PROGRESS IN HEMATOLOGY
Recent advance in thrombotic thrombocytopenic purpura
The function of ADAMTS13 in thrombogenesis in vivo:
insights from mutant mice
Fumiaki Banno•Anil K. Chauhan•
Received: 31 August 2009/Accepted: 16 December 2009/Published online: 5 January 2010
? The Japanese Society of Hematology 2010
lished ADAMTS13-deficient mice using gene-targeting
techniques. In humans, genetic or acquired deficiency in
ADAMTS13 leads to a potentially fatal syndrome, throm-
botic thrombocytopenic purpura (TTP). Surprisingly,
ADAMTS13-deficient mice are viable with no apparent
signs of TTP. However, these mouse models indicate that
ADAMTS13 down-regulates platelet adhesion and aggre-
gation in vivo, and ADAMTS13 deficiency can provide
enhanced thrombus formation at the site of vascular lesions.
von Willebrand factor multimers not only down-regulates
thrombosis but also inflammation. ADAMTS13-congenic
mice that carry a truncated form of ADAMTS13 lacking the
C-terminal domains have also been developed. Phenotypes
of the congenic mice indicate the physiological significance
of the C-terminal domains of ADAMTS13 in down-regu-
lating thrombus growth. The studies mentioned here in dif-
ferent mouse models uncover the in vivo function of
ADAMTS13 and strengthened the understanding of the
mechanism of systemic disease TTP.
Recently, two independent groups have estab-
ADAMTS13-deficient mice ? ADAMTS13-congenic mice ?
Thrombosis ? Inflammation
ADAMTS13 ? von Willebrand factor ?
ADAMTS13 is a plasma protease that cleaves von Wille-
brand factor (VWF) . VWF is a large protein that cir-
culates in blood as homomultimers of varied sizes. One of
main functions of VWF is to mediate adhesion between
platelets and between platelets and vascular subendothe-
lium. Both types of adhesion are essential to maintain the
balance between hemorrhage and thrombosis. The adhesive
activity of VWF depends on its molecular sizes and, in
exceeding 20,000 kDa can form high strength bonds with
platelet GPIba and induce excessive platelet aggregation
under shear stress. UL-VWF multimers are normally
cleaved by ADAMTS13 to smaller forms, thus restraining
spontaneous platelet thrombus formation. The lack of
ADAMTS13 activity allows UL-VWF multimers to persist
in the circulation and leads to the development of throm-
botic thrombocytopenic purpura (TTP) .
TTP is a serious systemic disease caused by excessive
aggregation of platelets and VWF in small vessels of many
and cause consumptive thrombocytopenia, fragmentation of
red blood cells with anemia, renal and cerebral failure, and
fever. Without treatment, the mortality rate of affected
rate to approximately 20%. The discovery of ADAMTS13 as
VWF-cleaving protease increases our understanding of TTP
pathophysiology. Congenital TTP (Upshaw-Schulman syn-
drome) is associated with the ADAMTS13 gene mutations.
F. Banno ? T. Miyata (&)
National Cardiovascular Center Research Institute,
5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
A. K. Chauhan
Department of Internal Medicine,
University of Iowa Carver College of Medicine,
500 Newton Road, Iowa, IA 52242, USA
Int J Hematol (2010) 91:30–35
Some forms of acquired TTP (e.g., idiopathic TTP, ticlopi-
dine-induced TTP) are associated with the production of
autoantibodies against ADAMTS13.
Recently, murine models of ADAMTS13 deficiency
have been developed by gene-targeting technique by two
independent groups [2, 3]. Models resulting from a natu-
rally occurring mutation have also been established .
These animal models have proven useful to elucidate
ADAMTS13 functions in vivo and the pathophysiology of
TTP. This review summarizes phenotypic characteristics of
Adamts13-mutant mice, focusing on roles of ADAMTS13
in thrombosis, endotoxemia and inflammation.
2 The gene structure of mouse Adamts13
In mice, two kinds of Adamts13 gene are present in a strain-
specific manner (Fig. 1) . The Adamts13 gene of the 129/
Sv, FVB/NJ, and CAST/EiJ strains contains 29 exons like
the human ADAMTS13 gene and encodes ADAMTS13
protein with the same domain constitutions as human
ADAMTS13, designated as ADAMTS13-L. On the other
C57BL/6, and DBA/2 strains, harbor the insertion of an
of the Adamts13 gene. The inserted IAP is one of the
endogenous transposable elements present at approximately
2,000 sites in the mouse genome. Like retroviruses, the IAP
contains two long terminal repeats with signals for the ini-
tiation and regulation of transcription and for the polyade-
nylation of transcripts. The IAP insertion into the Adamts13
in-frame stop codon and a polyadenylation signal derived
from the long terminal repeat. As a result, ADAMTS13
proteinthatlacksthe C-terminaltwothrombospondintype 1
motif (Tsp1) domains and two CUB domains, designated as
ADAMTS13-S, is predominantly expressed in these strains.
Both forms of mouse ADAMTS13 are mainly expressed
in the liver and retain a furin-recognition sequence in the
propeptide domain,a Zn2?-coordinating
sequence, the Met residue in a proposed Met-turn, and
structural Ca2?coordination residues in the metalloprotease
show VWF-cleaving activity in vitro but the truncated form
exhibits lower activity than the full-length form for purified
human VWF multimers .
3 Generation of ADAMTS13-deficient mice
Mice deficient in ADAMTS13 have been developed by con-
ventional gene-targeting approaches. Banno et al. generated
Adamts13-/-mice on a 129/Sv genetic background .
Disruption of the gene by replacing exons 3–6, encoding the
metalloprotease domain, with a neomycin resistance cassette
results in the absence of ADAMTS13 mRNA in liver. AD-
AMTS13 activity is not detected in plasma of Adamts13-/-
mice. Analysis of plasma VWF multimer patterns detects
UL-VWF multimers in Adamts13-/-mice but not in Adam-
ts13?/?or Adamts13?/-mice, suggesting that the deficiency
of ADAMTS13 alone can support the generation of plasma
with no apparent signs of TTP. Blood platelet counts, plasma
haptoglobin levels and peripheral blood smears are normal in
Adamts13-/-mice, suggesting a lack of thrombocytopenia
and hemolytic anemia. Although pregnancy is a triggering
event for TTP, Adamts13-/-females survive pregnancy and
produce viable offspring of normal-sized litters. Renal his-
deposition or excessive VWF accumulation in microvessels.
Motto et al.  have generated Adamts13-/-mice with
elimination of exons 1–6. On a mixed C57BL/6J and
129X1/SvJ genetic background, they are viable without
any TTP-like phenotypes, similar to Adamts13-/-mice on
a 129/Sv genetic background. Thus, both studies clearly
indicate that ADAMTS13 deficiency alone is not sufficient
to cause TTP-like symptoms in mice. Factors in addition to
ADAMTS13 deficiency may be necessary for the devel-
opment of TTP in mice.
4 The function of ADAMTS13 in thrombosis
4.1 Increased thrombogenesis in ADAMTS13-deficient
While Adamts13-/-micedo notspontaneously developTTP,
they are in prothrombotic state. Banno et al. revealed that
Fig. 1 Gene and protein structure of two kinds of mouse ADAM-
TS13. In some strains of mice (e.g., C57BL/6), an IAP-retrotranspo-
son (IAP) is inserted into intron 23 of the Adamts13 gene (arrow) and
creates a pseudo-exon 24 including a premature stop codon.
ADAMTS13-S with truncated C-terminal domains is mainly
expressed in these strains. S Signal peptide, P propeptide, MP
metalloprotease domain, Dis disintegrin-like domain, T (numbered
1-8) thrombospondin type 1 motif domain, Cys cysteine-rich domain,
Sp spacer domain, CUB complement components C1r/C1 s, urchin
epidermal growth factor, and bone morphogenic protein-1 domain
The function of ADAMTS13 in thrombogenesis in vivo31
accelerated thrombogenic responses in Adamts13-/-mice
under in vitro flow conditions (Fig. 2). When whole blood is
chamber at wall shear rates of 750–5,000 s-1, cumulative
platelet thrombus volume is significantly higher in Adam-
ts13-/-mice compared to Adamts13?/?mice [2, 4]. In vivo
consequence of a lack of ADAMTS13 was further evaluated
using collagen plus epinephrine infusion model experiments.
In this model, widespreadintravascular thrombosis is induced
epinephrine, and the incorporation of platelets into thrombi is
monitored by the reduction in circulating platelet counts.
of platelet counts is more severe in Adamts13-/-mice than
in Adamts13?/?mice, suggesting that a complete lack of
ADAMTS13 in mice results in a prothrombotic state.
elegantly shown prothrombotic phenotypes of Adamts13-/-
mice in vivo. Upon activation of endothelial cells with
secretagogues such as histamine and calcium ionophore
A23187, UL-VWF multimers stored in Weibel-Palade
bodies are released into circulation. It was demonstrated in
multimers resulting in formation of long platelet strings and
ADAMTS13 can cleave anchored platelet strings on the
surface of endothelium . Following stimulation with his-
tamine or A23187, long-lived platelet strings ranging from
strings remain anchored at one end and waved with another
end in the blood stream . In addition, following superfu-
Adamts13-/-mice compared to Adamts13?/?mice. Adhe-
sion isabsentinstimulatedveinsofVwf-/-mice confirming
results are the direct evidence that ADAMTS13 regulates
VWF-mediated platelet adhesion in vivo.
Adamts13?/?mice treated identically, small platelet aggre-
gates can be seen attached to the endothelium for 1–2 s, but
treatment, platelet binding to subendothelium is increased
and thrombus formation is significantly accelerated in
Adamts13-/-mice compared to Adamts13?/?mice . In
another set of FeCl3-induced vessel injury in Vwf-/-mice,
most of the vessels do not occlude in either mice expressing
ADAMTS13 or lacking ADAMTS13, demonstrating that
ADAMTS13 deficiency is not sufficient to overcome the
ADAMTS13 down-regulates platelet adhesion and aggre-
gation in vivo, and ADAMTS13 deficiency can provide
enhanced thrombus formation at the site of vascular lesions.
These findings also suggest that VWF, the only relevant
substrate for ADAMTS13, is critical in this model of
thrombus growth under arterial shear conditions.
4.2 TTP-like phenotypes induced by shigatoxin
challenge in ADAMTS13-deficient mice
on the specific genetic background
CASA/Rk strain is a wild-derived mouse strain of Mus
musculus castaneus that exhibits plasma VWF levels 5- to
Fig. 2 Platelet thrombus formation in ADAMTS13-mutant mice on
collagen surface under flow. a Thrombus formation at 1,000 s-1.
Whole blood samples from Adamts13L/L(Adamts13?/?), Adamts13S/S,
or Adamts13-/-mice containing mepacrine-labeled platelets are
perfused over anacid-insoluble type I collagen-coated surface at a wall
shear rate of 1,000 s-1. The cumulative thrombus volume, analyzed
using a multi-dimensional imaging system, is measured every 0.5 min
until 4 min. Data are the mean ± SEM of 25 mice for each genotype.
b Thrombus formation at 5,000 s-1. Whole blood samples from
indicated mice are perfused over an acid-insoluble type I collagen-
coated surface at a wall shear rate of 5,000 s-1. The cumulative
thrombus volume is measured every 20 s until 80 s. Blood from two
mice is pooled and used for experiments. Data are the mean ± SEM of
15 samples for each genotype. Asterisks indicate significant differ-
ences at P\0.05 in comparison to Adamts13L/Lmice
32F. Banno et al.
10-fold higher than C57BL/6J strain. The major genetic
factor that accounts for this difference is associated with a
gene modifier Mvwf2, corresponding to the R2657Q muta-
tion in Vwf gene resulting in increased biosynthesis/secre-
tion of VWF . Additional modifier loci correlating with
increased VWF levels are identified in CASA/Rk strain as
Mvwf3 on chromosome 4 and Mvwf4 on chromosome 13
. The genetic background of CASA/Rk strain has been
introduced onto the C57BL/6J and 129/SvJ mixed-back-
ground Adamts13-/-mice by backcrossing with wild-type
CASA mice for two generations. These mice are born in
expected Mendelian distribution, however, mean platelet
counts of the Adamts13-/-mice are significantly reduced
compared to Adamts13?/?littermates.
When challenged with shigatoxin produced by Shigella
dysenteriae and the Shigatoxigenic group of Escherichia
coli, a subset of this Adamts13-/-mice show clinical signs
of TTP including thrombocytopenia, hemolytic anemia
with fragmented red blood cells, and VWF-rich thrombi in
multiple organs including brain, heart and kidneys .
Shigatoxin is toxic to endothelial cells and known to induce
hemolytic uremic syndrome (HUS) that exhibits similar
clinical and pathologic findings to TTP. Shigatoxin also
stimulates the release of UL-VWF multimers from human
umbilical vein endothelial cells and perfused quiescent
platelets immediately adhere to UL-VWF multimers,
resulting in formation of platelet strings . Thus, envi-
ronmental factors causing endothelial activation or damage
can trigger TTP in Adamts13-/-mice. Because shigatoxin
challenge does not evoke TTP-like symptoms in Adam-
ts13-/-mice on the mixed background , introduction of
the CASA/Rk genetic background provides susceptibility
to TTP in Adamts13-/-mice. Of note, there is no corre-
lation between plasma VWF level and degree of shiga-
toxin-induced thrombocytopenia or mortality, suggesting
that TTP-modifier genes that are not associated with
plasma VWF levels may be delivered from a CASA/Rk
genetic background .
In human, there is a large variation in the phenotypes of
TTP patients with ADAMTS13 deficiency . Many TTP
patients with congenital ADAMTS13 deficiency have their
first acute episode in the neonatal period or early infancy,
but late-onset cases and asymptomatic carriers in adulthood
have been reported. Patients with identical ADAMTS13
mutations but different clinical courses have been descri-
bed, indicating that ADAMTS13 deficiency brings a seri-
ous risk but is not a sufficient condition for TTP. Data from
Adamts13-/-mice support this view, and Adamts13-/-
mice can contribute to the identification of additional
genetic and/or environmental TTP triggers.
The only known substrate for ADAMTS13 is VWF. To
investigate the absolute requirement of VWF in shigatoxin-
induced thrombocytopenia, VWF-null allele is crossed
onto the CASA/Adamts13-/-background . Challenge of
VWF expressing (Vwf?/?or Vwf?/-) CASA/Adamts13-/-
mice with shigatoxin results in thrombocytopenia and
mortality. In contrast, littermate CASA/Adamts13-/-mice
deficient for VWF (Vwf-/-) do not result in thrombocy-
topenia. These results clearly demonstrate that a threshold
of VWF is required for shigatoxin-induced thrombocyto-
penia and provide experimental evidence for the crucial
role of VWF in TTP pathogenesis.
5 Thrombogenic phenotypes in congenic mice
having C-terminal truncated ADAMTS13-S
The specific functions of each of the ADAMTS13 domains
in the VWF-cleavage have been studied using different
types of in vitro assays. These studies have shown an
essential role of the N-terminal domains from the metal-
loprotease to the spacer domains in substrate recognition
and proteolysis . However, physiological significance of
the remaining C-terminal Tsp1 and CUB domains was not
clearly defined in vivo. Taking advantage of the presence
of the spontaneous IAP-insertional mutation in the Adam-
ts13 gene of some laboratory mouse strains, a congenic
mouse strain (Adamts13S/S) that has ADAMTS13-S on
129/Sv genetic background has recently been established
. In this model, C57BL/6-Adamts13 gene with IAP
mutation has been applied to 129/Sv mice by ten-genera-
Similar to wild-type 129/Sv mice (Adamts13L/L),
mice do not have UL-VWF multimers
in plasma, in contrast to 129/Sv-genetic background
ADAMTS13-deficient mice (Adamts13-/-) . Hence, the
C-terminal domains of ADAMTS13 are not necessary for
removal of UL-VWF multimers in plasma under physio-
logical conditions. However, parallel plate flow chamber
experiments show that blood from Adamts13S/Smice is
more thrombogenic under flow at a high shear rate of
5,000 s-1in compared to blood from Adamts13L/Lmice
(Fig. 2) . In addition, both in vivo thrombus formation in
FeCl3-injured arterioles and thrombocytopenia induced by
collagen plus epinephrine challenge are accelerated in
Adamts13S/Smice compared to Adamts13L/Lmice .
These results provide in vivo insights on physiological
significance of the C-terminal domains of ADAMTS13 in
down-regulating thrombus growth.
6 The function of ADAMTS13 in sepsis
Some of the recent studies have found reduced ADAM-
TS13 activity in patients with acute systemic inflammation
The function of ADAMTS13 in thrombogenesis in vivo33
or sepsis, suggesting a role for VWF-ADAMTS13 axis in
sepsis . To investigate the functions of VWF and
ADAMTS13 in sepsis and endotoxemia, two different
groups have done independent studies using two different
models; one by LPS-induced sepsis  and the other by
cecum ligature and puncture (CLP) in mice . When
Vwf?/?or Vwf-/-mice are challenged with LPS, there is
no significant difference in LPS-induced thrombocytopenia
or mortality up to 4 days of observation period . In
contrast, in CLP-induced sepsis model there is a decrease
in mortality of VWF-deficient mice compared to wild-type
mice, suggesting important role for VWF secretion in
sepsis-induced mortality . The different finding in two
independent studies illustrates the importance of different
models used for sepsis.
There is also no significant difference in LPS-induced
mortality in VWF expressing mice that are either lacking or
expressing ADAMTS13. Additionally, mice deficient for
VWF and ADAMTS13 also exhibited similar thrombocy-
topenia and mortality. These observations in mice suggest
that neither absolute VWF deficiency nor ADAMTS13 has
effect on LPS-induced sepsis . These findings are in
agreement with the report that complete deficiency of
ADAMTS13 in mice is not associated with excess mor-
tality in CLP-induced sepsis . However, they have
found a decrease in ADAMTS13 activity in wild-type mice
after CLP-induced sepsis, similar to that reported previ-
ously in human sepsis . However, deficiency of
ADAMTS13 in mouse does not modulate CLP-induced
sepsis is most probably due to consumption of ADAMTS13
to VWF released in large amounts.
7 The function of ADAMTS13 in inflammation
Recently, Chauhan and colleagues  have investigated
the role of ADAMTS13 and its substrate VWF in
inflammation by studying leukocyte rolling and adhesion
in Adamts13?/?/Vwf?/?, Adamts13-/-/Vwf?/?, Adamts-
intravital microscopy. They have shown that ADAMTS13-
deficiency in mice results in higher numbers of leukocytes
rolling on the unstimulated endothelium compared to wild-
type. The increase in the leukocyte rolling observed in
Adamts13-/-mice is VWF-dependent.
There is also an increase in endothelial P-selectin
expression, soluble P-selectin and VWF in plasma of
Adamts13-/-mice. These observations raise the question
how ADAMTS13 deficiency results in increased plasma
VWF. One of the reasons could be that ADAMTS13
deficiency results in slower clearance of UL-VWF multi-
mers from the circulation and thus elevated VWF levels.
which in turn may activate the endothelium. Previously, it
has been shown that activated platelets, by binding to
leukocytes, promote Weibel-Palade bodies release and
stimulate leukocyte rolling . Interestingly, depletion of
platelets in Adamts13-/-mice results in normalization of
leukocyte rolling as compared to wild-type mice. This
indicates that platelets, likely activated by UL-VWF either
in circulation or directly on endothelium, stimulate Weibel-
Palade body’s secretion. Moreover, when Adamts13-/-
mice veins are stimulated with histamine, a secretagogue of
Weibel-Palade bodies, in order to release UL-VWF mul-
timers, leukocyte rolling velocity is slower when compared
to wild-type mice veins where platelet strings do not form
. These in vivo findings are in agreement with previous
in vitro studies where it was shown that platelets bound to
endothelial UL-VWF could support leukocyte tethering
UL-VWF multimersactivate platelets,
Fig. 3 Increased leukocyte adhesion in the TNF a-stimulated mes-
enteric venules of ADAMTS13-deficient mice. Mice are treated with
the inflammatory cytokine TNF-a for 3.5 h before intravital micros-
copy. A single mesenteric venule (25–30 lm diameter) is studied per
mouse. a Representative images are shown. Arrows indicate leuko-
cytes adhering to inflamed endothelium. b Quantification of the
adherent leukocytes. The number of adherent leukocytes is markedly
increased in the microvenules of Adamts13-/-mice compared to
Adamts13?/?mice. In contrast, the number of leukocytes adhering in
venules of Adamts13-/-/Vwf-/-mice is similar to Adamts13?/?/
Vwf-/-mice, suggesting that VWF plays a role in increased leukocyte
adhesion in Adamts13-/-vessels. Data represent the mean ± SEM.
34 F. Banno et al.
and rolling and that VWF acts as a ligand for leukocyte
receptors PSGL-1 and b2 integrin .
Inflammatory cytokines TNF-a and IL-8 have been
shown to release UL-VWF from human umbilical vein
endothelial cells in vitro . When Adamts13-/-mice are
challenged with TNF-a, the number of adherent leukocytes
increases approximately twofold in activated venules of
Adamts13-/-mice when compared to wild-type mice .
This process is dependent on VWF (Fig. 3). In addition,
ADAMTS13 deficiency in mouse results in increased
extravasation of neutrophils in both thioglycollate-induced
peritonitis and wound healing . These in vitro and in
vivo studies suggest that UL-VWF multimers released
from Weibel-Palade bodies by many stimuli including
hypoxia, changes in shear stress, and inflammatory cyto-
kines could accelerate inflammatory responses in diseases
such as atherosclerosis and stroke when not digested by
The results from the Adamts13-/-mice suggest that, by
cleaving hyperactive UL-VWF multimers, ADAMTS13
not only down-regulates thrombosis but also inflammation.
The studies reported here may provide new insights on the
possible uses of ADAMTS13 as a therapeutic agent.
1. Banno F, Miyata T. Biology of an antithrombotic factor-
ADAMTS13. In: Tanaka K, Davie EW, editors. Recent advances
in thrombosis and hemostasis 2008. Springer; 2008. p. 162–76.
2. Banno F, Kokame K, Okuda T, Honda S, Miyata S, Kato H, et al.
Complete deficiency in ADAMTS13 is prothrombotic, but it
alone is not sufficient to cause thrombotic thrombocytopenic
purpura. Blood. 2006;107:3161–6.
3. Motto DG, Chauhan AK, Zhu G, Homeister J, Lamb CB, Desch
KC, et al. Shigatoxin triggers thrombotic thrombocytopenic
purpura in genetically susceptible ADAMTS13-deficient mice.
J Clin Invest. 2005;115:2752–61.
4. Banno F, Chauhan AK, Kokame K, Yang J, Miyata S, Wagner
DD, et al. The distal carboxyl-terminal domains of ADAMTS13
are required for regulation of in vivo thrombus formation. Blood.
5. Banno F, Kaminaka K, Soejima K, Kokame K, Miyata T. Iden-
tification of strain-specific variants of mouse Adamts13 gene
encoding von Willebrand factor-cleaving protease. J Biol Chem.
6. Zhou W, Bouhassira EE, Tsai HM. An IAP retrotransposon in the
mouse ADAMTS13 gene creates ADAMTS13 variant proteins
that are less effective in cleaving von Willebrand factor multi-
mers. Blood. 2007;110:886–93.
7. Dong JF, Moake JL, Nolasco L, Bernardo A, Arceneaux W,
Shrimpton CN, et al. ADAMTS-13 rapidly cleaves newly
secreted ultralarge von Willebrand factor multimers on the
endothelial surface under flowing conditions. Blood. 2002;
8. Chauhan AK, Motto DG, Lamb CB, Bergmeier W, Dockal M,
Plaimauer B, et al. Systemic antithrombotic effects of ADAM-
TS13. J Exp Med. 2006;203:767–76.
9. Chauhan AK, Walsh MT, Zhu G, Ginsburg D, Wagner DD,
Motto DG. The combined roles of ADAMTS13 and VWF in
murine models of TTP, endotoxemia, and thrombosis. Blood.
10. Westrick RJ, Ginsburg D. Modifier genes for disorders of
thrombosis and hemostasis. J Thromb Haemost. 2009;7(Suppl
11. Nolasco LH, Turner NA, Bernardo A, Tao Z, Cleary TG, Dong
JF, et al. Hemolytic uremic syndrome-associated Shiga toxins
promote endothelial-cell secretion and impair ADAMTS13
cleavage of unusually large von Willebrand factor multimers.
12. La ¨mmle B, Kremer Hovinga JA, Alberio L. Thrombotic throm-
bocytopenic purpura. J Thromb Haemost. 2005;3:1663–75.
13. Martin K, Borgel D, Lerolle N, Feys HB, Trinquart L,
Vanhoorelbeke K, et al. Decreased ADAMTS-13 (A disintegrin-
like and metalloprotease with thrombospondin type 1 repeats) is
associated with a poor prognosis in sepsis-induced organ failure.
Crit Care Med. 2007;35:2375–82.
14. Lerolle N, Dunois-Larde C, Badirou I, Motto DG, Hill G,
Bruneval P, et al. von Willebrand factor is a major determinant of
ADAMTS-13 decrease during mouse sepsis induced by cecum
ligation and puncture. J Thromb Haemost. 2009;7:843–50.
15. Chauhan AK, Kisucka J, Brill A, Walsh MT, Scheiflinger F,
Wagner DD. ADAMTS13: a new link between thrombosis and
inflammation. J Exp Med. 2008;205:2065–74.
16. Dole VS, Bergmeier W, Mitchell HA, Eichenberger SC, Wagner
DD. Activated platelets induce Weibel-Palade-body secretion and
leukocyte rolling in vivo: role of P-selectin. Blood. 2005;
17. Pendu R, Terraube V, Christophe OD, Gahmberg CG, de Groot
PG, Lenting PJ, et al. P-selectin glycoprotein ligand 1 and beta2-
integrins cooperate in the adhesion of leukocytes to von Wille-
brand factor. Blood. 2006;108:3746–52.
18. Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of
inflammatory cytokines on the release and cleavage of the
endothelial cell-derived ultralarge von Willebrand factor multi-
mers under flow. Blood. 2004;104:100–6.
The function of ADAMTS13 in thrombogenesis in vivo35