976) Factor VIII (Willebrand) antigen and ristocetin-
Willebrand factor in pigs with von Willebrand’s disease.
Thromb. Res. 8: 319–327 62
Brinkhous K. M. (1978) Animal models: Importance in
research on hemorrhage and thrombosis. Adv. Exp. Med.
Biol. 102: 123–133
44
von Willebrand disease models
Bowie E. J. W., Owen C.A. Jr, Zollman P. E., Thompson J.
H. Jr and Fass D. N. (1973) Test of hemostasis in swine:
normal values and values in pigs affected with von Wille-
brand’s disease. Am. J. Vet. Res. 34: 1405–1407
Fass D. N., Bowie E. J. W., Owen C.A. Jr and Zollman P.
E. (1979) Inheritance of porcine von Willebrand’s disease:
study of a kindred of over 700 pigs. Blood 53: 712–719
Wu Q. Y., Drouet L., Carrier J. L., Rothschild C., Berard M.,
Rouault C. et al. (1987) Differential distribution of von
Willebrand factor in endothelial cells. Comparison between
normal pigs and pigs with von Willebrand disease. Arterioscle-
rosis 7: 47–54
Bahou W. F., Bowie E. J. W., Fass D. N. and Ginsburg D.
(1988) Molecular genetic analysis of porcine von Willebrand
disease: tight linkage to the von Willebrand factor locus. Blood
72: 308–313
Sjoberg A., Seaman W. T., Bellinger D. A., Griggs T. R.,
Nichols T. C. and Chowdhary B. P. (1996) FISH mapping of
the porcine vWF gene to chromosome 5q21 extends synteny
homology with human chromosome 12. Hereditas 124: 199–
202
Wu Q. Y., Bahnak B. R., Coulombel L., Kerbiriou-Nabias D.,
Drouet L., Pietu G. et al. (1988) Analysis of von Willebrand
factor mRNA from the lungs of pigs with severe von Wille-
brand disease by using a human cDNA probe. Blood 71:
1341–1346
Lewis J. C. and Bowie F. J. W. (1978) Ultrastructural studies
of platelets of von Willebrand and normal swine. 53: 179–183
Cramer E. M., Caen J. P., Drouet L. and Breton-Gorius J.
(1986) Absence of tubular structures and immunolabeling for
von Willebrand factor in the platelets -granules from porcine
von Willebrand disease. Blood 68: 774–778
Sawada Y., Fass D. N., Katzman J. A., Bahn R. C. and Bowie
E. J. W. (1986) Hemostatic plug formation in normal and von
Willebrand pigs: the effect of administration of cryoprecipitate
and a monoclonal antibody to von Willebrand factor. Blood
67: 1229–1239
Reddick R. L., Griggs T. R., Lamb M. A. and Brinkhous K.
M. (1982) Platelet adhesion to damaged coronary arteries:
comparison in normal and von Willebrand disease swine.
Proc. Natl. Acad. Sci. USA 79: 5076–5079
Badimon L., Badimon J. J., Turrito V. T. and Fuster V. (1989)
Role of von Willebrand factor in mediating platelet-vessel wall
interaction at low shear rate; the importance of perfusion
conditions. Blood 73: 961–967
Bowie E. J. W., Solberg L. A. Jr, Fass D. N., Johnson C. M.,
Knutson G. J., Stewart M. L. et al. (1986) Transplantation of
normal bone marrow into a pig with severe von Willebrand’s
disease. J. Clin. Invest. 78: 26–30
Nichols T. C., Samama C. M., Bellinger D. A., Roussi J.,
Reddick R. L., Bonneau M. et al. (1995) Function of von
Willebrand factor after crossed bone marrow transplantation
between normal and von Willebrand disease pigs: effect on
arterial thrombosis in chimeras. Proc. Natl. Acad. Sci. USA
92: 2455–2459
Andre P., Brouland J. P., Roussi J., Bonneau M., Pignaud G.,
Bal dit Sollier C. et al. (1998) Role of plasma and platelet von
Willebrand factor in arterial thrombogenesis and hemostasis
in the pig. Hematology 26: 1–7
Roussi J., Samama M., Vaiman M., Nichols T., Pignaud G.,
Bonneau M. et al. (1996) An experimental model for testing
von Willebrand factor function: successful SLA-matched
crossed bone marrow transplantations between normal and
von Willebrand pigs. Exp. Hematol. 24: 585–591
Duguid J. B. (1946) Thrombosis as a factor in the pathogenesis
of coronary atherosclerosis. J. Pathol. Bacteriol. 58: 207–212
Stemerman M. B. and Ross R. (1972) Experimental arte-
riosclerosis. I. Fibrous plaque formation in primates, and
electron microscope study. J. Exp. Med. 136: 769–789
Ross R., Glomset J., Kariya B. and Harker L. (1974) A
platelet-dependent serum factor that stimulates the prolifera-
tion of arterial smooth muscle cells. Proc. Natl. Acad. Sci.
USA 71: 1207–1210
CMLS, Cell. Mol. Life Sci. Vol. 56, 1999
63 Harker L. A., Ross R., Slichter S. J. and Scott C. R. (1976) 80
Homocystine-induced arteriosclerosis: the role of endothelial
cell injury and platelet response to its genesis. J. Clin. Invest. 81
58: 731–741
64 Fuster V., Badimon L., Badimon J. J., Ip J. H. and Chese-
bro J. H. (1991) The porcine model for the understanding of 82
thrombogenesis and atherogenesis. Mayo Clin. Proc. 66:
818–831
65 Fuster V., Bowie E. J. W., Lewis J. C., Fass D. N. and Owen 83
C. A. Jr (1978) Resistance to atherosclerosis in pigs with von
Willebrand’s disease. Spontaneous and high cholesterol diet-
induced arteriosclerosis. J. Clin. Invest. 61: 722–730
66 Fuster V. and Bowie E. J. W. (1978) The von Willebrand pig 84
as a model for atherosclerosis research. Thromb. Haemost.
39: 322–327
67 Badimon L., Steele P., Badimon J. J., Bowie E. J. W. and
Fuster V. (1985) Aortic atherosclerosis in pigs with het-
erozygous von Willebrand disease. Comparison with ho- 85
mozygous von Willebrand and normal pigs. Arteriosclerosis
5: 366–370
68 Griggs T. R., Bauman R. W., Reddick R. L., Read M. S., 86
Koch G. G. and Lamb M. A. (1986) Development of
coronary atherosclerosis in swine with severe hypercholes-
87
terolemia. Lack of influence of von Willebrand factor or
acute intimal injury. Arteriosclerosis 6: 155–165
88
69 Nichols T. C., Bellinger D. A., Davis K. E., Koch G. G.,
Reddick R. L., Read M. S. et al. (1992) Porcine von
89
Willebrand disease and atherosclerosis. Influence of poly-
morphism in apolipoprotein B100 genotype. Am. J. Pathol.
90
140: 403–415
70 Federici A. B., Mannucci P. M., Fogato E., Ghidoni P. and
Matturri L. (1993) Autopsy ï¬ndings in three patients with
von Willebrand disease type IIB and type III: presence of
atherosclerotic lesions without occlusive arterial thrombi.
91
Thromb. Haemost. 70: 758–761
71 Reddick R. L., Read M. S., Brinkhous K. M., Bellinger D.,
Nichols T. and Griggs T. R. (1990) Coronary atherosclerosis
in the pig. Induced plaque injury and platelet response.
Arteriosclerosis 10: 541–550
92
72 Nichols T. C., Bellinger D. A., Tate D. A., Reddick R. L.,
Read M. S., Koch G. G. et al. (1990) von Willebrand factor
and occlusive arterial thrombosis. A study in normal and
93
von Willebrand’s disease pigs with diet-induced hypercholes-
terolemia and atherosclerosis. Arteriosclerosis 10: 449–461
73 Nichols T. C., Bellinger D. A., Reddick R. L., Read M. S.,
Koch G. G. and Brinkhous K. M. et al. (1991) Role of von
Willebrand factor in arterial thrombosis. Studies in normal
94
and von Willebrand disease pigs. Circulation 83 (Suppl. IV):
IV 56-IV 64
74 Nichols T. C., Bellinger D. A., Reddick R. L., Koch G. G., 95
Sigman J. L., Erickson G. et al. (1998) von Willebrand
factor does not influence atherogenesis in arteries subjected
to altered shear stress. Arterioscler. Thromb. Vasc. Biol. 18:
323–330 96
75 Bowie E. J. W., Fass D. N. and Owen C.A. Jr (1980)
Hemostatic effect of transfused Willebrand factor in porcine
von Willebrand’s disease. Similarities with human disease.
Haemostasis 9: 352–365 97
76 Griggs T. R., Webster W. P., Cooper H. A., Wagner R. H.
and Brinkhous K. M. (1974) von Willebrand factor: gene 98
dosage relationship and transfusion response in bleeder
swine. A new bioassay. Proc. Natl. Acad. Sci. USA 71:
2087–2090
77 Cornu P., Larrieu M. J., Caen J. and Bernard J. (1963) 99
Transfusion studies in von Willebrand’s disease: effect on
bleeding time and FVIII. Br. J. Haemat. 9: 189–202
78 Perkins H. A. (1967) Correction of the hemostatic defects in 100
von Willebrand’s disease. Blood 30: 375–380
79 Roussi J., Turecek P. L., Andre´ P., Bonneau M., Pignaud
G., Bal dit Sollier C. et al. (1998) Effects of human recombi- 101
nant, plasma-derived and porcine von Willebrand factor in
pigs with severe von Willebrand disease. Blood Coag. Fibri-
nol. 9: 361–372
Review Article 989
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